Florey Projects

The
Florey offers placements for

Honours, Masters and PhD students in
2015. This booklet contains the
available projects along with contact
details of the supervisors involved.
Florey
Students
2015
Available projects
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Contents
Behavioural Neurosciences - Investigation of paternal influence on offspring mental health ................................................................ 7
Behavioural Neurosciences - Gene-environment interactions in the regulation of cellular plasticity, cognitive function and
behaviour ........................................................................................................................................................................................................................................ 8
Behavioural Neurosciences - Utilising Touchscreen technology for preclinical modeling of attention in autism spectrum
disorder ........................................................................................................................................................................................................................................... 9
Behavioural Neurosciences - Investigating social communication in the Neuroligin 3 mouse model of Autism ........................... 10
Behavioural Neurosciences - Diet induced obesity: is it an addiction? ............................................................................................................. 12
Behavioural Neurosciences - mGlu5 receptors & extinction of reward-seeking ........................................................................................... 13
Behavioural Neurosciences - Salt, opiates and addiction ....................................................................................................................................... 14
Behavioural Neurosciences - Network disruptions following brain infarction: cognition, behaviour and regional brain
volume change ............................................................................................................................................................................................................................ 15
Behavioural Neurosciences - Motor speech disorders in degenerative brain disease ................................................................................ 16
Behavioural Neurosciences - Adolescent vulnerability to anxiety: a dopamine story ................................................................................ 17
Behavioural Neurosciences - Neural circuitry underlying extinction of fear across development ....................................................... 18
Behavioural Neurosciences - The effects of adolescent toluene exposure on metabolic function ......................................................... 19
Behavioural Neurosciences - The effects of adolescent toluene exposure on metabolic function ......................................................... 20
Behavioural Neurosciences - Gene-environment interactions in the regulation of cellular plasticity, cognitive function and
behaviour ...................................................................................................................................................................................................................................... 21
Behavioural Neurosciences - Utilising Touchscreen technology for preclinical modeling of attention in autism spectrum
disorder ......................................................................................................................................................................................................................................... 23
Behavioural Neurosciences - Investigation of paternal influence on offspring mental health .............................................................. 24
Behavioural Neurosciences - Understanding the role of synaptic genes in cognition and disease ....................................................... 25
Brain Development & Regeneration - How is the major tumour suppressor protein PTEN trafficked in the cell? ....................... 26
Brain Development & Regeneration - Protein trafficking in neurodegenerative diseases. ...................................................................... 27
Brain Development & Regeneration - Control of protein transport in exosomes by Ndfip1 .................................................................... 28
Brain Development & Regeneration - How can Ndfip1 reduce brain damage following stroke? ......................................................... 29
Brain Development & Regeneration - How does the brain protect itself during injury? ........................................................................... 30
Brain Development & Regeneration - Investigating interneuron migration and placement into cortical circuits ...................... 31
Epilepsy - Drug Impacts on Behaviour and Epigenetics .......................................................................................................................................... 32
Epilepsy - Developing better Bionics for Brain stimulation and recording ..................................................................................................... 33
Epilepsy - Functional neuroimaging analysis to identify brain abnormality in epilepsy .......................................................................... 34
Epilepsy - Multi-site patch clamp recording of cortical micro networks ......................................................................................................... 35
Epilepsy - Projects in network analysis of genetic epilepsy .................................................................................................................................... 36
Epilepsy - Will HCN channel antagonists be good antiepileptic drugs? ............................................................................................................ 37
Epilepsy - 9. Zinc and seizures ............................................................................................................................................................................................. 38
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Epilepsy - Neuroanatomical determinants of susceptibility in a model of genetic epilepsy .................................................................... 39

Epilepsy - High content automated analysis of ion channels in epilepsy.......................................................................................................... 40
Epilepsy - MRI tractography in mouse models of genetic epilepsy: Creation of prognostic and diagnostic structural
biomarkers ................................................................................................................................................................................................................................... 41
Epilepsy - CLARITY based glass brain imaging in health and disease ........................................................................................................... 42
Epilepsy - Optogenetic modulation of the area tempestas an epilepsy hot spot ....................................................................................... 43
Epilepsy - In vivo electrophysiological analysis in mouse models of genetic epilepsy ................................................................................ 44
Epilepsy - High density multi-electrode array recording of in vitro networks in epilepsy ....................................................................... 45
Epilepsy - How does the brain remove the excess number of neurons during development and aging ............................................. 46
Epilepsy - Identification of serum glycoproteins inhibiting innate immunity ................................................................................................ 47
Epilepsy - Identify the transcriptional regulatory factors of the P2X7 receptor ........................................................................................... 48
Epilepsy - The role of P2X7 in a mouse model of oligodendrocyte apoptosis ................................................................................................. 49
Epilepsy - Search the P2X7 related biomarkers for Alzheimers disease .......................................................................................................... 50
Epilepsy - The nature of the P2X4 receptor ................................................................................................................................................................... 51
Imaging - Super-resolution MRI methods for the Human Brain Connectome ............................................................................................... 52
Imaging - Perfusion MRI: novel methods to image cerebral blood flow and brain function ................................................................... 53
Mental Health - The influence of alpha-synuclein on olfaction ............................................................................................................................ 54
Mental Health - Nitric oxide synthesis and function in C. elegans ....................................................................................................................... 55
Mental Health - Modeling Parkinsons disease in C. elegans .................................................................................................................................. 56
Mental Health - New Animal models of Alzheimers Disease ................................................................................................................................. 57
Mental Health - Iron and Biological Ageing .................................................................................................................................................................. 58
Mental Health - The mechanism of de novo prion formation ................................................................................................................................ 59
Mental Health - Compound development for A related toxicity in Alzheimer's disease .......................................................................... 60
Mental Health - Biomarker discovery for Neurodegenerative disease .............................................................................................................. 61
Mental Health - Understanding the natural biology of A peptides in human brain ................................................................................. 62
Mental Health - Understanding the role of the zinc transporter ZIP12 in schizophrenia ........................................................................ 63
Mental Health - Investigating the involvement of the serotonin 2A receptor in the incidence suicide. .............................................. 64
Mental Health - Investigating the effect of antipsychotic drugs on the levels of TNF receptor in the brain .................................... 65
Mental Health - Determining whether muscarinic cholinergic receptors contribute to the pathophysiology of Parkinsons
disease. ........................................................................................................................................................................................................................................... 66
Mental Health - Effect of Abeta on excitotoxic signalling pathways .................................................................................................................. 67
Mental Health - The role of peroxinitrite in depression ........................................................................................................................................... 68
Mental Health - The role of tau protein in olfactory processes ............................................................................................................................. 69
Mental Health - Effect of tau phosphorylation on exosome release in cell culture systems ..................................................................... 70
Mental Health - Overcoming the sprouting limit of axons in the brain - using biomaterials for the treatment of Parkinson's
disease ............................................................................................................................................................................................................................................ 71
Mental Health - Does early life exposure to iron represent a risk for Parkinsons disease? ..................................................................... 72
Mental Health - Characterising a mouse model of Acrodermatitis enteropathica ...................................................................................... 73
Mental Health - Understanding the role of metals in neurodegenerative disease ....................................................................................... 74
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Mental Health - Examining local transcriptional profiling of RNA populations in pre- and post-synaptic terminals................. 75
Multiple Sclerosis - Examining the role of neuronal activity in modulating CNS remyelination ........................................................... 76
Multiple Sclerosis - Role of innate immunity in driving axonal pathology after oligodendrocyte death ........................................... 77
Multiple Sclerosis - Role of alternate energy sources in overcoming oligodendrocyte dysfunction ..................................................... 78
Multiple Sclerosis - Characterising oligodendrocyte and myelin organisation in the brain after social and/or sensory
deprivation ................................................................................................................................................................................................................................... 79
Multiple Sclerosis - Neural stem cell responses to close versus distant oligodendrocyte loss ................................................................. 80
Neurodegeneration Understanding autism ............................................................................................................................................................... 81
Neurodegeneration - Mechanisms of dopamine phenotype plasticity in adult midbrain neurons ....................................................... 82
Neurodegeneration - Bioengineered 3D astrocytes to reveal healthy biology and neurotherapeutic targets ............................... 83
Neurodegeneration - The role of Co in brain health and disease ........................................................................................................................ 84
Neurodegeneration - Astrocyte Regulators of Synaptic Plasticity in the Adult Central Nervous System .......................................... 85
Neuropeptides - Neuromodulatory control of complex behaviour - focus on ascending peptidergic networks ............................. 86
Neuropeptides - Developing peptidomimetics of insulin-like peptide 5, a novel orexigenic gut hormone, to target its GPCR,
RXFP4 ............................................................................................................................................................................................................................................. 90
Neuropeptides - Developing novel chemical methods to produce insulin mimetics .................................................................................... 91
Neuropeptides - Developing small peptidomimetics to target RXFP1 for the treatment of acute heart failure ............................ 92
Neuropeptides - Engineering improved fluorescent proteins for imaging and proteomics. .................................................................... 94
Neuropeptides - Drug discovery targeting 1-adrenoceptors (1-ARs) .......................................................................................................... 95
Neuropeptides - Designing allosteric modulators of the neurotensin receptor 1 (NTS1) as potential drugs for schizophrenia.
........................................................................................................................................................................................................................................................... 96
Neuropeptides - Studies on G protein-coupled receptors; structure, function and drug development ............................................... 97
Neurophysiology Characterisation of the onset and progression of tauopathy in the pontomedullary brainstem nuclei of
mice undergoing neurodegeneration ............................................................................................................................................................................... 99
Neurophysiology Characterisation of the onset and progression of tauopathy in the pontomedullary brainstem nuclei of
mice undergoing neurodegeneration ............................................................................................................................................................................ 100
Neurophysiology Inhale-swallow-exhale: neurotransmitters that prevent food going down the wrong pipes ....................... 101
Neurophysiology - Synaptic gating mechanisms involving inhibitory interneurons in the nucleus of the solitary tract. ....... 102
Neurophysiology - Unravelling the role of chemokines in central control of the cardiovascular system ....................................... 103
Neurophysiology - Reinnervating the kidneys ........................................................................................................................................................... 104
Stroke - A Very Early Rehabilitation Trial in China (AVERT China) ............................................................................................................... 105
Stroke - Exploring the therapeutic potential of progranulin for the treatment of stroke ..................................................................... 106
Stroke - The ability of progranulin to attenuate blood brain barrier (BBB) disruption in response to pro-permeability
agents .......................................................................................................................................................................................................................................... 108
Stroke - Stratifying stroke patients in rehabilitation and recovery trials. ................................................................................................... 109
Stroke - Cerebral Haemodynamics and Orthostatic Response to Upright position in acute ischaemic Stroke (CHORUS) ..... 110
Stroke - Improving outcome assessment in stroke rehabilitation trials (Project 2) ................................................................................ 111
Stroke - Predicting gains from therapy from the anatomy of stroke injury ................................................................................................. 112
Stroke - What is the minimum dose of exercise needed for stroke survivors? ............................................................................................. 113
Stroke - Increasing physical activity in stroke rehabilitation units towards an effective solution ................................................ 114
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Stroke - Improving outcome assessment in stroke rehabilitation trials (Project 1) ................................................................................ 115
Stroke - Testing for contamination of standard care in a trial of acute stroke rehabilitation ......................................................... 116
Stroke - Identifying super-responders to exercise training after stroke: A biomarker approach ...................................................... 117
Stroke - The impact of psychological factors on engagement in stroke rehabilitation .......................................................................... 118
Stroke - Improving recovery early after stroke: Can we make the hospital environment more stimulating? .............................. 119
Stroke - The effect of blue light on post-stroke fatigue ......................................................................................................................................... 120
Stroke - The rationality (or otherwise) of medical decision-making .............................................................................................................. 121
Stroke - The effect of exercise training early after stroke .................................................................................................................................... 122
Stroke - Observing changes in bone density and structure, lean mass and glucose metabolism after stroke for targeting of
therapeutic exercise .............................................................................................................................................................................................................. 123
Stroke - Progranulin as a novel blood-brain barrier-protecting agent during ischaemic stroke: an in vitro study. ................. 124
Stroke - Improving the quality of stroke care in Australia: exploring stroke care using data from a national clinical quality
stroke registry ......................................................................................................................................................................................................................... 125
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Graduate Research at the Florey

The Florey Institute of Neuroscience and Mental Health is one of the worlds leading brain research centres. At the
Florey, we employ more than 500 staff and educate in excess of 100 post-graduate students each year. Our
scientists comprise the largest neuroscience research team in Australia.

The Florey Department of Neuroscience and Mental Health at The University of Melbourne offers PhD and MPhil
programs. MSc (Biomedical & Health Sciences) and Honours projects based at Florey are also offered by several
laboratories, through enrolment in other departments.
Graduate researchers enrolled through the Florey can expect:
1. High quality and internationally recognised supervisors.
2. A highly supportive training environment with state-of-the-art facilities and equipment; an annual
scholarship top-up of $2,000; annual funding of up to $1,000 for 3 years for conference attendance and
personal development expenses, in addition to other travel scholarships available competitively, such as e.g.
the Melbourne Abroad Travelling Scholarship (MATS).
3. A sound foundation upon which to build the thesis research project and networking before starting the
research, through a doctoral-level short course (also open to MPhil students). This provides a broad
overview of the multi-disciplinary field of neurosciences, introduces a wide range of contemporary
methodologies and techniques, and facilitates critical reading of the literature.
4. Stimulating Seminar series all year-round; multiple scientific meetings, symposia and workshops.
5. Membership of Student of the Florey Institute (SOFI) student group & Student of Brain Research (SoBR)
network, providing social and academic activities.

Each year, the Florey at Melbourne Brain Centre welcomes first-year PhD (and some MPhil) provisional candidates
from across the University, coming from a wide range of background disciplines interested in neuroscience: basic
sciences, biomedical sciences, clinical medicine, psychiatry and psychology, allied health and engineering, to the
PhD coursework in Neuroscience.

The PhD coursework program includes four subjects in intensive mode:
NEUR90007/8 Design & Analyses for Neurosciences
NEUR90009/10 Brain Imaging & Neural Networks
NEUR90011/2 Molecular & Cellular Neuroscience
NEUR90013/4 Neuroscience of Behaviour & Cognition

The course teaches advanced research skills such as inter-disciplinary collaboration, and provides a framework for
designing a solid research project through writing the literature review and an analysis plan, gaining additional
individual feedback and building confidence.

All subjects must be completed successfully (ungraded pass) before confirmation. The decision to award the degree
is entirely based on the examination of the thesis.

For more information visit www.florey.edu.au/students

Contact details
Graduate Research Administrator studentssupport@florey.edu.au- +61 (0)3 903 56789
Graduate Research Coordinator Chris Reid (Parkville campus) chris.reid@florey.edu.au and David Abbott (Austin
campus) david.abbott@florey.edu.au
MDHS Student Centre - mdhs-rhd@unimelb.edu.au - +61 (0)3 8344 5890
Research Education - Dr Kathy Lefevere lefevere@unimelb.edu.au +61(0)3 9035 7082
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Projects
Behavioural Neurosciences - Investigation of paternal influence on offspring mental health
As diploid animals, each individual human being is a genetic combination of their parents. Emerging evidence now indicates that
the environment that our parents were exposed to can also influence us. The potential for maternal health and well-being to
impact on the development of their offspring is well demonstrated and established. Stress during pregnancy has a negative
impact on offspring by slowing developmental milestones, cognitive growth, and is also associated with adult-onset mental
disorders. In contrast, the paternal influence on offspring development and mental health is largely unknown. Given the
increasing exposure to stressors (physical , psychosocial and occupational) that are prevalent in our society, it is important to
investigate the possible transgenerational effects of stress on the mental health of future generations. Our lab has developed a
model of elevated physiological stress in mice. Male mice are administered the stress hormone corticosterone via their drinking
water, resulting in behavioural alterations associated with anxiety and depression. We have subsequently found that the
offspring of these mice also exhibit alterations in anxiety and depressive tests. Interestingly, the effects on male offspring seem
to be detrimental compared to female offspring that appear to be more resilient. Our lab is keen to expand on those findings by
investigating potential environmental modifiers of these behaviours. We have adopted several hypotheses which we are
offering as potential projects. The first is a study of exercise and how the cognitive ability and response to stress of offspring
born to exercising fathers might be changed. The second study will explore enhanced cognitive stimulation as a protectant for
offspring born to stressed fathers. A third study would explore the benefits of regular exercise in preventing the
transgenerational effects of stress in fathers.
1.
2.
3.
4.
5.
6.
7.
8.
9.
Mo C, Pang TY, Ransome MI, Hill RA, Renoir T, Hannan AJ. High stress hormone levels accelerate the onset of
memory deficits in male Huntington's disease mice. Neurobiol Dis. 2014;69:248-62.
Pang TY, Du X, Catchlove WA, Renoir T, Lawrence AJ, Hannan AJ. Positive environmental modification of depressive
phenotype and abnormal hypothalamic-pituitary-adrenal axis activity in female C57BL/6J mice during abstinence
from chronic ethanol consumption. Front Pharmacol. 2013;4:93.
Du X, Pang TY, Hannan AJ. A Tale of Two Maladies? Pathogenesis of Depression with and without the Huntington's
Disease Gene Mutation. Front Neurol. 2013;4:81.
Pang TY, Renoir T, Du X, Lawrence AJ, Hannan AJ. Depression-related behaviours displayed by female C57BL/6J mice
during abstinence from chronic ethanol consumption are rescued by wheel-running. Eur J Neurosci. 2013;37:1803-
10.
Pang TY, Hannan AJ. Enhancement of cognitive function in models of brain disease through environmental
enrichment and physical activity. Neuropharmacology. 2013;64:515-28.
Du X, Leang L, Mustafa T, Renoir T, Pang TY, Hannan AJ. Environmental enrichment rescues female-specific
hyperactivity of the hypothalamic-pituitary-adrenal axis in a model of Huntington's disease. Transl Psychiatry.
2012;2:e133.
Renoir T, Pang TY, Hannan AJ. Effects of environmental manipulations in genetically targeted animal models of
affective disorders. Neurobiol Dis. 2013;57:12-27.
Pang TY, Du X, Zajac MS, Howard ML, Hannan AJ. Altered serotonin receptor expression is associated with
depression-related behavior in the R6/1 transgenic mouse model of Huntington's disease. Hum Mol Genet.
2009;18:753-66.
Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the
nervous system. Nat Rev Neurosci. 2006;7:697-709.
Supervisor(s):
Dr Terence Pang and Prof. Anthony Hannan
Campus:
Parkville
Contact details:
903 56316
Email:
terence.pang@florey.edu.au ; anthony.hannan@florey.edu.au
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Projects
Behavioural Neurosciences - Gene-environment interactions in the regulation of cellular
plasticity, cognitive function and behaviour
The hippocampus is a dynamic brain structure believed to be critical to cognitive functions including memory consolidation and
emotion regulation. One of its unusual features is that the dentate gyrus subfield is known to constitutively engage in the
process of neurogenesis throughout adulthood. Interestingly, this process is not static, and behavioural manipulations such as
housing animals in an enriched environment (EE), or allowing them to engage in voluntary exercise (VEx) on a running wheel,
can increase the rate of hippocampal neurogenesis. The real impact of enhanced hippocampal neuroplasticity on cognitive
functions remains unclear and very few studies have used genetically targeted animals to unravel neuroplasticity mechanisms
associated with the effects of long-term environmental manipulations. Serotonin (5-HT) is known to influence adult
neurogenesis, with recent studies suggesting that 5-HT in the hippocampus is more instrumental in cell proliferation than in cell
survival; this might account for the differences in proliferation and survival observed between VEx and EE. Existing research
suggests a sex difference in the regulation of hippocampal neurogenesis as well as sexually dimorphic neurochemical changes
underlying the effects of environmental factors on hippocampal-related functions such as memory and emotion regulation.
Clearly, further studies are necessary to substantiate sex differences in gene-environment interactions on hippocampal-related
functions. The role of 5-HT in the cellular changes induced by both EE and VEx needs to be explored more exhaustively to
elucidate its involvement in the process of neurogenesis. Surprisingly, although they display valuable advantages, no study has
yet used genetically targeted animal models with disrupted 5-HT signalling for such fundamental explorations. These questions
will be the focus of this project. A student taking on this project will have the opportunity to gain experience in at least one of
the following experimental techniques: behavioural testing (modeling affective/cognitive symptoms) of wild-type and
genetically targeted mice, and drug administration gene expression and protein analysis using quantitative real-time PCR,
western blotting, ELISA , autoradiography, immunohistochemistry
1.
2.
3.
4.
5.
6.
7.
Mo C, Pang TY, Ransome MI, Hill RA, Renoir T, Hannan AJ. High stress hormone levels accelerate the onset of memory
deficits in male Huntington's disease mice. Neurobiol Dis. 2014;69:248-62.
Renoir T, Pang TY, Mo C, Chan G, Chevarin C, Lanfumey L, Hannan AJ. Differential effects of early environmental
enrichment on emotionality related behaviours in Huntington's disease transgenic mice. J Physiol. 2013;591:41-55.
Renoir T, Pang TY, Hannan AJ. Effects of environmental manipulations in genetically targeted animal models of affective
disorders. Neurobiol Dis. 2013;57:12-27.
Renoir T, Pang TY, Zajac MS, Chan G, Du X, Leang L, Chevarin C, Lanfumey L, Hannan AJ. Treatment of depressive-like
behaviour in Huntington's disease mice by chronic sertraline and exercise. Br J Pharmacol. 2012;165:1375-89.
Nithianantharajah J, Hannan AJ. The neurobiology of brain and cognitive reserve: mental and physical activity as
modulators of brain disorders. Prog Neurobiol. 2009;89:369-82.
McOmish CE, Burrows E, Howard M, Scarr E, Kim D, Shin HS, Dean B, van den Buuse M, Hannan AJ. Phospholipase C-
beta1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment
and clozapine administration. Mol Psychiatry. 2008;13:661-72.
Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous
system. Nat Rev Neurosci. 2006;7:697-709.
Supervisor(s):
Dr Thibault Renoir and Prof. Anthony Hannan
Campus:
Parkville
Contact details:
903 56614
Email:
thibault.renoir@florey.edu.au ; anthony.hannan@florey.edu.au
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Projects
Behavioural Neurosciences - Utilising Touchscreen technology for preclinical modeling of
attention in autism spectrum disorder
Autism is a complex spectrum of disorders characterized by core behavioural deficits in social interaction, communication, and
behavioural flexibility. Autism spectrum disorder (ASD) frequently presents with additional cognitive symptoms, including
attentional deficits and perceptual processing deficits. Current estimates of comorbidity of ASD and attention deficit
hyperactivity disorder (ADHD) range from 4178%. Preclinical animal models are important tools for studying the behavioural
domains and biological underpinnings of autism, and potential treatment targets. Many gene mutations that contribute to ASD
have recently been identified. These findings have lead to the development of genetic mouse models which display behavioural
phenotypes mimicking ASD traits. This project takes advantage of a mouse model expressing a gene mutation coding for the
Neuroligin-3 (NL3) synaptic protein identified in ASD patients. We have shown that NL3 mice show impairments in social
interaction, a key criteria for validating mouse models of ASD, but other aspects of their cognitive phenotype, including
attentional performance and behavioural flexibility, are not well characterised. This project will investigate attentional abilities
and behavioural flexibility of NL3 mice and their WT littermates using a novel touchscreen testing apparatus. Mice will be
trained in a step-wise process to touch a computer screen for a reward. Through increasing the complexity of stimuli on the
screen mice will then be assessed for visual discrimination, reversal learning, and attention. Utilising touchscreen technology
may not only uncover new phenotypes in NL3 mice, but will allow us to investigate brain changes that underlie attention and
behavioural flexibility. This will inform the future development of treatments for attentional deficits and impairments in
behavioural flexibility in brain disorders such as ASD.
1.
2.
3.
4.
5.
McOmish CE, Burrows EL, Hannan AJ. Identifying novel interventional strategies for psychiatric disorders: integrating
genomics, 'enviromics' and gene-environment interactions in valid preclinical models. Br J Pharmacol. 2014 May 21.
Burrows EL, Hannan AJ. Decanalization mediating gene-environment interactions in schizophrenia and other psychiatric
disorders with neurodevelopmental etiology. Front Behav Neurosci. 2013 Nov 13;7:157.
Burrows EL, Hannan AJ. Characterizing social behavior in genetically targeted mouse models of brain disorders.
Methods Mol Biol. 2013;1017:95-104.
and clozapine administration. Mol Psychiatry. 2008 Jul;13(7):661-72.
McOmish CE, Burrows EL, Howard M, Hannan AJ. PLC-beta1 knockout mice as a model of disrupted cortical
development and plasticity: behavioral endophenotypes and dysregulation of RGS4 gene expression. Hippocampus.
2008;18(8):824-34.
Supervisor(s):
Dr Emma Burrows and Prof. Anthony Hannan
Campus:
Parkville
Contact details:
903 56629
Email:
emma.burrows@florey.edu.au ; anthony.hannan@florey.edu.au
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Projects
Behavioural Neurosciences - Investigating social communication in the Neuroligin 3 mouse
model of Autism
behavioural flexibility. The cause of ASD is unknown. Many gene mutations that contribute to ASD have recently been identified.
These findings have lead to the development of genetic mouse models which display behavioural phenotypes mimicking ASD
traits. This project takes advantage of a mouse model expressing a gene mutation coding for the Neuroligin-3 (NL3) synaptic
protein identified in ASD patients. We have shown that NL3 mice show impairments in social interaction, a key criteria for
validating mouse models of ASD, but other aspects of their phenotype, including communication, are not well characterised.
Rodents emit audible sounds (i.e. squeaks) but communicate among themselves predominantly in the ultrasonic range of sound
frequencies. Male mouse ultrasonic vocalizations consist of rapid series of chirp-like syllables, each call varies in duration, is
uttered at rates of about ten per second and involves rapid sweeps in frequency. Once pitch-shifted these vocalizations are
reminiscent of birdsong to the human listener. Of particular relevance to social behaviour are the ultrasonic vocalizations
emitted by male mice in the presence of females or when they detect female urinary pheromones. It is believed that the
vocalizations made by males are a critical step in initiating mating and represent a form of communication. It is for this reason
that multiple groups assessing genetic mouse models of ASD have reported reduced numbers of ultrasonic vocalizations as a
proxy for the language impairment in ASD patients. These studies have focused on number of calls and latency to call however
there is evidence to suggest that shape or waveform pattern of the call influences behaviour and may more accurately represent
differences in communication. A major challenge for quantitatively assessing differences between mutant and wild-type
vocalizations lies in the quantity and complexity of data which must be analysed. Mice emit between 400-1200 calls during a
typical 5 minute social interaction so manual detection and classification of calls is not feasible. Additionally, although specific
call types have been identified previously in the literature, it remains unclear whether mutants and wild-types even produce the
same types of calls. Therefore, a novel approach is required to first automatically identify individual calls, then to classify each
call type. This project will involve recording NL3 mice and WT mice communicating with female mice and then developing an
automated detection and classification method using MATLAB to decode the calls. This will allow us to playback calls to female
mice and search for relevant behavioural responses. We hope to identify specific genetic loci that play a role in species-specific
vocalizations and are potentially implicated in disorders that involve social communication deficits.
1.
2.
3.
4.
5.
2008;18(8):824-34.
Supervisor(s):
Dr Emma Burrows, Dr Scott Kolbe, Prof. Anthony Hannan
Campus:
Parkville
Contact details:
903 56629
Email:
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Projects
model of Autism
1.
2.
3.
4.
5.
2008;18(8):824-34.
Supervisor(s):
Dr Emma Burrows, Dr Scott Kolbe, Prof. Anthony Hannan
Campus:
Parkville
Contact details:
903 56629
Email:

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Projects
Behavioural Neurosciences - Diet induced obesity: is it an addiction?
Difficulty in managing food intake, especially highly palatable food, can result in obesity and substantial associated health
liabilities. A cardinal feature of the pathological over-eating often underlying obesity is that although the individual can describe
the negative consequences of their behaviour, they have great difficulty intervening and changing their behaviour. Thus,
difficulty in reducing food intake has qualities of an addictive disorder. The disconnect between stated goals to reduce food
consumption and actual behaviour suggests the presence of impairments in how information from the frontal cortex is
integrating with basal ganglia circuitry to direct behaviour. We have found that rats prone to diet-induced obesity display some
features of addiction-like behaviour towards palatable food. This provides important preliminary evidence to support our
central hypothesis that the pathological over-eating commonly observed in diet-induced obesity shares common features with
the compulsive drug-taking observed in drug addiction.
Therefore we aim to:
1: Investigate the presence of addiction-like behaviour in rats prone to diet-induced obesity.
2: Conduct a preclinical trial of the glutamate homeostasis restoring drug N-acetylcysteine to reverse synaptic impairments in
obesity prone rats to ameliorate aberrant feeding behaviour.
Supervisor(s):
Professor Andrew Lawrence & Dr Robyn Brown
Campus:
Parkville
Contact details:
03 90356692
Email:
Andrew.Lawrence@florey.edu.au
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Projects
Behavioural Neurosciences - mGlu5 receptors & extinction of reward-seeking
Relapse is a major clinical problem in the successful treatment of drug addicts. Relapse can be modelled in animals using an
extinction-reinstatement protocol. Extinction refers to the process by which learned associations can be inhibited in order to
change behaviour. However, the inhibitory effect of extinction learning can be removed in several ways, presentations of the
drug-associated cues or contexts. Strengthening the formation or maintenance of extinction memory significantly reduces
relapse of drug-seeking, thus, understanding the mechanisms for extinction of drug self-administration is important because it
may help identify and develop new approaches to treat drug abuse. mGlu5 receptors are important for addiction-like
behaviour, because down regulation of activity at this receptor decreases the reinforcing effects of drugs and drug-associated
cues. However, mGlu5 is also important for a variety of cognitive functions, especially learning and memory. This is important
because extinction involves new learning. We have recently demonstrated a critical role for mGlu5 in extinction of cocaine
driven behaviours. We propose that enhancement of mGlu5 signalling will facilitate extinction of reward associated cues and
contexts resulting in more effective inhibition of reward-seeking responding during subsequent reinstatement tests. This project
will directly test this hypothesis using a combination of behavioural and anatomical studies.
1.
2.
Bird MK, Lohmann P, West B, Brown RM, Kirchhoff J, Raymond CR & Lawrence AJ (2014) The mGlu5 receptor regulates
extinction of cocaine-driven behaviors. Drug Alc. Depend., 137, 83-89.
Kim JH, Perry C, Luikinga S, Zbukvic I, Brown RM & Lawrence AJ (2014) Extinction of a cocaine-taking context that
protects against drug-primed reinstatement is dependent on the metabotropic glutamate 5 receptor. Addiction Biol., in
press.
Supervisor(s):
Professor Andrew Lawrence, Dr Christina Perry & Dr Jee Hyun Kim
Campus:
Parkville
Contact details:
03 90356692
Email:
13 | P a g e

Projects
Behavioural Neurosciences - Salt, opiates and addiction
We have recently used models of salt depletion / gratification in rodents to examine the central integration of this behaviour. By
using gene set enrichment analysis, we found that genes regulated with sodium appetite were enriched for gene sets associated
with cocaine and opiate addiction. Given the association of gene changes with salt appetite and opiate addiction, we
hypothesize that the process of gratification of a salt appetite involves the release of endogenous opioids within the brain. This
would be consistent with a rapid reinforcement that precedes physiological re-normalisation of plasma ionic balance. To test
this hypothesis, we examined whether the opioid receptor antagonist, naltrexone (used clinically to treat heroin addicts and
alcoholics), had any impact upon a salt appetite. Pretreatment of mice with naltrexone attenuated the gratification of a salt
appetite. Furthermore, gratification of salt appetite is augmented in opiate-dependent mice, providing a link between instinctive
behaviours and addiction.
Therefore, our overall goals include:
1.
2.
Delineate the organisation and integration of salt (sodium) appetite in control, opiate-dependent and opiate-withdrawn
mice
Assess responses to repeated bouts of salt (sodium) deprivation in control, opiate-dependent and opiate-withdrawn
mice This will be achieved by a combination of behavioural, anatomical and electrophysiological studies.
Supervisor(s):
Professor Andrew Lawrence & Dr Stuart McDougall
Campus:
Parkville
Contact details:
03 90356692
Email:
14 | P a g e

Projects
Behavioural Neurosciences - Network disruptions following brain infarction: cognition,
behaviour and regional brain volume change
One in 3 Australians will develop dementia after retirement. Thirty percent of the cost of dementia care is driven by the
management of the behavioural and psychiatric symptoms of dementia, an estimated $USD200 billion globally. For many
patients and their families, the management of these symptoms is one of the most difficult aspects of their dementia journey.
Unfortunately, these symptoms are a common feature of brain disease. Current pharmacological treatments for BPSD have
limited efficacy and significant risk. Side effects from these therapies remain a significant cause of illness, disability and death in
the elderly [5]. Similarly, one in 3 patients will dement following stroke, yet the neuroanatomical substrates of these symptoms
remain poorly understood. Advanced imaging techniques allow us to interrogate not just the structural substrates associated
with such behaviours, but also their functional network correlates. We need to better understand the drivers of these
behaviours by investigating specific neuroanatomical networks and their associations with behavioural and cognitive change
using these advances.
1.
2.
3.
Li, Q., Pardoe, H., Lichter, R., Werden, E., Raffelt, A., Cumming., Brodtmann, A. Cortical thickness estimation in
longitudinal stroke studies: a comparison of 3 measurement methods NeuroImage:Clinical (in press)
Brodtmann A, Werden E, Pardoe H, Li Q, Jackson G, Donnan G, Cowie T, Bradshaw J, Darby D, Cumming T. Charting
cognitive and volumetric trajectories after stroke: protocol for the Cognition And Neocortical Volume After Stroke
(CANVAS) study. Int J Stroke. 2014 Aug;9(6):824-8
Brodtmann. A. Pardoe, H. Li, Q., Lichter, R. Ostergaard, L., Cumming, T. Regional variability in brain volume three
months after stroke Journal of the Neurological Sciences Nov 15 2012 322(1-2):122-8
Supervisor(s):
Amy Brodtmann
Campus:
Austin
Contact details:
400614922
Email:
agbrod@unimelb.edu.au
15 | P a g e

Projects
Behavioural Neurosciences - Motor speech disorders in degenerative brain disease
The frontotemporal dementias (FTD) are the second commonest cause of young-onset dementia after Alzheimer's disease.
Behavioural variant frontotemporal dementia (bvFTD) accounts for about half of FTD. Primary progressive aphasia (PPA)
includes two FTD variants (semantic (svPPA) and non-fluent (nvPPA) aphasias. The logopenic variant (lvPPA) of PPA is typically
associated with Alzheimers disease pathology, and can be regarded as language-onset Alzheimer's. Whilst language deficits are
not a core characteristic of bvFTD, motor speech deficits are a supporting diagnostic feature. We have found significant motor
speech disruption in our bvFTD patients using using a combination of perceptual examination (where a clinician listens to a
patient speak in order to evaluate the nature and severity their speech disorder), speech characterization (of both apraxic and
dysarthric features), and acoustic analysis of speech. All patients are imaged with high resolution volumetric MRI to allow
clinico-anatomical correlation. Speech and language abnormalities in neurodegenerative disease are important diagnostic
biomarkers. Further research with more advanced imaging methods would allow more detailed investigation of the pathways
underlying motor speech disruptions in disease.
Supervisor(s):
Adam Vogel and Amy Brodtmann
Campus:
Parkville
Contact details:
90357004
Email:
agbrod@unimelb.edu.au
16 | P a g e

Projects
Behavioural Neurosciences - Adolescent vulnerability to anxiety: a dopamine story
Anxiety disorders are a major worldwide public health concern, and according to the Australian Bureau of Statistics ~1 in 4
Australians suffer from a clinically diagnosed anxiety disorder at least once in their lifetime. While these disorders can affect
people of all ages, adolescence represents a particularly vulnerable period. For example, the median age of onset for anxiety
disorders is 14, and people who experience anxiety early in life are more likely to exhibit more severe symptoms later on in life.
One of the main focuses of our laboratory lies in determining what neurobiological factors underlie this increased vulnerability
observed in adolescents, with the aim of developing more effective therapeutic interventions. Fear conditioning is the most
commonly used model for studying anxiety disorders in rodents. Extinction refers to the decrease in fear due to the fear-eliciting
cue no longer being accompanied by an aversive event, and this forms the basis of exposure therapies used for the treatment of
anxiety disorders in humans. Using a fear conditioning/extinction paradigm we have shown that extinction training is less
effective in P35 (adolescent) compared to P70 (adult) rats due to maturational differences in the prefrontal cortex (PFC). This
difference may be due to the well-established disrupted balance of dopamine receptor 1 (DR1) vs 2 (DR2) signalling during
adolescence, however this has yet to be directly demonstrated. The aim of this project is to investigate potential age-related
differences in the activation of D1R vs D2R in the PFC of adult vs adolescent mice in response to extinction of conditioned fear.
Mice that express green flourescent protein- (GFP) tagged D1R and D2R will be utilised, and Fos/GFP immunohistochemistry will
be performed to identify activated D1R and D2R neurons. The effect of the D2 partial agonist Aripiprozole upon extinction
consolidation and D1R/D2R activation in the PFC will also be examined.
Supervisor(s):
Dr Jee Hyun Kim and Dr Heather Madsen
Campus:
Parkville
Contact details:
9035 6623
Email:
jeek@unimelb.edu.au
17 | P a g e

Projects
Behavioural Neurosciences - Neural circuitry underlying extinction of fear across development
Most anxiety disorders emerge during childhood, and individuals with childhood onset express more severe symptoms than do
individuals who have adult onset. In fact, there is growing recognition that mental disorders may actually be developmental
brain disorders and, as such, treatment strategies should focus on the young population. Currently, the effective treatments for
anxiety disorders are cognitive-behavioural therapies that rely on the process of extinction. Extinction is the decrease in fear
responses expressed to a fearful stimulus due to the repeated exposure to the stimulus without any aversive outcome. We have
accumulated powerful evidence supporting that extinction is erasure in juvenile rats whereas extinction is new learning in adult
rats. This developmental transition from erasure to new learning appears to be driven by changes in the functionality and the
circuitry between the amygdala, the hippocampus, and the medial prefrontal cortex (mPFC). This project will characterise the
functional organisation of that neural circuitry using intracranial microinfusions of retrograde tracers (cholera toxin b subunit
and fluorogold), using Pavlovian fear conditioning as a model of post-traumatic stress disorder in developing rats.
1.
Kim JH & Richardson R (2010). New findings on extinction of conditioned fear early in development: Theoretical and
clinical implications. Biological Psychiatry, 67: 297-303.
Supervisor(s):
Dr Jee Hyun Kim and Dr Despina Ganella
Campus:
Parkville
Contact details:
9035 6623
Email:
jeek@unimelb.edu.au
18 | P a g e

Projects
Behavioural Neurosciences - The effects of adolescent toluene exposure on metabolic function
Inhalant abuse (also known as chroming) is a major socio-economic problem in Australia, and a rapidly growing drug of choice
to reach a euphoric state. Inhalants such as paint, glue, hair-spray or petrol are among the cheapest drugs in the community,
and unlike illicit drugs, there are no legal restrictions on their purchase, supply, possession or use. The typical onset of
experimentation with inhalants occurs earlier than with most other drugs of abuse, in the preteen years. Indeed the incidence of
inhalant abuse is greatest in the adolescent population with numbers as high as 26% of adolescents abusing solvents; with 12-13
year olds comprising nearly 50% of this population. As a result exposure to inhalants in early adolescence coincides with
dramatic periods of growth and maturation and thus has the potential to influence processes that could lead to long-term
changes in metabolic function including food consumption and caloric absorption. This could aid in the explanation of why many
chronic abusers lose weight and appear emaciated. The aim of this project is to utilise a rodent model of adolescent toluene
exposure via inhalation in order to increase our understanding of the effects inhalants have on long-term metabolic function. In
particular we aim to investigate whether inhalant induced changes in body composition are related to altered energy intake. If
so we then wish to explore whether this is driven by changes to systemic (ie changes to peripheral organs) or centrally (ie
changes to the brain) mediated processes that regulate energy balance. Finally we wish to explore whether inhalant-induce
alterations in energy balance may lead to a predisposition of developing adult onset disorders such as renal disease, diabetes
and heart disease. The results from these studies will increase our understanding of the long-term effects of inhalant abuse on
metabolic functions and increase our understanding of the mechanisms that may be underlying adverse outcomes following
inhalant exposure, especially if abuse occurs during adolescence when individuals may be more susceptible to drug induced
adaptations.
Supervisor(s):
Dr. Jhodie R. Duncan and Professor Andrew J. Lawrence
Campus:
Parkville
Contact details:
03 90356731
Email:
Jhodie.duncan@florey.edu.au
19 | P a g e

Projects
Behavioural Neurosciences - The effects of adolescent toluene exposure on metabolic function
Inhalant abuse (also known as chroming) is a major socio-economic problem in Australia, and a rapidly growing drug of choice
to reach a euphoric state. Inhalants such as paint, glue, hair-spray or petrol are among the cheapest drugs in the community,
and unlike illicit drugs, there are no legal restrictions on their purchase, supply, possession or use. The typical onset of
experimentation with inhalants occurs earlier than with most other drugs of abuse, in the preteen years. Indeed the incidence of
inhalant abuse is greatest in the adolescent population with numbers as high as 26% of adolescents abusing solvents; with 12-13
year olds comprising nearly 50% of this population. As a result exposure to inhalants in early adolescence coincides with
dramatic periods of growth and maturation and thus has the potential to influence processes that could lead to long-term
changes in metabolic function including food consumption and caloric absorption. This could aid in the explanation of why many
chronic abusers lose weight and appear emaciated. The aim of this project is to utilise a rodent model of adolescent toluene
exposure via inhalation in order to increase our understanding of the effects inhalants have on long-term metabolic function. In
particular we aim to investigate whether inhalant induced changes in body composition are related to altered energy intake. If
so we then wish to explore whether this is driven by changes to systemic (ie changes to peripheral organs) or centrally (ie
changes to the brain) mediated processes that regulate energy balance. Finally we wish to explore whether inhalant-induce
alterations in energy balance may lead to a predisposition of developing adult onset disorders such as renal disease, diabetes
and heart disease. The results from these studies will increase our understanding of the long-term effects of inhalant abuse on
metabolic functions and increase our understanding of the mechanisms that may be underlying adverse outcomes following
inhalant exposure, especially if abuse occurs during adolescence when individuals may be more susceptible to drug induced
adaptations.
Supervisor(s):
Dr. Jhodie R. Duncan and Professor Andrew J. Lawrence
Campus:
Parkville
Contact details:
03 90356731
Email:
Jhodie.duncan@florey.edu.au
20 | P a g e

Projects
Behavioural Neurosciences - Gene-environment interactions in the regulation of cellular
plasticity, cognitive function and behaviour
The hippocampus is a dynamic brain structure believed to be critical to cognitive functions including memory consolidation and
emotion regulation. One of its unusual features is that the dentate gyrus subfield is known to constitutively engage in the
process of neurogenesis throughout adulthood. Interestingly, this process is not static, and behavioural manipulations such as
housing animals in an enriched environment (EE), or allowing them to engage in voluntary exercise (VEx) on a running wheel,
can increase the rate of hippocampal neurogenesis. The real impact of enhanced hippocampal neuroplasticity on cognitive
functions remains unclear and very few studies have used genetically targeted animals to unravel neuroplasticity mechanisms
associated with the effects of long-term environmental manipulations. Serotonin (5-HT) is known to influence adult
neurogenesis, with recent studies suggesting that 5-HT in the hippocampus is more instrumental in cell proliferation than in cell
survival; this might account for the differences in proliferation and survival observed between VEx and EE. Existing research
suggests a sex difference in the regulation of hippocampal neurogenesis as well as sexually dimorphic neurochemical changes
underlying the effects of environmental factors on hippocampal-related functions such as memory and emotion regulation.
Clearly, further studies are necessary to substantiate sex differences in gene-environment interactions on hippocampal-related
functions. The role of 5-HT in the cellular changes induced by both EE and VEx needs to be explored more exhaustively to
elucidate its involvement in the process of neurogenesis. Surprisingly, although they display valuable advantages, no study has
yet used genetically targeted animal models with disrupted 5-HT signalling for such fundamental explorations. These questions
will be the focus of this project. A student taking on this project will have the opportunity to gain experience in at least one of
the following experimental techniques: behavioural testing (modeling affective/cognitive symptoms) of wild-type and
genetically targeted mice, and drug administration; gene expression and protein analysis using quantitative real-time PCR,
western blotting, ELISA , autoradiography, immunohistochemistry.
1.
2.
3.
4.
5.
6.
7.
8.
Hannan AJ. Neurobiol. Dis. 2013; 57:1-4.

Renoir T, Pang TY, Mo C, Chan G, Chevarin C, Lanfumey L, Hannan AJ. J. Physiol. 2013; 591:41-55.
Renoir T, Pang TY, Hannan AJ. Neurobiol. Dis. 2013; 57:12-27
McOmish CE, Burrows E, Howard M, Scarr E, Kim D, Shin HS, Dean B, van den Buuse M, Hannan AJ. Mol. Psychiatry
2008; 13:661-72.
Nithianantharajah J, Hannan AJ. Nature Rev. Neurosci. 2006; 7:697-709.
Pang TY, Du X, Zajac MS, Howard ML, Hannan AJ. Hum. Mol. Genet. 2009; 18:753-66.
Spires TL, Grote HE, Varshney NK, Cordery PM, van Dellen A, Blakemore C, Hannan AJ. J. Neurosci. 2004; 24:2270-6.
van Dellen A, Blakemore C, Deacon R, York D, Hannan AJ. Nature 2000; 404:721-2.
Supervisor(s):
Dr Thibault Renoir and A/Prof. Anthony Hannan
Campus:
Parkville
Contact details:
9035-6638
Email:
thibault.renoir@florey.edu.au
21 | P a g e

Projects
model of Autism
1.
2.
3.
4.
Methods Mol. Biol. 2013;1017:95-104.
Hill-Yardin EL, Hannan AJ. Translating preclinical environmental enrichment studies for the treatment of autism and
other brain disorders: Comment on Woo and Leon (2013). Behav. Neurosci. 2013;127:606-9.
Howard ML, Palmer SJ, et al. Mutation of Gtf2ird1 from the Williams-Beuren syndrome critical region results in facial
dysplasia, motor dysfunction, and altered vocalisations. Neurobiol. Dis. 2012;45:913-22.
McOmish CE, Burrows E, et al. Phospholipase C-beta1 knockout mice exhibit endophenotypes modeling schizophrenia
which are rescued by environmental enrichment and clozapine administration. Mol. Psychiatry. 2008;13:661-72.
Supervisor(s):
Dr Emma Burrows, Dr Scott Kolbe and A/Prof. Anthony Hannan
Campus:
Parkville
Contact details:
9035-6629
Email:
emma.burrows@florey.edu.au
22 | P a g e

Projects
Behavioural Neurosciences - Utilising Touchscreen technology for preclinical modeling of
attention in autism spectrum disorder
behavioural flexibility. Autism spectrum disorder (ASD) frequently presents with additional cognitive symptoms, including
attentional deficits and perceptual processing deficits. Current estimates of comorbidity of ASD and attention deficit
hyperactivity disorder (ADHD) range from 4178%. Preclinical animal models are important tools for studying the behavioural
domains and biological underpinnings of autism, and potential treatment targets. Many gene mutations that contribute to ASD
have recently been identified. These findings have lead to the development of genetic mouse models which display behavioural
phenotypes mimicking ASD traits. This project takes advantage of a mouse model expressing a gene mutation coding for the
Neuroligin-3 (NL3) synaptic protein identified in ASD patients. We have shown that NL3 mice show impairments in social
interaction, a key criteria for validating mouse models of ASD, but other aspects of their cognitive phenotype, including
attentional performance and behavioural flexibility, are not well characterised. This project will investigate attentional abilities
and behavioural flexibility of NL3 mice and their WT littermates using a novel touchscreen testing apparatus. Mice will be
trained in a step-wise process to touch a computer screen for a reward. Through increasing the complexity of stimuli on the
screen mice will then be assessed for visual discrimination, reversal learning, and attention. Utilising touchscreen technology
may not only uncover new phenotypes in NL3 mice, but will allow us to investigate brain changes that underlie attention and
behavioural flexibility. This will inform the future development of treatments for attentional deficits and impairments in
behavioural flexibility in brain disorders such as ASD.
1.
2.
3.
4.
5.
6.
Hill-Yardin EL, Hannan AJ. Behav. Neurosci. 2013 Aug;127:606-9.

Nithianantharajah J, et al. Nat. Neurosci. 2013;16:16-24.
Nithianantharajah J, Hannan AJ. Prog. Neurobiol. 2009;89:369-82.
Nithianantharajah J, et al. Neurobiol. Dis. 2008;29:490-504.
McOmish CE, et al. Mol. Psychiatry. 2008;13:661-72.
Mazarakis NK, et al. J. Neurosci. 2005;25:3059-66.
Supervisor(s):
Dr Emma Burrows and A/Prof. Anthony Hannan
Campus:
Parkville
Contact details:
9035-6629
Email:
emma.burrows@florey.edu.au
23 | P a g e

Projects
Behavioural Neurosciences - Investigation of paternal influence on offspring mental health
As diploid animals, each individual human being is a genetic combination of their parents. Emerging evidence now indicates that
the environment that our parents were exposed to can also influence us. The potential for maternal health and well-being to
impact on the development of their offspring is well demonstrated and established. Stress during pregnancy has a negative
impact on offspring by slowing developmental milestones, cognitive growth, and is also associated with adult-onset mental
disorders. In contrast, the paternal influence on offspring development and mental health is largely unknown. Given the
increasing exposure to stressors (physical , psychosocial and occupational) that are prevalent in our society, it is important to
investigate the possible transgenerational effects of stress on the mental health of future generations. Our lab has developed a
model of elevated physiological stress in mice. Male mice are administered the stress hormone corticosterone via their drinking
water, resulting in behavioural alterations associated with anxiety and depression. We have subsequently found that the
offspring of these mice also exhibit alterations in anxiety and depressive tests. Interestingly, the effects on male offspring seem
to be detrimental compared to female offspring that appear to be more resilient. Our lab is keen to expand on those findings by
investigating potential environmental modifiers of these behaviours. We have adopted several hypotheses which we are
offering as potential projects. The first is a study of exercise and how the cognitive ability and response to stress of offspring
born to exercising fathers might be changed. The second study will explore enhanced cognitive stimulation as a protectant for
offspring born to stressed fathers. A third study would explore the benefits of regular exercise in preventing the
transgenerational effects of stress in fathers.
1.
2.
3.
4.
5.
6.
7.
8.
Mo C, Renoir T, Pang TY, Hannan AJ. Behav. Brain Res. 2013;253C:318-322.

Pang TY, Du X, Catchlove WA, Renoir T, Lawrence AJ, Hannan AJ. Front. Pharmacol. 2013;4:93.
Pang TY, Renoir T, Du X, Lawrence AJ, Hannan AJ. Eur. J. Neurosci. 2013;37:1803-10.
Pang TY, Hannan AJ. Neuropharmacology. 2013;64:515-28.
Du X, Leang L, Mustafa T, Renoir T, Pang TY, Hannan AJ. Transl.
Psychiatry. 2012;2:e133.
Pang TY, Du X, Zajac MS, Howard ML, Hannan AJ. Hum. Mol. Genet. 2009;18:753-66.
Nithianantharajah J, Hannan AJ. Nat. Rev. Neurosci. 2006;7:697-709.
Supervisor(s):
Dr Terence Pang and A/Prof. Anthony Hannan
Campus:
Parkville
Contact details:
9035-6316
Email:
anthony.hannan@florey.edu.au
24 | P a g e

Projects
Behavioural Neurosciences - Understanding the role of synaptic genes in cognition and disease
Sensory information from the environment is ultimately processed at the level of synapses, the connection between neurons
that form the most fundamental information-processing units in the nervous system. Vertebrate synapses contain a large yet
intricately organised signalling complex of proteins encompassing neurotransmitter receptors, scaffold proteins and cell
adhesion proteins. In recent years, human genetic studies have increasingly highlighted that disruption of over 200 genes that
encode postsynaptic proteins result in over 130 brain diseases. While it is accepted that postsynaptic proteins are fundamental
for synaptic function, plasticity and thus behaviour, very little is actually known about the impact of postsynaptic gene
mutations in regulating complex cognition and higher order processing. Modelling the complex cognitive processes that are
routinely assessed in the clinical setting has been challenging in animal models. Bridging the gap between mouse and human
cognitive testing, the recently developed touchscreen methodology provides an innovative tool for dissecting higher cognitive
functions in rodents. Multiple projects are currently available. In our laboratory, we use mice as models carrying mutations in
key postsynaptic genes - including the NMDA receptor, synaptic scaffolds and cell-adhesion proteins - to study how these genes
regulate synapse formation, function and cognitive behaviours. In addition to in-depth behavioural analysis using novel
methodology which our lab has unique expertise in, projects will involve training in key cellular and molecular techniques
including immunohistochemical and biochemical analysis.
1.
2.
3.
4.
Nithianantharajah J et al., (2013) Nat. Neurosci; 16, 16-24.

Ryan TJ, Kopanitsa MV, Indersmitten T, Nithianantharajah J et al., (2013) Nat. Neurosci; 16, 25-32.
Coba MP*, Komiyama NH*, Nithianantharajah J* et al., (2012). J. Neurosci; 32, 13987-13999. *Authors contributed
equally.
Bussey TJ*, Holmes A*, Lyon L*, Mar A*, McAllister KAL*, Nithianantharajah J* et al., (2012) Neuropharmacol; 62, 1191-
203. *All authors contributed equally.
Supervisor(s):
Dr Jess Nithianantharajah
Campus:
Parkville
Contact details:
8344 1684
Email:
jess.n@florey.edu.au
25 | P a g e

Projects
Brain Development & Regeneration - How is the major tumour suppressor protein PTEN
trafficked in the cell?
PTEN is a tumour suppressor protein that is lost or mutated in nearly all forms of cancer. Outside of cancer PTEN has many
functions in regulating cell survival, growth and metabolism and has been linked to a number of brain disorders such as autism.
The function of PTEN is dependent on where it is localised in the cell. Much like a courier company such as FEDEX, the cell has a
distribution network setup in order to move proteins around the cell. This project will study how PTEN can be distributed in the
cell that results in the different functions of the protein. The project will use a technique called bimolecular fluorescence
complementation to study the location of PTEN under different cellular settings. We have recently published the first phase of
this project. The project will involve cell culture, microscopy and molecular biology techniques.
1.
2.
3.
Li Y, Low LH, Putz U, Goh CP, Tan SS, Howitt J. Rab5 and Ndfip1 Are Involved in Pten Ubiquitination and Nuclear
Trafficking. Traffic. 2014 Jul;15(7):749-61.
Howitt, J., Lackovic, J., Low, L-H., Naguib, A., Macintyre, A., Goh, C-P., Callaway, J.K., Hammond V., Thomas, T., Dixon,
M., Putz, U. Silke, J., Bartlett, P., Yang, B., Kumar, S., Trotman, L.C., Tan, S-S. (2012). Ndfip1 regulates nuclear Pten
import in vivo to promote neuronal survival following cerebral ischemia. J. Cell Biol. 196:29-36
Putz U, Howitt J, Doan A, Goh CP, Low LH, Silke J, Tan SS. The Tumor Suppressor PTEN Is Exported in Exosomes and Has
Phosphatase Activity in Recipient Cells. Sci Signal. 2012 Sep 25;5(243).
Supervisor(s):
Dr Jason Howitt and Pof Seong-Seng Tan
Campus:
Parkville
Contact details:
90356322
Email:
jason.howitt@florey.edu.au
26 | P a g e

Projects
Brain Development & Regeneration - Protein trafficking in neurodegenerative diseases.
Neurons under stress require rapid degradation or export of proteins that may be toxic. We have discovered that Ndfip1 is
important for this process, for example, under conditions of metal poisoining, Ndfip1 directs degradation of the metal
transporter DMT1 to seal off the entry of toxic metals. Under brain injury conditions, Ndfip1 is increased to mediate transport
of proteins to promote neuron survival. Recently, we discovered that Ndfip1 is increased in degenerating neurons found in
Parkinson's disease brain. In addition, Ndfip1 controls the abundance of proteins involved in the pathogenesis of Alzheimer's
disease, such as APP and Fe65. In this project, we will examine more closely the molecular basis of this interaction, and use
mouse disease models to interrogate this pathway. This project will use, knockout and transgenic mice, mouse models of
disease and various biochemistry techniques
1.
2.
3.
Howitt, J., Putz, U., Lackovic, J., Doan, A., Dorstyn, L., Cheng, H., Yang, B., Chan-Ling, T., Silke, J., Kumar, S. and Tan, S-S
(2009). Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc. Natl.
Acad. Sci. USA 106:15489-15494
import in vivo to promote neuronal survival following cerebral ischemia J. Cell Biol. 196:29-36
Howitt, J., Gybers, A., Ayton, S., Carew-Jones, F., Putz, U., Finkelstein, D., Halliday, G., and Tan, S-S. (2014). Increased
Ndfip1 in the substantia nigra of Parkinsonian brains is associated with elevated iron levels. Plos One 9(1):e87119.
Supervisor(s):
Prof Seong-Seng Tan and Dr Jason Howitt
Campus:
Parkville
Contact details:
9035 6718
Email:
stan@florey.edu.au

27 | P a g e
Projects
Brain Development & Regeneration - Control of protein transport in exosomes by Ndfip1
Exosomes are secreted extracellular vesicles that carry proteins and nucleic acids for export. The contents of exosomes can be
internalized by recipient cells with physiological and sometimes pathological consequences. We have discovered that Ndfip1 can
control the loading of proteins for export. One important exosome passenger is PTEN, a tumour suppressor that is important for
cancers in the breast, brain, prostate and skin. Without Ndfip1, the tumour suppressor PTEN fails to be exported. In this project,
we will ask what factors are responsible for directing PTEN into exosomes, and how can these be harnessed to increased PTEN
transport in exosomes for reducing tumours.
1.
2.
3.
Putz, U.,, Howitt, J., Lackovic, J., Foot, N., Kumar, S., Silke, J. and Tan, S-S (2008) Nedd4-family interacting protein 1
(Ndfip1) is required for the exosomal secretion of Nedd4-family proteins. J. Biol. Chem 283:32621-32627
Putz, U., Howitt, J., Doan, A., Goh, C-P., Low, L-H., Silke, J., Tan, S-S (2012)The tumor suppressor PTEN is exported in
exosomes for phosphatase activity in recipient cells. Science Signaling 5:ra70
Supervisor(s):
Prof Seong-Seng Tan and Dr Ulrich Putz
Campus:
Parkville
Contact details:
9035 6718
Email:
stan@florey.edu.au
28 | P a g e

Projects
Brain Development & Regeneration - How can Ndfip1 reduce brain damage following stroke?
Stroke is the third most common cause of death. After the onset of cerebral ischemia, about 2 million neurons die per minute,
mostly from brain tissue surrounding the hemorrhage. We have discovered that if neurons in these areas increase their levels of
Ndfip1, they are protected from death during the vulnerable period. In this project, we aim to test a number of factors that are
known to increase Ndfip1 in neurons. We will discover the molecular pathways that allow these factors to upregulate Ndfip1,
and therefore increase the number of surviving neurons following stroke.
1.
2.
3.
4.
5.
(2009)Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc. Natl.
Acad. Sci. USA 106:15489-15494
Schieber, C., Howitt, J., Putz, U., White, J.M., Parish, C.L., Donnelly, P.S. and Tan, S-S (2011) Cellular upregulation of
Nedd4-family interacting protein 1 (Ndfip1) using low levels of bioactive cobalt complexes. J. Biol. Chem 286:8555-8564
Lackovic, J., Howitt, J., Callaway, J.K., Silke, J., Bartlett, P., and Tan, S-S. (2012) Differential regulation of Nedd4 ubiquitin
ligases and their adaptor protein Ndfip1 in a rat model of ischemic stroke. Exp. Neurol. 235:326-335
Goh, C.P., Putz, U., Howitt, J., Low, L.H., Gunnersen, J., Bye, N., Morganti-Kossmann, C. and Tan, S-S. (2014) Nuclear
trafficking of Pten after brain injury leads to neuron survival not death Exp. Neurol 252:37-46
Supervisor(s):
Prof Seong-Seng Tan and Dr Jason Howitt
Campus:
Parkville
Contact details:
9035 6718
Email:
stan@florey.edu.au

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Projects
Brain Development & Regeneration - How does the brain protect itself during injury?
Following brain injury, neurons die for days and even weeks after the event. Some neurons die as a consequence of the injury
(e.g. trauma, stroke) but neurons in adjacent areas die from uncontrolled released of toxic substances and excessive firing
activity. The brain tries to protect itself from this secondary cell death by increasing Ndfip1, a protein that is normally present at
low levels but upregulated by stress. Neurons that increase Ndfip1 are protected from death; unfortunately this protective
mechanism appears to be limited to a small number of participating neurons. The reason for this is unknown but it opens up a
therapeutic opportunity. In this project, we seek to understand how Ndfip1 in the brain protects neurons from death, and to
devise methods (e.g. drugs) of amplifying the Ndfip1 response to cover other neurons that normally succumb to death. You will
be using knockout mice without Ndfip1 and also mice engineered to over-express Ndfip1.
1.
2.
3.
4.
5.
(2009) Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc. Natl.
Acad. Sci. USA 106:15489-15494
Schieber, C., Howitt, J., Putz, U., White, J.M., Parish, C.L., Donnelly, P.S. and Tan, S-S (2011) Cellular upregulation of
Nedd4-family interacting protein 1 (Ndfip1) using low levels of bioactive cobalt complexes. J. Biol. Chem 286:8555-8564
import in vivo to promote neuronal survival following cerebral ischemia. J. Cell Biol. 196:29-36
Lackovic, J., Howitt, J., Callaway, J.K., Silke, J., Bartlett, P., and Tan, S-S. (2012) Differential regulation of Nedd4 ubiquitin
ligases and their adaptor protein Ndfip1 in a rat model of ischemic stroke. Exp. Neurol. 235:326-335
Goh, C.P., Putz, U., Howitt, J., Low, L.H., Gunnersen, J., Bye, N., Morganti-Kossmann, C. and Tan, S-S. (2014) Nuclear
trafficking of Pten after brain injury leads to neuron survival not death Exp. Neurol 252:37-46
Supervisor(s):
Prof Seong_Seng Tan and Dr Jason Howitt
Campus:
Parkville
Contact details:
9035 6718
Email:
stan@florey.edu.au
30 | P a g e

Projects
Brain Development & Regeneration - Investigating interneuron migration and placement into
cortical circuits
The cortex is comprised of two neuronal populations, the excitatory pyramidal neurons and the inhibitory interneurons that
modulate this excitatory output. The balance between excitatory and inhibitory neuronal activity is required for normal function
and any disruption to this balance can give rise to abnormal cortical processing. Increasing evidence suggests that there is a
decrease in the number of interneurons detected in post-mortem samples of patients suffering from epilepsy. Any irregularities
in interneuron production, positioning or activity within the cortex have been implicated in a number of psychiatric disorders
such as epilepsy, schizophrenia and autism. Despite the advances in the treatment of seizure disorders, medically intractable
epilepsy requires surgical treatments. The concept of treating seizures by grafting inhibitory interneurons is more than a decade
old, but has gained momentum recently due to our greater understanding of interneuron development, specification and
function. The purpose of this project is to examine the ability of transplanted interneurons to integrate into a host cortex. It aims
to test whether this is dependent upon two key factors: the age of the donor interneurons and the age of the host/recipient
cortical tissue. Techniques to learn during this project include, surgical procedures, tissue processing, immunohistochemistry,
microscopy and high-resolution real-time confocal imaging. The Brain Development and Regeneration division at the Florey
Neuroscience Institutes investigates how neurons are generated and assemble to form the cerebral cortex. This part of the brain
is responsible for originating the complex motor, sensory and cognitive functions in mammals and its assembly during
development occurs through a series of highly coordinated events. We aim to identify genes involved in this process, particularly
on how individual neurons are born, change shape, migrate and adopt different neuronal identities that are essential for cortical
function. Our studies disclose new information on how genes have shaped brain evolution and help explain the cellular basis of
neurological and psychiatric disorders.
Supervisor(s):
Dr Joanne Britto
Campus:
Parkville
Contact details:
9035 6586
Email:
joanne.britto@florey.edu.au

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Projects
Epilepsy - Drug Impacts on Behaviour and Epigenetics
For PhD Candidates, scholarships (e.g top-up, partial and full) may be available for this project - further information on request.
This project will explore the role of drug actions may play to augment behaviours within and transcending generations. A
combination of behavioural and molecular techniques will be adopted to explore the long term consequences of certain
stressors in the presence of current widely used drug therapies for the treatment of neurological disorders such as epilepsy. Not
all stressors have detrimental effects. Mild food restriction has been shown to have beneficial outcomes for anxiety and
maternal behaviour. The interactions between drug, environment and epigenetics will be investigated. DNA methylation will be
explored in the context of epigenetics and drug actions in this context. This project will use a combination of behavioural and
molecular techniques. Drug actions will be assessed behaviourally using a number of paradigms. Anxiety and fear are primary
areas of investigation within this study. Behaviour will be explored in the context of an environmental stressor such as caloric
restriction or noise stress. A primary focus is on the stress pathway and the autonomic responses.
Supervisor(s):
Prof Tony Paolini/Dr Amanda Paolini/Prof Graeme Jackson
Campus:
Austin
Contact details:
90359986
Email:
antonio.paolini@florey.edu.au
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Projects
Epilepsy - Developing better Bionics for Brain stimulation and recording
This project explores how best to interface neural prosthetic devices into the brain for the treatment of many neurological
disorders and sensory related dysfunction. The primary goal of this project is to decode neural processing using novel neural
engineering and neuroscientific methods including brain microstimulation and multichannel neural recording. The information
obtained through this exercise would benefit coding more generally leading to enhanced neural interfacing options and clues to
assist the development of intelligent bionics in the future. Options for the treatment of sensory dysfunction, tinnitus and
neurological disorders such as epilepsy using deep brain stimulation can also be explored as multiple projects in this area are
offered. This project has the capacity to use a number of different techniques tailored to the students interest. While the
primary focus is on small animal multichannel brain recording and micro stimulation, given the multidisciplinary nature of this
work there are opportunities to undertake projects in many fields. Students with an interest in neuroscience together with
biological sciences, neural and biomedical engineering, mathematics, computer science or psychology are encouraged to
undertake this exciting visionary project. Watch the exciting JOVE article that illustrates some of the techniques now available
at our new Florey Institute labs at Melbourne Brain Centre Austin Campus. http://www.jove.com/video/3598/behavioral-
determination-stimulus-pair-discrimination-auditory
1.
Morgan S and Paolini A.G. (2012) Behavioural determination of stimulus pair discrimination of auditory acoustic and
electrical stimuli using a classical conditioning and heart-rate approach. J Vis Exp. 6;(64):e3598.
Supervisor(s):
Professor Tony Paolini/Prof Graeme Jackson
Campus:
Austin
Contact details:
90359986
Email:
antonio.paolini@florey.edu.au
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Projects
Epilepsy - Functional neuroimaging analysis to identify brain abnormality in epilepsy
Combined functional magnetic resonance imaging (fMRI) and electro-encephalography (EEG) approaches can be used to define
the brain networks in patients with epilepsy. The aim of this project is to further develop and apply algorithms that can best
identify the components of the network that are responsible for the generation of the hyper-synchronisation that is
characteristic of the epileptic seizure. This project uses advanced neuroimaging methods in functional imaging including
functional connectivity, signal processing and data-driven analysis methods. The project may suit a candidate with a background
or strong interest in physics, engineering, computer science, mathematics or statistics. Figure caption: Example demonstrating
how methodological improvement can yield additional information from functional imaging data. Here the same brain imaging
data are analysed in two ways. The analysis on the right included a novel de-noising algorithm (SOCK, developed by Florey PhD
student Kaushik Bhaganagarapu) and yielded additional information regarding the spatio-temporal pattern of brain activity
compared to the conventional analysis without SOCK.
Supervisor(s):
Dr David Abbott
Campus:
Austin
Contact details:
9035 7025
Email:
david.abbott@florey.edu.au

Figure caption: Example demonstrating how methodological improvement can yield additional information from functional
imaging data. Here the same brain imaging data are analysed in two ways. The analysis on the right included a novel de-noising
algorithm (SOCK, developed by Florey PhD student Kaushik Bhaganagarapu) and yielded additional information regarding the
spatio-temporal pattern of brain activity compared to the conventional analysis without SOCK.
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Projects
Epilepsy - Multi-site patch clamp recording of cortical micro networks
In this project the candidate will be trained in the use of an emerging method in brain slice electrophysiology that allows for the
simultaneous intracellular recording of 4 connected neurons. Using this recording mode it is possible to examine how neurons
function in coupled micro networks in epileptic and normal brains to lead to a deeper understanding of the functional basis of
epilepsy. If the candidate makes sufficient progress and is motivated this project may also expand into network analysis using
multiphoton imaging where 50 or more neurons in a living brain can be labelled with a Ca2+ indicator dye and imaged in real
time.
Supervisor(s):
A/Professor Steve Petrou & A/Professor Chris Reid
Campus:
Parkville
Contact details:
9035 3628
Email:
spetrou@unimelb.edu.au
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Projects
Epilepsy - Projects in network analysis of genetic epilepsy
Epilepsy impacts around 3% of the population and in many cases has clear genetic underpinnings. Our laboratory has created
several genetically engineered models of epilepsy that have helped provide the most detailed understanding of how a single
gene mutation can lead to behavioural seizures. Perhaps the largest gap in our understanding lies at the level of the network
that bridges cellular and synaptic function with the actual seizure phenotype itself.
1.
2.
3.
4.
Reid et al Brain 2014

Reid et al Neurology 2013
Wimmer et al JCI 2010
Tan et al PNAS 2008
Supervisor(s):
A/Professor Steve Petrou & A/Professor Chris Reid
Campus:
Parkville
Contact details:
9035 3628
Email:
36 | P a g e

Projects
Epilepsy - Will HCN channel antagonists be good antiepileptic drugs?
Our laboratory has discovered that some antiepileptic drugs act on certain HCN channel subtypes. We now need to address
whether this mechanism is part of the anti-seizure effect of these drugs. In this project we will use a combination of selective
HCN subtype-selective channels in a variety of seizure models to establish this. We will also extend the project to look
specifically at mechanisms using electrophysiological methods that directly measure neuron excitability. Establishing if these
channels are good targets will motivate drug discovery programs. These channels are also thought to be important to the
generation of pain and may be useful in this condition as well.
Supervisor(s):
A/Prof Chris Reid, A/Professor Steve Petrou
Campus:
Parkville
Contact details:
90356372
Email:
christopher.reid@florey.edu.au
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Projects
Epilepsy - 9. Zinc and seizures
Zn2+ is an essential element having a multitude of biological functions throughout the body. Febrile seizures are common
affecting approximately 3% of children. There is good evidence that febrile seizures can trigger a cascade of events that lead to
more severe forms of epilepsy later in life. Clinically, several studies have suggested that Zn2+ levels are significantly lower in
blood and CSF of children that suffer febrile seizures but these studies are not conclusive. In this project we will directly test the
hypothesis that low brain Zn2+ may be one environmental factor in increasing the chance of having a febrile seizure. In this
project the student will learn a range of experimental techniques aimed at understanding the role Zn2+ plays in changing
neuronal excitability. The results have clear clinical implications and could be particularly important in for developing countries,
where epilepsy rates are high and nutritional supplementation is a potential practical therapy.
Supervisor(s):
A/Prof Chris Reid, A/Professor Steve Petrou, A/Prof Paul Adlard
Campus:
Parkville
Contact details:
90356372
Email:
christopher.reid@florey.edu.au
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Projects
Epilepsy - Neuroanatomical determinants of susceptibility in a model of genetic epilepsy
Epilepsy affects ~1-2% of the population, making it the most common neurological disorder. 50% of all epilepsies are genetic
generalized epilepsies (GGE), and currently more than 100.000 Australians live with this disease. These numbers highlight the
dire clinical need for better therapy, diagnosis and prognosis. To achieve these goals we need to develop better knowledge of
the underlying pathogenic processes. To date, research has focused on acute functional effects of genetic mutations rather than
anatomical changes in the brain as GGEs have been traditionally been considered idiopathic without any visible changes in
brain structure. Recent results, however, indicate that subtle, microscopic alterations in brain anatomy and neuronal
connectivity underlie some aspects of seizure genesis. This prompts the question whether we can understand genetic epilepsy if
we are ignoring structural changes or assuming they are non-existent? This project will examine two forms of anatomical
change associated with GGE: Microdysgenesis, which refers to changes during brain development, and homeostatic plasticity,
which is an adaptive response to the seizures themselves. Anatomical alterations will be analysed in a mouse model carrying a
human epilepsy mutation using cutting edge imaging and quantification techniques. Results will improve our understanding of
pathogenic mechanisms in GGE with implications for therapy and diagnosis.
Supervisor(s):
Verena C Wimmer, Steven Petrou
Campus:
Parkville
Contact details:
9035 3628
Email:
vwimmer@florey.edu.au
39 | P a g e

Projects
Epilepsy - High content automated analysis of ion channels in epilepsy
Discovery of gene mutations in neurological disorders such as epilepsy is outstripping the ability to functionally validate them.
Because many epilepsy genes code for ion channels we have established high content automated patch clamp platforms based
on the Nanion Patchliner 16 and the Fluxion HT 64 systems to bridge the "discovery" gap between genetics and functional
validation. Several new mutations have been found by our geneticist collaborators that are awaiting detailed functional analysis
and the candidate will first have to produce mutant cDNAs then transiently transfect into HEK293 or CHO cells prior to analysis
on the automated platforms. Candidates will be trained in the necessary molecular biological methods and then in ion channel
electrophysiology and will work closely with a senior member of the team to ensure success.
1.
Milligan et al Annals of Neurology 2014
Supervisor(s):
Dr Carol Milligan & A/Professor Steve Petrou
Campus:
Parkville
Contact details:
9035 3628
Email:
40 | P a g e

Projects
Epilepsy - MRI tractography in mouse models of genetic epilepsy: Creation of prognostic and
diagnostic structural biomarkers
Our earlier classical histological analyses have shown that neuronal numbers and positioning are both altered in genetic forms of
epilepsy prior to the appearance of overt seizures suggesting that structural changes precede epilepsy. These changes,
however, would be below the level of detection of current clinical MRI scanning technology and have led to the potentially
erroneous conclusion that idiopathic generalised epilepsy (IGE) is characterised by a complete absence of structural change. By
combining recent developments in super resolution MRI (developed by members of the supervisory team) and high field MRI
acquisition (16.4T) the candidate will seek to reveal structural changes, or biomarkers, that precede or are a consequence of
epilepsy. Because these approaches are directly translatable into the clinic any finding could be rapidly tested in patients. The
candidate will develop skills in preparing fixed mouse brains for MRI scanning at 16.4T at the Queensland Brain Institute for
analysis using the MRtrix suite of software on a custom workstation to compare brains from control and genetic mouse models.
1.
Richards et al Neuroimage 2014
Supervisor(s):
Dr Kay richards, A/Professor Chris Reid, Professor Alan Connelly, A/Professor Fernando Calamente,
A/Professor Steve Petrou,
Campus:
Parkville
Contact details:
9035 3628
Email:
41 | P a g e

Projects
Epilepsy - CLARITY based glass brain imaging in health and disease
Recent improvements in the histochemical method of optically clearing whole tissues and the joint development of special
optics that can image deep into them have created unprecedented views into the wiring of networks. Changes in wiring of
cortical neurons have been implicated in a number of disorders such as epilepsy, schizophrenia and depression. In this project
the candidate will prepare brains from mice with fluorescently labelled neurons and use 2 photon excitation or custom light
sheet based microscopy to create 3D images in regions of the mouse cortex. By comparing normal and epilepsy models this
work will begin to unravel the changes that occur prior to and after the occurrence of seizures. This will shed important light on
the scale on which structural changes occur in epilepsy and will guide future experimental and clinical work.
Supervisor(s):
A/Professor Steve Petrou, Dr Verena Wimmer, Dr Kay Richards
Campus:
Parkville
Contact details:
9035 3628
Email:
42 | P a g e

Projects
Epilepsy - Optogenetic modulation of the area tempestas an epilepsy hot spot
Several lines of study have recently converged to reveal a new target for controlling epileptic seizures. Early work by Piredda and
Gale (Nature 1985, 317:623) provided unequivocal evidence that the prepiriform cortex, subsequently coined the area
tempestas, was a hot spot for initiation and spread of epileptic seizures. Within this region a population of specialised
inhibitory neurons called neurogliaform cells (NG) shows a stereotypic pattern of firing that implicates them seizures. In this
project the candidate will use in vivo electrophysiological recording and optogenetic stimulation to examine real time
modulation of the control of seizures to develop a role for the in vivo function of NG cells and explore their potential utility in
seizure suppression.
Supervisor(s):
Kay Richards, A/Professor Steve Petrou, A/Professor Chris Reid
Campus:
Parkville
Contact details:
9035 3628
Email:
43 | P a g e

Projects
Epilepsy - In vivo electrophysiological analysis in mouse models of genetic epilepsy
In this project the candidate will use multi-site in vivo unit recording in mouse models of genetic epilepsy to investigate network
function and dysfunction in freely moving mice. Using digital high density electrode recording the candidate will implant
multiple sites and then record from mice housed in a controlled environment with video monitoring. One possible addition to
these experiments is the incorporation of optogenetic stimulation whilst recording to probe network function in connected
networks of behaving mice. This will provide some of the first views into how real time intervention of networks modulates
seizure initiation and termination.
Supervisor(s):
A/Prof Steve Petrou
Campus:
Parkville
Contact details:
9035 3628
Email:
44 | P a g e

Projects
Epilepsy - High density multi-electrode array recording of in vitro networks in epilepsy
In this project the candidate will use high density extracellular multielectrode array recordings to investigate large scale network
function. This a level of organization beyond that studied in Project 1 and will reveal fundamental properties of how the
hippocampal and thalamocortical networks are altered in genetic models of epilepsy. The goal of these studies is to not only
understand more about the neurobiology of epilepsy but also to create novel disease state models for creating anti-epileptic
drugs. The method will involve cutting fresh brain slices and using 60 site multi-electrode arrays that enable electrical
stimulation and recording from all sites simultaneously. Slices will be subject to various stimulation and pharmacological
protocols to reveal aspects about excitability, synaptic transmission and plasticity.
Supervisor(s):
A/Professor Steve Petrou, A/Professor Chris Reid
Campus:
Parkville
Contact details:
9035 3628
Email:
45 | P a g e

Projects
Epilepsy - How does the brain remove the excess number of neurons during development and
aging
Many more neurons are produced during development than are present in the adult brain. Also many neurons are lost during
aging, however the process of innate phagocytosis, which removes unwanted and superfluous neurons is poorly defined. The
unwanted neurones enter apoptosis but subsequent clearance of these dying cells is important for our body to avoid
autoimmunity or inflammation in the brain. Apoptotic cells express unique markers which enable them to be recognized and
engulfed by phagocytes. The knowledge of these unique markers is limited at present to certain cell membrane lipids, e.g.
phosphatidylserine. Recent novel finding from our laboratory suggests that a unique protein epitope is expressed early in
apoptosis and this is recognized by P2X7 receptors on phagocytes. This project will examine how apoptotic cells are recognized
and cleared by phagocytes both in health and in disease. This result will have relevance to many neurological diseases as well as
early neurodevelopment. Techniques involved are cell culture, immunoprecipitation, western blotting, flow cytometry, peptide
screen, molecular biology and mass spectrometry.
Supervisor(s):
Dr. Ben J. Gu, Prof. James Wiley
Campus:
Parkville
Contact details:
9035 6317
Email:
ben.gu@florey.edu.au; james.wiley@florey.edu.au
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Projects
Epilepsy - Identification of serum glycoproteins inhibiting innate immunity
Innate immunity is the first line defense of host against invading pathogens. Phagocytosis of non-opsonized particles (bacteria or
viruses not coated by immunoglobulin, complement, etc) is an important part of innate immunity. Our recent findings show that
innate phagocytosis is completely abolished by a group of serum glycoproteins, i.e. serum inhibits innate immunity. These
proteins play an important role in regulation of innate immunity and the most potent protein remains unknown. Identifying this
protein will lead to a new therapies to boost resistance against infectious diseases. Techniques involved are chromatography,
cell culture, flow cytometry, electrophoresis, western blotting and mass spectrometry.
Supervisor(s):
Campus:
Parkville
Contact details:
9035 6317
Email:
47 | P a g e

Projects
Epilepsy - Identify the transcriptional regulatory factors of the P2X7 receptor
P2X7 is an ATP-gated purinergic receptor and plays a broad role in infection, inflammation, autoimmunity, neurodegeneration
and oncogenesis. Several isoforms of P2X7 have been identified to be associated with cancer or other diseases. High expression
of non-functional P2X7 has also been found in a broad range of tumour tissues. However, the transcriptional regulatory factors
leading to these isoforms and non-functional P2X7 are unclear. This project will identify the transcriptional factors in the P2X7
promoter region, and how these transcriptional factors regulate production of P2X7 isoforms and non-functional P2X7. The
results will provide insights on how cancer cells avoid removal by innate immunity. Techniques involved include molecular
biology, including primer extension, transfection, fluorescent super electrophoresis mobility shift assay and chromotin-
immunoprecipitation, as well as cell culture, flow cytometry.
Supervisor(s):
Dr. Ben J. Gu, Dr. Tobias Merson, Prof. James Wiley
Campus:
Parkville
Contact details:
9035 6317
Email:
ben.gu@florey.edu.au; tmerson@unimelb.edu.au; james.wiley@florey.edu.au
48 | P a g e

Projects
Epilepsy - The role of P2X7 in a mouse model of oligodendrocyte apoptosis
Oligodendrocytes support the function of nerve cells by producing a fatty substance called myelin that insulates the axons of
nerve cells, much like plastic insulation around an electricity cable. Dying (apoptotic) cells are normally cleared from the brain by
specialised scavenger cells called microglia that engulf and digest them. Previous studies of our group have shown that the P2X7
protein found on the surface of these scavenger cells recognizes the dying cells and helps their engulfment. If dying cells are not
removed, they leak molecules causing inflammation of the brain, which worsens symptoms of neurological disorders. It appears
that P2X7 is important in limiting the extent of this neurodegeneration in MS since genetic variations in P2X7 in humans can
confer either an increased risk or protection against developing MS. In this project, we will investigate the role of P2X7 in
regulating the ability of microglial to remove dying oligodendrocytes from the brain using an established mouse model. The
results will provide insight on the role that P2X7 plays in orchestrating the inflammatory response to oligodendrocyte death.
This knowledge will aid in our long-term goal of developing methods to protect neurons from permanent damage. Techniques
involved are small animal handling, tissue collection, immunohistochemical staining, cell culture, flow cytometry.
Supervisor(s):
Dr. Ben J. Gu, Dr. Tobias Merson, Prof. James Wiley
Campus:
Parkville
Contact details:
9035 6317
Email:
ben.gu@florey.edu.au; tmerson@unimelb.edu.au; james.wiley@florey.edu.au
49 | P a g e

Projects
Epilepsy - Search the P2X7 related biomarkers for Alzheimers disease
Alzheimers disease is an age-related dementia with major impact in people aged 60 or over. Typical symptoms including
memory loss and cognitive impairment but the pathogenesis is unclear and treatment options are limited. Recent evidence
suggests the P2X7 receptor may be involved in the pathogenesis of this disease. This project will study the peripheral blood cells
obtained from Alzheimers disease patients, subjects with minor cognitive impairment and age matched healthy controls. The
P2X7 expression and function on mononuclear cells and various phenotyping and serological assays will be performed. The
diagnostic and prognostic values of P2X7 expression and function will be evaluated. This work may provide a useful biomarker
for the diagnosis and prognosis of Alzheimers disease, as well as the possible pathogenesis mechanism.
Supervisor(s):
Campus:
Parkville
Contact details:
9035 6317
Email:
50 | P a g e

Projects
Epilepsy - The nature of the P2X4 receptor
The P2X4 receptor is a two trans-membrane ion channel activated by ATP. It is highly expressed on monocytic lineage cells
(monocytes, macrophages and microglia) and certain neuronal cells and has been shown to play an important role in
neuropathic pain. However, the cellular traffic of this receptor and its co-associated molecules is unclear. This project will use
anti-P2X4 monoclonal antibody to examine the surface and intracellular expression of P2X4 in different cells, and identify the
possible membrane complex associated with P2X4. The result could help to better understand this receptor and its role in
neuropathic pain.
Supervisor(s):
Campus:
Parkville
Contact details:
9035 6317
Email:
51 | P a g e

Projects
Imaging - Super-resolution MRI methods for the Human Brain Connectome
Our group has shown that the technique of diffusion Magnetic Resonance Imaging (MRI) can be used to obtain an estimate of
the macroscopic white matter fibre orientations at each location in the brain, which in turn can be used with a fibre-tracking
algorithm to reconstruct a representation of the white matter pathways in the brain. For the case of whole-brain fibre-tracking,
several million tracks (also known as streamlines) are generated, thus providing an overall representation of white matter
pathways throughout the brain. More recently, we have shown that these data can be used to generate images with resolution
higher than the resolution of the acquired data (i.e. to achieve 'super-resolution'), in a technique we called super-resolution
track-weighted imaging (TWI). This methodology provides a natural means to combine structural and functional connectivity
information into a single image, and therefore can play a major role in the characterisation of the Human Brain Connectome (a
comprehensive map of neural connections in the human brain). This PhD project will involve the development of novel methods
for the analysis of super-resolution TWI, and their application to Connectomics. Following on the footsteps of the genome,
Connectomics (or the study of the connectome) is a major growing field in neuroscience, with the ultimate aim of developing a
comprehensive map of the structural and functional connections in the brain.
1.
2.
3.
4.
5.
6.
7.
8.
Calamante F, et al. Track-weighted functional connectivity (TW-FC): a tool for characterizing the structural-functional
connections in the brain. NeuroImage 70: 199210 (2013).
Calamante F, et al. Super-resolution track-density imaging of thalamic substructures: comparison with high-resolution
anatomical magnetic resonance imaging at 7.0T. Human Brain Mapping 34:25382548 (2013).
Calamante F, et al. A generalised framework for super-resolution track-weighted imaging. NeuroImage 59: 2494-2503
(2012).
Cho ZH, Calamante F, Chi JG. 7.0 Tesla MRI Brain White Matter Atlas (2nd Edition). Springer-Verlag (2014), Berlin,
Germany. ISBN: 978-3-642-54391-3.
Calamante F, et al. Super-resolution track-density imaging studies of mouse brain: comparison to histology. NeuroImage
59: 286-296 (2012).
Calamante F, et al. Track density imaging (TDI): validation of super-resolution property. NeuroImage 56:1259-1266
(2011).
Calamante F, et al. Track Density Imaging (TDI): Super-resolution white matter imaging using whole-brain track-density
mapping. NeuroImage 53: 12331243 (2010).
Tournier J-D, Calamante F, Connelly A. MRtrix: diffusion tractography in crossing fiber regions. Int. J. Imaging Sys.
Techno. 22: 53-66 (2012).
Supervisor(s):
Fernando Calamante, Alan Connelly
Campus:
Austin
Contact details:
90357041
Email:
fercala@brain.org.au

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Projects
Imaging - Perfusion MRI: novel methods to image cerebral blood flow and brain function
Magnetic Resonance Imaging (MRI) provides a powerful non-invasive tool to measure the rate of blood delivery to brain tissue
(also known as cerebral perfusion). Cerebral perfusion plays an essential role in tissue viability and function, and it is implicated
in many diseases (such as stroke, epilepsy, and tumours). Our group is among the international leaders in the development of
Perfusion MRI methods. This PhD project will involve the development of novel methods to measure and analyse Perfusion MRI
data, in particular using the technique known as Arterial Spin Labelling (ASL). These methods will then be used to investigate
brain disorders (e.g. stroke, epilepsy, dementia, etc.), and/or to characterise whole-brain networks (e.g. with connectomics) in
the healthy brain and how these networks are disrupted by disease. ASL Perfusion MRI offers a number of important advantages
compared with more traditional BOLD fMRI methods to study brain networks, including quantitation, reduced image distortions
and signal drop-out, increased spatial specificity, and increased sensitivity to low task frequency paradigms.
1.
2.
3.
4.
5.
6.
Calamante F, Thomas DL, Pell GS, Wiersma J, Turner R. Measuring cerebral blood flow using Magnetic Resonance
Imaging techniques. J. Cereb. Blood Flow Metab. 19:701-735 (1999).
Liang X, Connelly A, Calamante F. Graph analysis of resting-state ASL perfusion MRI data: nonlinear correlations among
CBF and network metrics. NeuroImage 87: 265275 (2014).
Liang X, Connelly A, Calamante F. Improved partial volume correction for single inversion time arterial spin labeling
data. Magn. Reson. Med. 69: 531537 (2013).
Liang X, Tournier J-D, Masterton R, Connelly A, Calamante F. A k-space sharing 3D GRASE pseudocontinuous ASL method
for whole-brain resting-state functional connectivity. Int. J. Imaging Sys. Techno. 22: 37-43 (2012).
Calamante F, Masterton RAJ, Tournier J-D, Smith RE, Willats L, Raffelt D, Connelly A. Track-weighted functional
connectivity (TW-FC): a tool for characterizing the structural-functional connections in the brain. NeuroImage 70: 199
210 (2013).
Wells JA, Thomas DL, King MD, Connelly A, Lythgoe MF, Calamante F. Reduction of Errors in ASL Cerebral Perfusion and
Arterial Transit Time Maps using Image De-noising. Magn. Reson. Med. 64:715724 (2010).
Supervisor(s):
Fernando Calamante, Alan Connelly
Campus:
Austin
Contact details:
90357041
Email:
fercala@brain.org.au
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Projects
Mental Health - The influence of alpha-synuclein on olfaction
Parkinsons disease (PD) is a devastating neurodegenerative disorder. In addition to the characteristic impairments in the
locomotor system, one of the earliest symptoms of PD is an impairment in the sense of smell (olfaction), which may be an early
predictor of PD. Our laboratory studies the role of alpha synuclein (-syn) in PD, a protein implicated in PD as a genetic cause,
risk factor and the primary constituent of Lewy bodies, a histopathological hallmark of PD that spreads across the brain with
disease progression. This project aims to characterise olfaction deficits in a new mouse mode of PD pathology, whereby we track
propagation of pathological changes in the mouse brain after the injection of -syn fibrils. Our initial data show impairment of
odour detection in this model, a feature highly relevant to PD. Methods used in this project will include stereotaxic surgery and
bromodeoxyuridine marking of new neurons to investigate the influence of -syn fibrils on neurogenesis and the migration of
new neurons to the olfactory bulb, in order to determine whether these processes are influenced in -syn-induced olfactory
deficits. An extension of the project may include examination of the integration and synaptic complexity of new neurons, and
the impact of -syn on the parallel vomeronasal/social odour olfactory system. Skills learned will include stereotaxic surgery,
animal behaviour testing, Western blotting techniques and immunohistochemistry.
Supervisor(s):
Kevin Barnham, Laura Jacobson
Campus:
Parkville
Contact details:
8344 1805
Email:
kbarnham@unimelb.edu.au
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Projects
Mental Health - Nitric oxide synthesis and function in C. elegans
Nitric oxide (NO), is a biologically important nitrogen free radical with an in vivo half-life of only few seconds. In vertebrates NO
is an essential cellular signaling molecule involved in numerous physiological and pathological processes, from vasodilation to
innate immunity. Recently, NO has become recognized as having a critical role in several neurodegenerative diseases. The
project will combine genetics, molecular biology and biophysics to characterize NO synthesis in C. elegans and investigate its
role in biological ageing.
Aims:
use radical trapping techniques and live imaging to quantify NO production in C. elegans
To modulate the production of NO in C. elegans using genetic and pharmacological approaches to investigate potential
effects on ageing and disease models.
Supervisor(s):
Dr. Gawain McColl and Dr. Simon Drew
Campus:
Parkville
Contact details:
990356608
Email:
gmccoll@florey.edu.au

Fig. In vivo imaging of free radical generation in Caenorhabditis elegans.
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Projects
Mental Health - Modeling Parkinsons disease in C. elegans
Parkinsons Disease (PD) is a debilitating disorder, classically characterized by progressive and selective loss of dopaminergic
(DAergic). Although current pharmacotherapies offer some effectiveness in early stages of disease, these medications offer only
symptomatic relief and fail to protect the remaining neurons from eventual degeneration. Devising therapeutics that address
not only the symptoms of PD but also the cause (so called disease modifiers) are of vital importance. While mammalian-based
PD research is clearly a necessary step in the validation of mode-of-action of drug candidates, sole reliance on mammalian
models limits the rate at which new therapeutics can be identified. Development of novel therapeutics would be greatly assisted
by more rapid whole animal screening technologies. The well-developed genetics of Caenorhabditis elegans makes it highly
suited for mode of action (MOA) studies of compound effect. This project involves the development of advanced screening
platforms to identify neuro-protective compounds using C. elegans and investigate mode-of-action. This project would suit a
student with an interest molecular biology and high throughput assay development.
1.
Chege & McColl. (2014). Caenorhabditis elegans: a model to investigate oxidative stress and metal dyshomeostasis in
Parkinson's disease. Frontiers in Aging Neuroscience, 6, 89. doi:10.3389/fnagi.2014.00089
Supervisor(s):
Dr. Gawain McColl
Campus:
Parkville
Contact details:
990356608
Email:

Fig. Brightfield and confocal images of adult Caenorhabditis elegans showing dopaminergic neurons in green.
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Projects
Mental Health - New Animal models of Alzheimers Disease
Alzheimers disease (AD) is the most common age related dementia, with the number of affected individuals expected to exceed
100 million worldwide by 2050. Despite the significance of this disease there are currently no disease modifying drugs to treat
AD. One of the pathological hallmarks of AD is the cerebral deposition of plaques composed of Amyloid-beta (A) peptide.
Clearance of A is slowed in cerebrospinal fluid from AD patients, which likely contributes to its pathological deposition. The
accumulation of A is thought to lead to disease progression, however, the underlying mechanism of A toxicity remains
unclear. Recent studies that soluble oligomers are likely to be the toxic form of A. The nematode, Caenorhabditis elegans offers
a simplified in vivo system in which to examine accumulation, oligomerization and toxicity of A. This project involves
developing new transgenic C. elegans strains expressing specific disease relevant amino-truncated A-species. This project
would suit a student with an interest in molecular biology, imaging and mass spectrometry.
1.
McColl et al. (2012). Utility of an improved model of amyloid-beta (A1-42) toxicity in Caenorhabditis elegans for drug
screening for Alzheimer's disease. Molecular Neurodegeneration, 7(1), 57. doi:10.1186/1750-1326-7-57
Supervisor(s):
Dr. Gawain McColl
Campus:
Parkville
Contact details:
990356608
Email:

Fig. Live in vivo imaging of aggregated A in transgenic Caenorhabditis elegans.

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Projects
Mental Health - Iron and Biological Ageing
Metal ions are essential for life, and approximately half of all proteins are metalloproteins. We aim to determine in the worm,
Caenorhabditis elegans, how the handling of redox-active iron fatigues with age, and creates a toxic, pro-ageing biochemistry.
Our focus is to determine the impact of genetic lifespan mutations on the handling of iron storage, distribution and redox
activity. This has relevance to understanding the fundamentals of the chemistry of ageing in higher organisms and humans.
Since age is the greatest risk factor for disease, these insights will build a platform for future studies that may have great
relevance for maintaining lifespan and healthspan in humans. This project would suit a student interested in biochemistry,
molecular biology and genetics.
1.
2.
3.
McColl et al. (2012). Caenorhabditis elegans Maintains Highly Compartmentalized Cellular Distribution of Metals and
Steep Concentration Gradients of Manganese. PLoS ONE, 7(2), e32685. doi:10.1371/journal.pone.0032685.g002
James et al. (2013). Direct in vivo imaging of essential bioinorganics in Caenorhabditis elegans. Metallomics 5(6), 627
635. doi:10.1039/c3mt00010a
Chege & McColl. (2014). Caenorhabditis elegans: a model to investigate oxidative stress and metal dyshomeostasis in
Parkinson's disease. Frontiers in Aging Neuroscience, 6, 89. doi:10.3389/fnagi.2014.00089
Supervisor(s):
Gawain McColl
Campus:
Parkville
Contact details:
903566078
Email:

Fig. X-ray fluorescence tomography of Caenorhabditis elegans intestinal cells. Shown is iron in green and zinc in blue.

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Projects
Mental Health - The mechanism of de novo prion formation
Sonication (application of ultrasound energy) during PMCA generates free radicals in solution and we can detect these radicals
and show they cause numerous post-translational modifications to PrP during PMCA. We hypothesise that these radicals,
combined with the unique physical conditions present during sonication, provide the necessary chemical and structural trigger
for PrP oxidation, covalent modification and misfolding into a de novo prion.
This project will characterise the biochemical changes induced by PMCA using a combination of immunodetection (ELISA,
western/dot/slot blotting), fluorescence, spectroscopy and mass spectrometry techniques. The various post-translational
modifications to PrP will be correlated with the de novo infectivity of PMCA reaction products using animal and/or cell culture
models of prion disease.
1.
2.
3.
Morales, R.; Duran-Aniotz, C.; Diaz-Espinoza, R.; Camacho, M. V.; Soto, C. Protein misfolding cyclic amplification of
infectious prions, Nature Protocols 2012, 7, 13971409.
Wang, F.; Wang, X.; Yuan, C-G.; Ma, J. Generating a Prion with Bacterially Expressed Recombinant Prion Protein, Science
2010, 327, 11321135.
Makino, K.; Mossoba, M. M.; Riesz, P. Chemical Effects of Ultrasound on Aqueous Solutions.Formation of Hydroxyl
Radicals and Hydrogen Atoms, J. Phys. Chem. 1983, 87, 13691377.
Supervisor(s):
Dr Simon Drew, Dr Cathryn Haigh, Dr Victoria Lawson
Campus:
Parkville
Contact details:
90358684
Email:
sdrew@unimelb.edu.au
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Projects
Mental Health - Compound development for A related toxicity in Alzheimer's disease
Alzheimers disease is a debilitating slow neurodegenerative disease that is the leading cause of dementia, and is the third
leading cause of disability and death in Australias elderly population, behind cancer and heart disease. Delaying the onset of
severe cognitive disability by 5 years will result in a significant enhancement of elderly peoples quality of life, and will reduce
the burden of this disease on the health system. While many approaches have been investigated in terms of reducing A
aggregation, increasing A clearance or reducing A toxicity, most have been targeted at either aggregated forms or in vitro
generated soluble oligomers of A. In general, these approaches have completely failed at bringing a drug to fruition at the
clinic. The reasons for these failures are varied, but in general there is a lack of appropriate cohorts to conduct the clinically
trials in, as the point at which cognitive symptoms become apparent is now considered to be too late to intervene effectively. A
second reason is that the targets that companies are aiming for are not necessarily representative of the in vivo forms of the A
peptide. We have some preliminary evidence that an alternative approach, where A peptides are stabilized as a non-toxic
entity that is more easily cleared from brain tissue is perhaps a better approach then targeting a specific oligomer. Thus the aim
of this project is to identify compounds that are already FDA approved with this activity. Techniques involved include
aggregation assays, including Thioflavin T and X-34 fluorescence time courses, electron microscopy, biophysical characterization
of the resulting complexes with circular dichroism spectroscopy, analytical ultracentrifugation and isothermal calorimetry.
Supervisor(s):
Dr. Blaine Roberts, Dr. Tim Ryan, Prof Colin Masters
Campus:
Parkville
Contact details:
9035-6635
Email:
blaine.roberts@florey.edu.au; ryan.t@florey.edu.au
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Projects
Mental Health - Biomarker discovery for Neurodegenerative disease
Alzheimers disease is a debilitating slow neurodegenerative disease that is the leading cause of dementia. This disease is
characterized by a slow decline in cognitive function, with the greatest risk factor for the disease being age. Currently, the main
diagnostic for Alzheimers disease is post-mortem, which is clearly inadequate in determining appropriate treatment regimens
for elderly patients presenting with dementia. The second best method for diagnosing the form of dementia is the use of
radiolabeled Pittsburgh compound B positron emission tomography (PIB-PET) imaging of the formation of amyloid plaques in
human brain tissue. This has its own set of limitations, the primary issue being that it is very expensive to conduct at around
$3000 per test, the second being that the radioisotopes used for the test are very shot-lived, requiring hospitals to house
extensive infrastructure to generate the required labeled compounds. The imaging techniques have however indicated that
there are pathological changes in brain tissue in neurodegenerative diseases that occur up to 10 years prior to the onset of the
cognitive symptoms of the disease. We, and others, believe that these changes should be reflected in the cerebrospinal fluid
and blood of Alzheimers disease patients. Thus, projects in this area are focused on investigating the changes in protein, and
other macromolecule, levels in these fluids in the hope of identifying a cheap and accurate blood test for Alzheimers disease.
Techniques commonly applied include the fractionation of blood, various methods for depleting abundant proteins, 2D DIGE,
and mass spectrometry.
Supervisor(s):
Campus:
Parkville
Contact details:
9035-6635
Email:
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Projects
Mental Health - Understanding the natural biology of A peptides in human brain
Alzheimers disease involves a significant loss of neurons and a resulting loss in cognitive ability. The defining pathological
characteristic of the disease is the formation of plaques of aggregate protein in the cortex of the brain. These plaques are
comprised of the A peptide and while are the defining feature of the disease, are thought to be a relatively inert end-point to a
toxic process that forms soluble oligomers of A. These soluble species are thought to be the toxic principle of the disease.
We believe that this is too much a simplification of the biology of A, and we have an overarching aim of understanding the role
of A, the distribution of A in the milieu of the brain tissue and how the A peptide is involved in the disease. We primarily
focus on studying facets of A biology in human brain tissue, with a view to understanding the behavior of the peptide in vivo.
Projects under this heading involve investigating the A distribution in the cellular milieu of human brain tissue, investigating
protease levels and determining changes in other proteins related to the disease. Techniques commonly applied in these
projects include brain tissue homogenization, chromatography, HPLC, mass spectrometry, 2D and 1 D SDS PAGE and western
blotting.
Supervisor(s):
Campus:
Parkville
Contact details:
9035-6635
Email:
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Projects
Mental Health - Understanding the role of the zinc transporter ZIP12 in schizophrenia
Schizophrenia is a debilitating mental illness that affects approximately 1% of the population. The biological basis of
schizophrenia remains largely unknown. Using human post-mortem brain tissue, we recently discovered that the gene for zinc
transporter member 12 (ZIP12) is upregulated in cortical regions in people with schizophrenia. This increase was not detected in
brain tissue from people with bipolar disorder or major depressive disorder, indicating the change is disease specific. This
project will involve: 1) Measuring ZIP12 expression, using real-time PCR, in the caudate-putamen from people with
schizophrenia, compared to control subjects, to determine how widespread the change of expression is throughout the brain. 2)
As we have now shown that human ZIP12 is capable of increasing zinc uptake in the cell, total and subcellular zinc levels will be
measured in human brain preparations, using ICP-MS, to determine if zinc regulation is affected by increased ZIP12 expression in
these individuals. 3) Finally, total and subcellular zinc levels will be measured in brain tissue from rats treated with antipsychotic
drugs to see whether the changes we observe in the brains from people with schizophrenia are influenced by medication.
Supervisor(s):
Assoc Prof Elizabeth Scarr, Dr Madhara Udawela
Campus:
Parkville
Contact details:
90356601
Email:
madhara.udawela@florey.edu.au
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Projects
Mental Health - Investigating the involvement of the serotonin 2A receptor in the incidence
suicide.
There is a high risk of suicide amongst people suffering with major depression. Furthermore, many antidepressant drugs that
target the serotonergic system may contribute to suicidal ideation. A recent study by our group showed that subjects with major
depression have lower levels of the serotonin receptor, 5-HT2A receptor, in the cingulate cortex compared to control subjects.
Amongst those subjects, people with mood disorders who died as a result of suicide also had lower levels of 5-HT2A receptor in
the cingulate cortex compared to non-suicide cases. Therefore, we are interested in understanding whether 5-HT2A receptor
could be involved in the pathophysiology of suicide, itself. This project aims to determine whether the levels of 5-HT2A receptor
are altered in the brains of people who have committed suicide. Levels of the 5-HT2A receptor will be measured in the cingulate
cortex, taken post-mortem, from subjects with no prior history of psychiatric illness who died as a result of suicide and
compared with tissue from non-suicide, control subjects. The techniques students will use in this project will include but not be
limited to: Processing of post-mortem tissue. Radioligand binding assays. Autoradiography.
1.
Dean B, Tawadros N, Seo MS, Jeon WJ, Everall I, Scarr E, Gibbons A. Lower cortical serotonin 2A receptors in major
depressive disorder, suicide and in rats after administration of imipramine. International Journal of
Neuropsychopharmacology, 2014,17(6):895-906. doi: 10.1017/S1461145713001648.
Supervisor(s):
Dr Andrew Gibbons, Dr Caitlin McOmish, Prof Brian Dean
Campus:
Parkville
Contact details:
9035 6746
Email:
agibbons@unimelb.edu.au
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Projects
Mental Health - Investigating the effect of antipsychotic drugs on the levels of TNF receptor in
the brain
There is growing evidence to suggest that proteins that are involved in inflammation are also affected in schizophrenia. Research
from our group suggests that the signalling pathway of the pro-inflammatory cytokine, Tumour Necrosis Factor (TNF), is involved
in the pathophysiology of schizophrenia. We have recently shown that the levels of the TNF receptor, TNFR1, are increased in
the frontal cortex of people with schizophrenia. Studies are currently underway within our laboratory to further investigate how
TNF signalling is affected in this disorder. This project aims to investigate whether antipsychotic drugs can affect the levels of
TNFR1 in the frontal cortex. TNFR1 protein will be measured in frontal cortical tissue from rats that have been treated with
antipsychotic drugs. TNFR1 protein will also be measured in the frontal cortex from mice treated with the psychotomimetic
phencyclidine (PCP) to investigate whether TNFR1 levels are altered in a mouse model of psychosis. The techniques that the
student will use in this project will include but not be limited to: Processing of post-mortem tissue. SDS-PAGE separation of
protein extracts. Western blotting and protein expression analysis.
1.
Dean B, Gibbons AS, Tawadros N, Brooks L, Everall IP, Scarr E. Different changes in cortical tumor necrosis factor--
related pathways in schizophrenia and mood disorders. Molecular Psychiatry, 2013, 18(7):767-73. doi:
10.1038/mp.2012.95
Supervisor(s):
Dr Andrew Gibbons, Dr Caitlin McOmish, Prof Brian Dean
Campus:
Parkville
Contact details:
9035 6746
Email:
agibbons@unimelb.edu.au
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Projects
Mental Health - Determining whether muscarinic cholinergic receptors contribute to the
pathophysiology of Parkinsons disease.
Anticholinergic drugs and cholinesterase inhibitors have been used as adjunct therapies in Parkinsons disease to reduce
tremors/ rigidity and symptoms of dementia respectively. With the recent advances in targeting specific muscarinic receptors, it
is hoped that more effective drugs can be developed targeting muscarinic M4 receptors to alleviate the tremor/rigidity and M1
receptors to reduce the impact of cognitive decline. Therefore, it is surprising that relatively little is known about the levels of
muscarinic receptors in the brains from people with Parkinsons disease. This project will use in situ radioligand binding and
autoradiography to determine levels of muscarinic M1, M2/4 and M3 receptors in cortical (involved in cognition) and sub-
cortical (involved in fine motor control) brain regions from 10 subjects with Parkinsons disease and 10 age and sex matched
control subjects. If compounds targeting specific muscarinic receptors are to be developed for the treatment of Parkinsons
disease, it is critical that we know whether the expression of the target receptors is altered in the brains of people suffering from
the disease. This project is suitable for either an Honours or an MSc (BHS) student with research as the major. The project will
only be offered to one (1) student in 2015.
Supervisor(s):
Elizabeth Scarr; Professor Brian Dean; Professor Malcolm Horne
Campus:
Parkville
Contact details:
903 56675
Email:
elscarr@unimelb.edu.au
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Projects
Mental Health - Effect of Abeta on excitotoxic signalling pathways
The NMDA receptor (NMDAR) is a ligand-gated ion channel essential for normal synaptic function and is vital in learning and
memory processes. However, when overstimulated, NMDARs are also responsible for a cascade of toxic events, termed
excitotoxicity, which are triggered by the excessive entry of calcium into the cell through the receptor channel. Excitotoxicity is
implicated in number of neurological disorders including Alzheimers disease (AD), in which the Abeta peptide, the major
component of plaques in AD brain, has been proposed to enhance the activity of NMDARs. One consequence of excitotoxicity is
the increased release of extracellular copper which may feedback on NMDARs to reduce calcium entry to the cell. Our
laboratory works with novel compounds that modulate the copper status of cells, and which are neuroprotective in NMDAR
excitotoxicity. These compounds appear to act primarily on downstream components in the calcium-signalling pathway rather
than at the level of the NMDAR itself, such as the calpain and calcineurin system. This project will further probe the involvement
of copper in calcium-mediated excitotoxicity, and determine how Abeta intersects with downstream components of this
pathway. Skills learned will include cell culture techniques, western blotting and immunohistochemistry.
Supervisor(s):
Campus:
Parkville
Contact details:
8344 1805
Email:
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Projects
Mental Health - The role of peroxinitrite in depression
Nitric oxide (NO) is a gaseous messenger molecule involved in the regulation of signalling of a number of neurotransmitter
systems, including serotonin and dopamine, which are systems underlying the neurochemical basis of mood and emotion. NO is
also involved in cellular damage by forming the peroxynitrite (-ONOO) radical when combined with the superoxide anion,
generating oxidative and nitrosative stress in the brain. A number of studies indicate that oxidative and nitrosative stress is
implicated in neuropsychiatric disorders such as major depression. Our laboratory works with novel compounds that potently
scavenge the ONOO radical, which we have shown to be effective in animal models of Parkinsons disease, a
neurodegenerative disorder where oxidative and nitrosative stress are strongly implicated. This project will probe the
involvement of the ONOO radical in the neuropsychiatric disorder, depression, testing the hypothesis that ONOO scavenging
will positively influence depression-related behaviours in animal models of depression. The project will employ pharmacological
tools to scavenge ONOO and to probe the serotonergic neurotransmitter system. Skills learned will include an introduction to
mouse behavioural analyses used in depression research, such as the forced swim test and measures of anhedonia,
neuropharmacologial techniques to probe the serotonin system, and analyses of oxidative and nitrosative stress by Western
blotting techniques.
Supervisor(s):
Campus:
Parkville
Contact details:
8344 1805
Email:
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Projects
Mental Health - The role of tau protein in olfactory processes
The structural protein tau is implicated in a number of debilitating neurodegenerative diseases, including Alzheimers disease
and Parkinsons disease (PD). Recent literature suggest that mice deficient in tau share some similarities with PD, and indeed our
laboratorys investigations indicate that loss of tau protein increases the level of insoluble, aggregated alpha-synuclein (-syn) in
the brain. This protein is implicated in PD as a genetic cause, risk factor and the primary constituent of Lewy bodies, a
histopathological hallmark of PD that spreads across the brain with disease progression. In addition to the characteristic,
devastating impairments in the locomotor system, one of the earliest symptoms of PD is an impairment in the sense of smell
(olfaction), which may be an early predictor of PD. In this study, we will examine the olfactory phenotype of mice deficient in
tau, including behavioural examinations (odour detection, discrimination and memory) and protein biochemistry of the olfactory
bulb. The project may be expanded to include examination of olfaction and biochemistry in a tau transgenic overexpression
mouse line. Skills gained will include behavioural testing in mice and Western blotting techniques.
Supervisor(s):
Campus:
Parkville
Contact details:
8344 1805
Email:
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Projects
Mental Health - Effect of tau phosphorylation on exosome release in cell culture systems
The structural protein tau is implicated in a number of debilitating neurodegenerative diseases, including Alzheimers disease
(AD) and Parkinsons disease. Following translation of the tau gene, the tau protein is subject to a number of post-translational
modifications (PTMs), one of which, Tau hyperphosphorylation, is characteristic in AD brain. Our laboratory studies the
functional consequences of tau modifications and their potential to underlie disease processes. Our recent findings indicate that
PTMs of tau may alter the ability of the cell to traffic and remove proteins scheduled for destruction in the cell, leading to
aberrant release of these proteins in encapsulated, extracellular vesicles termed exosomes. Exosomes are a recently discovered,
alternative inter-cellular signalling system that may be hijacked to transmit pathological signals from cell to cell across the body.
This project aims to examine the effect of tau hyperphosphorylation on the release of exosomes in cell culture systems, and to
determine the potential impact of this mechanism in the propagation of pathology in the Alzheimers disease. Techniques
employed will include cell culture, the use of pharmacological tools to manipulate tau phosphorylation, Western-blotting, and
exosome extraction and characterisation using transmission electron microscopy.
Supervisor(s):
Kevin Barnham, Laura Vella
Campus:
Parkville
Contact details:
8344 1805
Email:
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Projects
Mental Health - Overcoming the sprouting limit of axons in the brain - using biomaterials for
the treatment of Parkinson's disease
Current pharmacological or surgical therapies for Parkinsons disease (PD) offer only symptomatic relief. The loss of neurons
continues inexorably until the disease reaches its conclusion. Therefore new ways are being explored to prevent ongoing
neuronal degeneration and to restore functional pathways. Cell transplantation is a potentially effective treatment strategy for
PD. However for the success of this strategy, the implanted neurons must form sufficient and appropriate synaptic connections.
A major obstacle to this success is that the adult brain does not i) provide adequate trophic support, resulting in poor
engraftment and ii) provide guidance cues that promote growth of new neuronal fibres over significant distances, to restore the
hosts neural circuitry. This project builds upon our published and preliminary data and utilises a cross-disciplinary approach,
using an injectable hybrid matrix based exclusively on FDA-approved biodegradable biomaterials. The hybrid matrix is designed
to assist implanted dopaminergic (DA) neurons to survive and bridge the nigrostriatal neural pathway in the brain, which
deteriorate as a consequence of PD. Our research project builds upon recent research findings, which demonstrate that our
novel matrix: 1) provides a favourable 3-dimensional cellular microenvironment, 2) has a minimal inflammatory footprint and
integrates seamlessly into the brain and 3) provides functional recovery when used in conjunction with DA neurons in a mouse
model of PD. We therefore seek to use our cell-matrix construct and demonstrate functional recovery in animal models.
Figure text: An injectable matrix is implanted beside the nigrostriatal tract to improve engraftment and provide axonal guidance
cues for implanted DA neurons to reach their target. The distance in mouse is 5mm, marmoset 10mm and human 30mm.
Supervisor(s):
Assoc Prof David Finkelstein
Campus:
Parkville
Contact details:
9035-6680
Email:
david.finkelstein@florey.edu.au
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Projects
Mental Health - Does early life exposure to iron represent a risk for Parkinsons disease?
Brain iron increases with age; a phenomenon that is further accelerated in Parkinsons disease. Considering the relative
impermeability of the blood-brain barrier to peripheral iron, it is unclear how and why this elevation in brain iron with age
occurs, and why it is more pronounced in Parkinsons disease. We hypothesise that key stages of brain development represent a
critical window for maintaining healthy brain iron levels, and that iron overload in these periods increases the risk of age-related
disease.
Hypotheses:
1. Early life dietary intake of iron permanently elevates the brain iron content and thereby increases susceptibility to damage in
ageing and parkinsonian neurodegeneration
2. The permanent record of early life iron exposure in teeth can be related to adult brain iron concentration.
Specific aims:
1. To obtain baseline T2* MRI imaging of brains from living patients with Parkinsons disease (PD) and relate to tooth iron
concentration.
2. To determine if early life iron exposure is correlated to the brain iron levels of the ageing brain
3. To investigate if elevated brain iron levels in PD are a consequence in part of early life exposure or an independent disease-
related event using early life dietary transitions as a marker of iron intake.
4. To investigate if neurodegeneration observed in neonatal iron feeding models represents a suitable model for idiopathic PD
that could potentially be arrested through iron chelation. 5. To investigate if metal chelation will prevent neurodegeneration.
Supervisor(s):
Assoc Prof David Finkelstein
Campus:
ParkvilleParkville
Contact details:
9035-6680
Email:
david.finkelstein@florey.edu.au
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Projects
Mental Health - Characterising a mouse model of Acrodermatitis enteropathica
A devastating, lethal genetic disease of zinc metabolism is acrodermatitis enteropathica (AE) which is caused by compromised
absorption of dietary zinc. AE symptoms develop after birth in bottle fed infants or after weaning in breast fed infants and
patients must be provided lifelong zinc supplementation or they suffer from a myriad of symptoms of severe zinc deficiency
which eventually lead to death if not treated with zinc. However, some patients are resistant to zinc supplementation and excess
zinc can affect the homeostasis of other essential metals. Utilising a conditional knockout mouse model of AE we are going t o
characterise the brain response to zinc deficits, the associated effect on learning and memory and related signalling pathways,
and the subsequent benefit that can be achieved through administration of compounds that act to normalise zinc homeostasis.
1.
Geiser et al., PLOS ONE e72543
Supervisor(s):
Paul Adlard
Campus:
Parkville
Contact details:
90356775
Email:
paul.adlard@florey.edu.au
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Projects
Mental Health - Understanding the role of metals in neurodegenerative disease
One of the broad projects within the lab involves understanding how a dyshomeostasis in metal ions (particularly zinc) may
precipitate and potentiate neurodegenerative diseases such as Alzheimer's disease and Frontotemporal dementia, as well as
other conditions such as normal age-related cognitive decline and the cellular consequences of traumatic brain injury. We use a
variety of techniques, such as in vivo mouse models (animal behavior, surgery, microdialysis, controlled cortical impact TBI
model etc), multielectrode arrays (for high throughput electrophysiology), cell culture (primary cultures, cell lines, microfluidic
cultures), synaptic RNA profiling using next generation sequencing and other more standard methodologies such as western blot
and histological work (stereological analysis using both animal and human tissues) to explore the basic biology and to also
address potential therapeutic applications in these conditions. We invite PhD candidates to come and discuss potential projects
that interest them in this space.
Supervisor(s):
Paul Adlard
Campus:
Parkville
Contact details:
90356775
Email:
paul.adlard@florey.edu.au
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Projects
Mental Health - Examining local transcriptional profiling of RNA populations in pre- and post-
synaptic terminals
This new project in the Synaptic Neurobiology lab will develop a unique and innovative technique to isolate and describe
synaptic RNA populations in isolated synapses. Localization of RNA transcripts in both axons and dendrites has been known for
some time but there are limited techniques to examine how synaptic mRNAs and noncoding RNA contribute to synaptic
function. There is also some evidence of local splicing with both the splicing factors Nova and intron containing sequences
localized to dendrites. We have recently established a novel system capable of labelling and isolating growing axons and
synapses for molecular biological analysis. We will use this technique, together with Next Gen sequencing, to profile the synaptic
transcriptome. This project will then have application to a number of different disease models used within the lab.
Supervisor(s):
Victoria Perreau and Paul Adlard
Campus:
Parkville
Contact details:
9035 4945
Email:
vperreau@unimelb.edu.au
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Projects
Multiple Sclerosis - Examining the role of neuronal activity in modulating CNS remyelination
Enhancing myelin repair is a promising avenue for the treatment of demyelinating diseases such as multiple sclerosis. This is
because failure to regenerate myelin causes irreversible axonal damage and underlies permanent neurological disability. To
understand how best to promote efficient remyelination, we need to understand the mechanisms that drive this process. This
project seeks to investigate the role that electrical activity plays in driving the remyelination program and in defining the
topographical relationship between arrays of oligodendrocytes and the populations of axons that become remyelinated.
Recently, the idea that electrical activity within axons produces a specific signal that promotes myelination has been revived
with the discovery that unmyelinated axons synapse onto OPCs. Accumulating data suggest that electrical activity within axons
in the early postnatal life promotes myelination by either enhancing OPC proliferation and/or OPC differentiation into mature
myelinating oligodendrocytes. Whether or not electrical activity is also important for driving remyelination remains unknown.
This project will directly test this idea by modulating electrical activity during the course remyelination in mice. In so doing, the
project will also examine how electrical activity influences the 3D topographical organisation of myelin using transgenic mice to
visualise the structure of newly-formed myelin.
HYPOTHESES: Modulating electrical activity within axons of the demyelinated brain influences the efficiency of remyelination.
The three-dimensional pattern of myelination generated by clonally-derived chains of interfascicular oligodendrocytes is
influenced by modulating electrical activity of axons during remyelination.
AIMS: To examine the effect of modulating the electrical activity of callosal axons upon remyelination in the cuprizone model of
demyelination. To topographically map the myelin territories generated by linear arrays of oligodendrocytes and the subsets of
axons that become remyelinated when electrical activity is modulated.
TECHNIQUES: Molecular biology, small animal surgery, animal model of demyelination, immunohistochemistry, confocal
microscopy.
Supervisor(s):
Toby Merson
Campus:
Parkville
Contact details:
9035 6535
Email:
tmerson@unimelb.edu.au
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Projects
Multiple Sclerosis - Role of innate immunity in driving axonal pathology after oligodendrocyte
death
Activation of microglia, the resident immune cells in the central nervous system, is a pathological hallmark of newly forming
multiple sclerosis (MS) lesions. The conversion of microglia from relative quiescence to an activated phenotype contributes to
demyelination and chronic MS lesion pathology. Once activated, microglia release pro-inflammatory cytokines, chemokines and
inflammatory mediators that have been shown to contribute to axonal pathology in acute and chronic demyelinating lesions. In
this project we will utilise a transgenic model of newly forming MS lesion formation to further investigate how whether blocking
microglial activation protects animals against the early effects of oligodendrocyte death. We have previously demonstrated that
treatment of mice with minocycline, a potent inhibitor of microglial activation, significantly delays symptom onset and axonal
damage. In this project we will adopt an alternate approach to investigate the role of microglia upon symptom onset and axonal
pathology. We will use a transgenic approach that enables us to specifically kill activated microglia and examine whether this
protects against secondary damage to axons.
HYPOTHESES: The rapid emergence of a pro-inflammatory M1-type microglial response following oligodendrocyte death
contributes to early axonal damage.
AIMS: Determine if blocking innate immune responses can attenuate clinical disease and axonal pathology following the
induction of oligodendrocyte apoptosis in mice. Assess the temporal profile of cytokine expression following oligodendrocyte
apoptosis.
TECHNIQUES: small animal surgery, behavioural phenotyping, gene expression analysis, immunohistochemistry, confocal
microscopy.
Supervisor(s):
Toby Merson
Campus:
Parkville
Contact details:
9035 6535
Email:
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Projects
Multiple Sclerosis - Role of alternate energy sources in overcoming oligodendrocyte
dysfunction
The disruption of neuron-glial interactions is a fundamental pathological process common to many neurodegenerative diseases.
In Multiple Sclerosis (MS), an inflammatory neurodegenerative disease of the central nervous system (CNS), the breakdown of
axon-oligodendrocyte interactions underlies demyelination and axonal degeneration. A critical new insight into early pathogenic
mechanisms has emerged from studies examining newly forming human MS lesions. These studies revealed widespread
oligodendrocyte apoptosis. These findings have provoked a complete revision of dogma by suggesting that oligodendrocyte
apoptosis could be a critical early event in MS pathogenesis and in particular, in the initiation of acute axonal degeneration.
Revolutionary studies in 2012 have revealed that oligodendrocytes provide direct metabolic support to axons by transporting
energy metabolites to the axons they myelinate. This has crystallised the perspective that oligodendrocyte apoptosis could
contribute to axonal pathology at the earliest stage of lesion development in MS. The objective of this study is to investigate
whether axonal pathology initiated by oligodendrocyte apoptosis is caused by metabolic starvation of axons depleted of
oligodendrocyte support. We will utilise a unique transgenic mouse model of inducible oligodendrocyte apoptosis MBP-DTR
mice that we recently generated to study the consequences of acute oligodendrocyte death. Oligodendrocyte apoptosis in MBP-
DTR mice causes neurological deficits and axonal pathology before overt demyelination, with evidence of microglial cell
activation but no obvious adaptive immune response. The pathology in our MBP-DTR model therefore mirrors the
histopathology of the newly forming human MS lesions. We hypothesise that oligodendrocyte death contributes to acute axonal
pathology by causing impaired energy metabolism within axons via inhibition of the transport of metabolites from
oligodendrocytes. We will attempt to circumvent this by providing additional energy metabolites to symptomatic mice and use
an in vivo overexpression system to attempt to potentiate metabolite entry into affected neurons.
HYPOTHESIS: Early axonal pathology following oligodendrocyte death is due in large part to impaired access of axons to energy
metabolites.
AIM: To determine if provision of alternate energy metabolites can attenuate axonal pathology after oligodendrocyte death and
whether this can be enhanced by ectopic transporter expression in axons.
TECHNIQUES: Molecular biology, small animal surgery, clinical assessment of disease, behavioural phenotyping,
immunohistochemistry, confocal microscopy, electron microscopy.
Supervisor(s):
Toby Merson
Campus:
Parkville
Contact details:
9035 6535
Email:
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Projects
Multiple Sclerosis - Characterising oligodendrocyte and myelin organisation in the brain after
social and/or sensory deprivation
Experience-dependent plasticity of the central nervous system (CNS) is a fundamental process for the modification of neural
networks during normal development, learning, memory and in the course of adaptation following brain injury or pathology.
Among the various mechanisms demonstrated to account for this process, synaptic pruning, non-synaptic plasticity and
postnatal neurogenesis are the best described. Most recently, the pattern of myelin formation by oligodendrocytes (OLs) had
been proposed to contribute to experience-dependent plasticity. Through insulating neurons, myelin markedly enhances both
the speed and efficiency of conduction along axons. Selective myelination of specific neural pathways could thus provide the
means to enhance conduction in an experience-dependent manner. This hypothesis is supported by the finding that myelination
in humans does not peak until the fourth decade of life and increased myelination is positively correlated with the learning of
specific cognitive and motor skills. Furthermore, in laboratory mice behavioural and cognitive deficiencies caused by social
isolation arises from impaired myelination in the medial prefrontal cortex (mPFC). Social isolation from postnatal (P) 21-35
selectively and irreversibly impairs myelination of the mPFC. This phenomenon can also occur in adult mice subjected to
prolonged social isolation but is reversed by reintroduction into group housing, presumably due to remyelination. These data
reveal that myelination is a highly dynamic process that is essential not only for establishing neural networks in development but
also contributes to brain plasticity by increasing or decreasing myelination of white matter tracts according to environmental
experience. Despite the emerging interest in myelination as an essential component of brain plasticity, there are significant gaps
in our knowledge concerning how OLs and neurons interact as groups of cells to achieve this. We have focussed our attention on
the anatomical organisation of OLs residing in myelinated axon tracts. White matter OLs exhibit a highly ordered structure in
which their cell bodies abut one another to form groups of 4-12 cells in linear arrays that align parallel to the longitudinal axis of
axons. We have demonstrated that the development of these linear OL arrays occurs at the onset of myelination. We posit that
the establishment of linear OL arrays is a critical component of activity-dependent myelination that enables co-ordinated
myelination of functionally and anatomically related axon bundles to strengthen specific neural networks.
HYPOTHESIS: Social isolation in mice inhibits myelination of the mPFC by preventing the formation of OL arrays. Re-socialising
adult mice after isolation will facilitate remyelination by de novo generation of linear OL arrays.
AIM: To assess how social isolation influences the generation of OL arrays in the mPFC during development and in adult life.
TECHNIQUES: Immunohistochemistry, confocal microscopy, electron microscopy, behavioural analysis.
Supervisor(s):
Toby Merson
Campus:
Parkville
Contact details:
9035 6535
Email:
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Projects
Multiple Sclerosis - Neural stem cell responses to close versus distant oligodendrocyte loss
Parenchymal oligodendrocyte progenitor cells (pOPCs) are considered the principal cell type responsible for oligodendrogenesis
and remyelinaton in demyelinating diseases. However recent research in our laboratory has provoked a rethink of this
commonly held view. We have demonstrated that adult neural stem/progenitor cells play a major role in the regeneration of
oligodendrocytes and myelin following CNS demyelination. Specifically, using in vivo genetic fate-mapping we have revealed that
adult neural stem cells located adjacent to white matter tracts that undergo demyelination are the predominant cell type
responsible for remyelinating these axons. A major implication of this research is that stem cells could represent a critical
untapped reserve for regeneration of myelin in the human brain. However the extent to which stem cells can respond to more
distant demyelination remains unknown. This project will take advantage of a transgenic mouse that we recently generated to
specifically kill oligodendrocytes in the adult brain. The project will involve stereotaxic injection of oligodendrocyte toxin into
various white and gray matter regions at different distances from the subventricular zone. The aim will be first to define the
whether there exists a maximal distance from which stem cells can respond to distal demyelination. Second, we will combine
localised oligodendrocyte ablation with the provision of a stem cell mobilising growth factor to attempt to potentiate the extent
to which neural stem cells contribute to remyelinating distal sites of demyelination. Collectively these approaches will provide a
basis to test the hypothesis that therapeutic strategies seeking to mobilise neural stem cells for repair of distal demyelination
are feasible. This research could translate to novel stem cell based therapies for Multiple Sclerosis and other myelin pathologies.
HYPOTHESIS: The ability of neural precursors to migrate to lesions depends upon proximity to the subventricular zone and the
exogenous cues to which they are exposed.
AIMS: To examine the maximal distance of a demyelinating injury to which neural precursor cells can respond. To attempt to
potentiate responsiveness by provision of a stem cell mobilising growth factor.
TECHNIQUES: Small animal surgery, stereotaxic brain injection, immunohistochemistry, confocal microscopy, electron
microscopy, use of transgenic mice.
Supervisor(s):
Toby Merson
Campus:
Parkville
Contact details:
9035 6535
Email:
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Projects
Neurodegeneration Understanding autism
Our group aims to understand the cause of autism and to discover the treatment/s for Autism. This could be achieved by
understanding the neural circuit involves in social interaction and communication. We will utilise transgenic mice, behavioural
studies, immunohistological techniques, epigenetics and molecular biology.
Supervisor(s):
Wah Chin Boon
Campus:
Parkville
Contact details:
90356759
Email:
wah.chin.boon@florey.edu.au
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Projects
Neurodegeneration - Mechanisms of dopamine phenotype plasticity in adult midbrain neurons
Evidence is emerging that the neurotransmitter used by some adult neurons is regulated by the environment, and that this has
behavioral consequences for the animal; a novel form of brain plasticity. Our laboratory has discovered this is true for midbrain
dopamine neurons, which are affected in Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder, and drug
addiction, among others. So far we have shown exposing mice to certain environments for 1-2 weeks increases or decreases the
number of midbrain dopamine neurons, that this is dependent on neuronal activity, and that it affects their ability to learn new
behaviors. We now wish to learn more about this including the identity of midbrain neurons that can up- or down-regulate
dopamine synthesis, why they do this, how they do this, and what are the downstream consequences on midbrain dopamine
signaling and brain function. The significance of this research is it may lead to new treatments for these diseases and disorders,
including those that are environment-based (i.e. drug-free), as well as drug-based, once we identify molecular mechanisms of
midbrain dopamine phenotype plasticity. There are a number of honors and PhD projects available as part of this research.
1.
2.
3.
4.
5.
Aumann T, Horne M. Journal of neurochemistry. 2012;121(4):497-515. Epub 2012/02/24.

Aumann TD, Egan K, Lim J, et al. Journal of neurochemistry. 2011;116(4):646-58. Epub 2010/12/21.
Aumann TD, Gantois I, Egan K, et al. Experimental neurology. 2008;213(2):419-30. Epub 2008/08/06.
Dulcis D, Jamshidi P, Leutgeb S, et al. Science. 2013;340(6131):449-53. Epub 2013/04/27.
Aumann TD, Tomas D, Horne MK. Brain and behavior. 2013;3(6):617-25. Epub 2013/12/24.
Supervisor(s):
Tim Aumann
Campus:
Parkville
Contact details:
90356705
Email:
taumann@unimelb.edu.au
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Projects
Neurodegeneration - Bioengineered 3D astrocytes to reveal healthy biology and
neurotherapeutic targets
Are Astrocytes are the most important cells in the mammalian brain? They are not just housekeeping cells; Outnumber
neurons (60% of total cells) ; Maintain the integrity of blood-brain-barrier; Support tight junction formation; Provide energy
substrates to neurons; Remove toxic L-glutamate; Release L-glutamine for neuronal synthesis of L-glutamate; Release
gliotransmitters; ynthesise and release BDNF/GDNF; Site of major anti-oxidant activity in brain
And this is healthy brain! They are even more important in pathologies? A revolution is underway in our understanding of
astrogliosis researchers now believe astrocytes can be recruited to display a good (i.e. healthy) rather than bad phenotype
in the inflammatory milieu of reactive gliosis. Using a unique experimental model (3D astrocytes) we have defined this healthy
phenotype as possessing elevated L-glutamate (Glu) transport, BDNF and anti-oxidant activities, and stellated morphology
reminiscent of in vivo. We are the FIRST GROUP INTERNATIONALLY to achieve long-term culture of mature astrocytes in 3D
(Journal of Neurochemistry (2014) 130: 215-26), giving us a unique opportunity to advance astrocyte biology! We contend the
failure to manage inflammation in neuropathologies has been a shortcoming in our understanding of molecular signatures
governing astrocyte health. Thus whilst we have the signposts of a healthy astrocyte, we shall use our 3D astrocytes to fully
elucidate the mechanisms governing promotion of this healthy phenotype and to identify neurotherapeutic targets beneficial in
diverse pathologies. Aim: To elucidate the mechanisms altering astrocytic morphology and biology, and hence determining
astrocytic health. Techniques involved: Primary culture; Use of bioengineered scaffolds; Immunocytochemistry; Confocal
microscopy; Western blotting; Proteomics; Bioinformatics
1.
2.
3.
3D Electrospun scaffolds promote a cytotrophic phenotype of cultured primary astrocytes. Lau CL, Kovacevic M, Tingleff
TS, Forsythe JS, Cate HS, Merlo D, Cederfur C, Maclean FL, Parish CL, Horne MK, Nisbet DR, Beart PM. J Neurochem. 130:
215-26 (2014).
Transcriptomic profiling of astrocytes treated with the Rho kinase inhibitor fasudil reveals cytoskeletal and pro-survival
responses. Lau CL, Perreau VM, Chen MJ, Cate HS, Merlo D, Cheung NS, O'Shea RD, Beart PM. J Cell Physiol. 227: 1199-
211 (2012).
The Rho kinase inhibitor Fasudil up-regulates astrocytic glutamate transport subsequent to actin remodelling in murine
cultured astrocytes. Lau CL, O'Shea RD, Broberg BV, Bischof L, Beart PM. Br J Pharmacol. 163: 533-45 (2011).
Supervisor(s):
Prof Philip Beart & Dr Linda Lau
Campus:
Parkville
Contact details:
8344-7324
Email:
philip.beart@florey.edu.au
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Projects
Neurodegeneration - The role of Co in brain health and disease
Cobalt is an essential micronutrient that acts as a cofactor in a number of neurologically important metalloproteins and small
molecules. We have recently found that there is a perturbation in the levels of cobalt and other biometals following traumatic
brain injury (TBI) in humans and a number of acute brain injury animal models. This project will use a metalloproteomic
approach to determine the precise cobalt-binding species that is responsible for this alteration in brain cobalt levels following
TBI. Specifically, this project will use multidimensional chromatography and a range of mass spectrometry approaches to isolate,
characterise and quantify the protein or proteins associated with cobalt dyshomeostasis, and to determine if this effect is due to
either disrupted cobalt brining or altered protein expression. Additionally, this project will examine if this perturbation in cobalt
levels is reflected in the periphery, and if so, the possibility of a rapid field-test for TBI via cobalt assay.
1.
Metalloproteomics: principles, challenges, and applications to neurodegeneration. Lothian et al. Frontiers in Aging
Neuroscience, Vol 5, 35:1-7, 2013.
Supervisor(s):
Blaine R. Roberts, Dominic Hare, Colin Masters
Campus:
Parkville
Contact details:
390356635
Email:
blaine.roberts@florey.edu.au
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Projects
Neurodegeneration - Astrocyte Regulators of Synaptic Plasticity in the Adult Central Nervous
System
Astrocytes are thought to play a key role in regulating synaptic plasticity within the central nervous system (CNS). Decorin is a
small leucine-rich proteoglycan expressed by neurons, astrocytes and many other cell types throughout the body. The Davies lab
has recently shown that infusion of Decorin can promote synaptic plasticity and functional recovery in pre-clinical spinal cord
injury models. Therefore, my proposed thesis project is to investigate whether Decorin can promote expression and secretion
of synaptogenesis regulators by astrocytes and their roles in supporting synaptic plasticity in the adult CNS.
Supervisor(s):
Geoffery Donnan, Stephen Davies
Campus:
Parkville
Contact details:
N/A
Email:
yeompyo.lee@florey.edu.au
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Projects
Neuropeptides - Neuromodulatory control of complex behaviour - focus on ascending
peptidergic networks
Our laboratory is part of the Neuropeptides Division of The Florey Institute of Neuroscience and Mental Health and our research
is in the broad area of systems neuroscience. Our main research interest is in the role of neuropeptide signalling in the control of
complex behaviours such as arousal, stress and mood, and associated cognitive and memory processes under normal and
neuropathological conditions. We are researching the neurobiology of the relaxin-3/RXFP3 (peptide-receptor) system in brain,
as well as the role of the neural network driven by an area known as the nucleus incertus. Senior scientists in the laboratory
offer a range of distinct research projects that involve studies in experimental animal models of health and psychiatric disease
(in normal and transgenic mice), using a range of biomolecular tools, including receptor-selective peptides and viral-vector
delivered - neural tracing molecules, receptor-targeting peptides, DREADDs (designer receptors exclusively activated by
designer drugs) or optogenetic, light-activated channelrhodopsins.
The different projects are suitable for Honours or PhD students and are detailed below.
Project 1 - Relaxin-3/RXFP3 signalling in limbic networks in emotional and social behaviour in mice transgenic and viral
pharmacogenetic studies The neuropeptide relaxin-3 is expressed by GABA neurons in the nucleus incertus (NI) and these
neurons innervate and modulate neural circuits that regulate stress- and arousal-related motivated or goal-directed
behaviours. These neurons appear to target and inhibit mostly GABA neurons in the limbic brain (i.e. GABA cells expressing
RXFP3) and likely regulate amygdala and frontal cortex circuits that control emotional and social behaviours, including fear and
anxiety, social recognition and/or aggression, as well as associated cognitive processes [1-5]. In this project, we are employing
molecular tools and techniques, and transgenic mouse strains to determine the effect of NI (and relaxin-3/RXFP3) activity on
anxiety, social and other behaviours. We are using excitatory and inhibitory DREADDs [6] delivered into the brain using viral
vectors to regulate the activity of target neurons. Mice undergo testing in specific validated assays of behaviour; and the effects
of excitatory or inhibitory DREAAD activation in NI neurons by peripheral injection of the designer ligand, clozapine-N-oxide
(CNO) are assessed using state-of-the-art equipment and video analysis. Studies are also examining the effect of relaxin-3 and
RXFP3 gene deletion on these behaviours and whether centrally-injected RXFP3 agonist or antagonist peptides alter responses
in anxiety and social recognition tests. Effects of DREADD and peptide receptor activation on brain activity patterns are assessed
using neurochemical assays and quantitative measures of gene expression. These studies will help reveal the role of nucleus
incertus circuits and relaxin-3 transmission in the modulation of affective behaviour and be extended to studies in genetic
models of social, cognitive and other deficits seen in psychiatric illnesses. Students will receive training in neurochemical
anatomy, physiology and behaviour and techniques including stereotaxic surgery for peptide and viral delivery; behavioural
assays and analysis; mRNA/peptide/protein analysis; and light/confocal microscopy.
1.
2.
3.
4.
5.
6.
Ma S et al. (2007) Neuroscience 144: 165-190

Smith CM et al. (2010) J Comp Neurol 518: 4016-4045
Ryan PJ et al. (2011) Neurosci Biobehav Rev 35: 1326-1341
Smith CM et al. (2011) J Chem Neuroanat 42: 262-275
Ma S et al. (2013) J Physiol (Lond) 591: 3981-4001
Krashes MJ et al. (2011) J Clin Invest 121: 1424-1428
Project 2 - Relaxin-3/RXFP3 signalling in control of behavioural state - arousal and related behaviours in mice Sleep and
wakefulness are controlled by brain circuits referred to as arousal pathways. These pathways facilitate heightened awareness,
attention and cognition, and are also implicated in reward signals associated with food- and drug-seeking behaviour.
Established arousal systems include serotonin neurons in the raph nuclei and dopamine neurons in the ventral tegmental area,
and orexin peptide neurons in lateral hypothalamus [1,2]. Anatomical and functional studies suggest relaxin-3 neurons in
nucleus incertus (NI) and periaqueductal grey (PAG) represent an arousal pathway that modulates a range of behaviours such as
feeding, attention, motivation and exploratory behaviour [3-8]. Mice genetically lacking relaxin-3 display a circadian hypoactivity
and may represent a model for aspects of clinical depression [4-7]. Therefore, the brain relaxin-3/RXFP3 system represents a
potential target for drugs to treat conditions such as insomnia, anorexia, obesity, drug abuse and depression. These studies
utilise unique mouse strains, including conditional RXFP3 knockout (KO) and RXFP3-Cre reporter lines, highly selective relaxin-3
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Projects
receptor (RXFP3) agonist and antagonist peptides and viral-driven peptide vectors, and state-of-the-art equipment and
behavioural paradigms to determine the behavioural effects of relaxin-3 and RXFP3 deficiency. Relaxin-3 and RXFP3 KO mice
have been shown to display hypoactivity in novel environments and other characteristics of mood disturbances. These mice and
a new conditional RXFP3 KO will be characterised by testing their performance versus wild-type littermates on running wheels,
and by measuring 24 h sleep/wake patterns and motivated and mood related behaviours. We will also conduct assessments of
the baseline responses of the conditional RXFP3 KO mice in a range of behavioural tests to identify any new phenotypes
associated with deletion of the receptor in adulthood. The ability of acute or chronic central RXFP3 activation to rescue
behavioural alterations in relaxin-3 KO mice can also be determined using acute central injections of an RXFP3 agonist peptide
and/or a viral-driven RXFP3 agonist peptide.
1.
2.
3.
4.
5.
6.
7.
8.
9.
Fuller PM et al. J Biol Rhythms 21 (2006) 482-493

Sakurai T. Nature Rev Neurosci 8 (2007) 171-181
Gundlach AL et al. Ann NY Acad Sci 1160 (2009) 226-235
Smith CM et al. Ann NY Acad Sci 1160 (2009) 236-241
Smith CM et al. J Comp Neurol 518 (2010) 4016-4045
Smith CM et al. J Chem Neuroanat 43 (2011) 262-275
Smith CM et al. Genes Brain Behav 11 (2012) 94-104
Blasiak A et al. Eur J Neurosci 37 (2013) 1284-1294
Ryan PJ et al. Proc Natl Acad Sci USA 110 (2013) 20789-94

Projects 1 and 2 figures.
Project 3 - Role of relaxin-3 neurons and RXFP3 signalling in fear memory and stress-related cognitive dysfunction in rat brain
Anxiety disorders are one of the most prevalent mental illnesses in society and include generalized anxiety-, phobic-, panic- and
post-traumatic stress- disorders (PTSD). Research has identified a core feature of anxiety disorders is impairment of fear
memory extinction or safety learning. Relaxin-3 and its receptor, RXFP3 are present in brain regions associated with stress and
fear behaviour, and the relaxin-3/RXFP3 network is involved in behavioural activation, arousal and cognition. Stress strongly
activates relaxin-3 neurons and increases relaxin-3 gene expression. We have observed that central RXFP3 activation in the
amygdala, a brain region critical for fear memory and extinction, significantly reduced fear behaviour in rats and reduced
memory of the fear the following day. Our current research is extending the investigation of relaxin-3/RXFP3 effects on fear
memory by examining the impact of stress on the relaxin-3/RXFP3 system in a rodent model of chronic stress and anxiety,
comparable to human anxiety and PTSD. The project involves fear conditioning studies in rats and provides training in
stereotaxic surgery, animal handling, behavioural testing (fear conditioning) and analysis, and advanced histology techniques.
1.
2.
3.
Ma S et al. (2007) Neuroscience 144: 165-190

Ma S et al. (2009) Learn Mem 16: 730-742
Banerjee A et al. (2010) Neuropharmacology 58: 145-155
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Projects
4.
5.
6.
7.
Smith CM et al. (2011) J Chem Neuroanat 42: 262-275

Ehrlich I et al. (2009) Neuron 62: 757-771
Ma S et al. J Physiol (Lond) 591 (2013) 3981-4001
Ryan PJ et al. Proc Natl Acad Sci USA 110 (2013) 20789-94

Project 3 figures.
Project 4 - Functional topography of serotonin (5-HT) and peptide (relaxin-3) systems in the control of anxiety-like behaviour
Anxiety disorders are a major health issue and it is thought that dysfunction of brain stress pathways underlie their pathology.
Further research is required to better understand the nature of normal neurotransmission associated with innate anxiety and
stress responses to provide insights into psychiatric illness. The monoamine transmitter, serotonin (5-HT) and the peptide,
corticotropin-releasing factor (CRF) have recognised roles in the control of stress and anxiety and recent studies indicate that
relaxin-3 signalling may also be involved. Therefore, these studies are assessing the anatomical and functional relationship of
neural networks that utilise serotonin, CRF and relaxin-3 as neuromodulatory transmitters and their possible interactive role in
controlling innate anxiety-like behaviour. Previous studies have determined the neuroanatomical distribution of groups of
serotonin-containing neurons in the various raphe nuclei and major groups of relaxin-3 containing neurons in distinct
populations of GABA neurons in the nucleus incertus (NI) and periaqueductal grey (PAG) and the likely separate functions of
subgroups of these 5-HT and relaxin-3 neurons and their regulation by stress. These studies will help identify structural and
functional interactions between separate components of two ascending modulatory networks that regulate sensorimotor
behaviours and associated cognitive processes, including arousal and motivation, feeding and metabolism, biorhythms, and
emotional responses such as fear and anxiety in health and disease and will lay the foundation for pharmaco- and optogenetic
analysis of topographic relaxin-3 and 5HT pathways.
1.
2.
3.
4.
5.
6.
7.
Ma S et al. Neuroscience 144 (2007) 165-190

Smith CM et al. J Comp Neurol 518 (2010) 4016-4045
Smith CM et al. J Chem Neuroanat 42 (2011) 262-275
Ryan PJ et al. Behav Brain Res 244 (2013) 142-151
Hale MW, Lowry CA. Psychopharmacology (Berl) 213 (2011) 243-26
Hale MW et al. Neuroscience 157 (2008) 733-748
Kelly KJ et al. Neuroscience 197 (2011) 251-268
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Projects
Project 5 - Additional Research Projects (under development) In collaboration with other scientists and laboratories within the
Neuropeptides and other Florey Divisions and international laboratories in Europe, we continue to develop new molecular tools
and assays and survey additional animal models of physiology and pathology to probe the nature of brain relaxin-3/RXFP3 and
their interactions with other related neurotransmitter and neuromodulatory systems. These include the development of specific
promoter sequences to facilitate the targeting of particular neuron populations, studies of mouse models of neurodegeneration,
maternal/aggressive behaviour, and descending control of chronic pain; and assays to assess synaptic plasticity and
neurochemical alterations in response to altered RXFP3 signalling. We are also working with staff of the Florey Bioinformatics
platform to produce new insights into possible genetic links between relaxin-3 systems and neurodegenerative and psychiatric
disease.
Supervisor(s):
Andrew L Gundlach
Campus:
Parkville
Contact details:
9035 6507
Email:
andrew.gundlach@florey.edu.au
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Projects
Neuropeptides - Developing peptidomimetics of insulin-like peptide 5, a novel orexigenic gut
hormone, to target its GPCR, RXFP4
Obesity has been termed a worldwide epidemic by the World Health Organisation (WHO). Conversely, anorexia and cachexia
are significant health problems that cause high mortality. Our collaborators and we have identified insulin-like peptide 5 (INSL5)
as a novel orexigenic gut hormone which promotes appetite during conditions of energy deprivation. It is only the second
orexigenic hormone to be discovered after ghrelin. Its G-protein coupled receptor, RXFP4, is thus a potentially very important
therapeutic target for treating human conditions with reduced food intake, whereas an RXFP4 antagonist may be of therapeutic
use for the treatment of obesity. In a significant achievement, we recently developed a simplified INSL5 analogue with potent
agonist actions at RXFP4. This peptide, we named Analogue 5, has just two disulfide bonds (compared with three for INSL5) and
is thus easier to assemble in large quantity to validate the target in animal models. We now propose to minimize and simplify
this peptide further to produce a small "drug-like" structure having potent activity. To minimize the structure, we will
sequentially truncate this peptide from the N-terminus of the B-chain. We will determine the activation domains by structure-
activity relationship studies and then replace or truncate those domains in order to achieve an antagonist. In addition, we will
aim to develop single chain RXFP4 agonist or antagonist by using stapling (click chemistry/dicarba technology). These novel
peptides will undergo comprehensive pharmacological and structural characterisation in order to confirm their native peptide-
like activity and structures. These minimized peptides will be attractive and very important pharmacological tools for studying
the physiological role of the INSL5/RXFP4 system in preclinical animal models. In addition, they can be developed as candidate
therapeutic entities: as agonists or antagonists of RXFP4 with potential uses in treating human conditions such as anorexia a nd
obesity.
Supervisor(s):
Dr Akhter Hossain, Dr Julien Tailhades, Prof John Wade
Campus:
Parkville
Contact details:
61425791473
Email:
akhter.hossain@florey.edu.au
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Projects
Neuropeptides - Developing novel chemical methods to produce insulin mimetics
Central to the successful clinical use of new and improved insulin analogues is the availability of efficient methods to prepare
them in high overall yield and purity. Previous chemical methods reported in the literature for stepwise disulfide bond formation
for insulin assembly require special conditions such as harsh chemical reagents or enzymes that can modify some sensitive
amino acid residues leading to lower yields. We have developed a novel procedure, where one of the three disulfide
connections in insulin is formed in aqueous media by irradiation with light resulting in significantly improved overall yield.
However, this method can further be improved. Our team will focus on advancing current photochemistry knowledge to develop
new ways of making two or all three disulfide bonds in insulin under ambient conditions. We will use this improved method for
developing novel insulin analogues with better pharmacokinetic properties. Native human insulin, for example, suffers from a
short survival time in blood. Longer acting insulin analogues (such as Lantus and Levemir) have recently become available, but
they have side effects. Lantus, for example, causes a pathological condition called injection amyloidosis. Therefore,
development of longer acting but soluble and non-amyloidogenic form of insulin is highly desirable. Our team aims to efficiently
synthesize soluble, non-fibrilogenic and more stable insulin analogues for future clinical evaluation. More specifically, chemical
synthesis of insulin and analogues will be achieved by using wavelength-selective orthogonality. We will engineer non-
fibrilogenic insulin analogues by site-specific glycosylation to slow down liver-mediated decomposition. Pre-clinical evaluation of
insulin analogues will be tested both in vitro (cell based assay) and in vivo (animal models).
Supervisor(s):
Campus:
Parkville
Contact details:
61425791473
Email:
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Projects
Neuropeptides - Developing small peptidomimetics to target RXFP1 for the treatment of acute
heart failure
Florey patented H2 relaxin was recently granted a breakthrough therapy designation by the FDA for the treatment of acute
heart failure. The indications are that H2 relaxin will enter the clinic soon by next couple of years. It is likely that the beneficial
effects of H2 relaxin were also related to its anti-fibrotic effects, which we have shown occurs rapidly and independently of the
cause of disease. This project aims to improve this current drug and develop the next generation molecule.
In order to maximize its future translational potential, we will address the three following issues:
1. Large size and complex structure: The size (53 amino acids) and complex structure (two chains, linked by three disulfide
bonds; Fig. 1) of H2 relaxin represent a considerable challenge for its synthesis; limiting modifications of the peptide to optimize
its efficacy and stability.
2. Cross-reactivity with other receptors: H2 relaxin exerts its biological actions through its cognate receptor, Relaxin Family
Peptide Receptor 1 (RXFP1; initially discovered as LGR7). However, it also activates RXFP2, the native receptor for the related
insulin-like peptide 3, INSL3; opening the possibility of potential side-effects through RXFP2-mediated physiological processes.
3. Short half-life in blood: Like insulin, H2 relaxin has a very short half-life. Hence, when injected into patients, H2 relaxin will
lose half its activity within 10 minutes because it is degraded by blood enzymes and cleared by the kidney and liver.
Thus, there is an urgent need to develop simpler H2 relaxin analogues that are easier to prepare and modify, have high
selectivity for RXFP1 and retain their activity for an extended therapeutic time-frame in patients with acute heart failure. A
considerable effort has been made to reduce H2 relaxin into developing a single chain analogue with RXFP1-specific agonist
activity. As the B-chain of H2 relaxin seems to possess most, if not all, of the amino acids responsible for RXFP1 binding and
activation, it was probable that a B-chain-only analogue would be active at RXFP1. Preliminary single-chain analogues (such as
native B-chain, B1-29) were found to be insoluble (Fig. 1B) and inactive over the years, but, very recently, in an exciting finding
we have identified an N-terminus-truncated and C-terminus-extended B-chain analogue (B7-33) (Fig. 1A), which was found to be
soluble in water (Fig 1B), binds to RXFP1 (data now shown) and acts as an agonist in over-expressing RXFP1 cells, albeit with less
potency compared with native H2-relaxin (Fig 1C). However, unlike H2 relaxin, B7-33 is selective at RXFP1 over RXFP2 (data
not shown), and demonstrates similar activity to H2 relaxin in cells natively expressing RXFP1 in vitro (in rat renal myofibrobalst
cells, Fig. 1D) and in models of diseases in vivo (Isoproterenol ISO-induced heart fibrosis model Fig. 1E; Ovalbumin OVA-induced
lung fibrosis model Fig. 1F, G). The B7-33 peptide provides us with a great starting point for further development as small
peptidomimetic agonists of RXFP1. The peptide "B7-33", however, is less potent compared with native H2 relaxin. This proposal
focuses on the utility of this lead compound as the basis for its further modification to improve its potency as well as in vivo
stability. We will improve the structures, stability and potency of single chain "B7-33" analogue by using rational and structure-
based drug design, point mutations with natural, non-natural, isometric amino acids, dicarba stapling, combinatorial library and
lipidation.
Supervisor(s):
Campus:
Parkville
Contact details:
61425791473
Email:
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Projects
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Projects
Neuropeptides - Engineering improved fluorescent proteins for imaging and proteomics.
Fluorescent proteins (FPs) such as green fluorescent protein (GFP) and red fluorescent proteins (e.g. mCherry) are widely used to
visualise cells or proteins of interest with microscopy in animal tissue sections and whole brain preparations. Tissues are usually
fixed with chemicals such as aldehydes or alcohols, which preserve the tissue architecture but denature proteins, leading to a
loss in the fluorescence of FPs. We have used directed evolution to rapidly generate ultra-stable GFP mutants that are resistant
to denaturation and thus remain highly fluorescent after exposure to fixatives. Such FPs offer huge advantages for fluorescence
imaging and protein biochemistry. In this project the same process will be applied to mCherry to generate red FPs that are
resistant to fixatives and detergents. Engineered proteins will then be tested in several imaging and biochemical paradigms to
prove their utility. Students will be trained in techniques including fluorescence microscopy, directed evolution, CHESS, protein
expression and purification, robotic fluorescence assays, fluorescence activated cell sorting (FACS), cell culture and potentially
protein crystallization. Ultimately this project will provide new tools for researchers to use for highly sensitive fluorescence
imaging of tissue sections and whole brains.
1.
Scott DJ, Plckthun A, Direct molecular evolution of detergent stable G protein-coupled receptors using polymer
encapsulated cells, Journal of Molecular Biology, 2013 Feb; 425(3):662-667.
Supervisor(s):
Dr Daniel Scott
Campus:
Parkville
Contact details:
90357584
Email:
daniel.scott@florey.edu.au

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Projects
Neuropeptides - Drug discovery targeting 1-adrenoceptors (1-ARs)
1A- and 1B-adrenoceptors (1A-AR and 1B-AR) are critical receptors that modulate the nervous system in response to
binding adrenaline and noradrenaline, and are currently targeted by hypertension drugs. Chronic activity of these receptors can
be either damaging or protective to heart and brain function and evidence suggests that these opposing responses are mediated
by individual receptor subtypes. 1-ARs are the most abundantly expressed adrenoceptors in the CNS, where they serve as
stimulatory receptors in post synaptic cell bodies. Stimulation of 1-ARs in these cells serves to increase the excitatory potential
of glutamate and acetylcholine and to prime excitatory synapses. Transgenic mice have been used to demonstrate that 1A-AR
and 1B-AR mediate opposing responses to noradrenaline release in the CNS. Whereas 1A-AR activation is antiepileptic,
constitutive activation of 1B-AR is pro-epileptic. Similarly, 1A-AR stimulation increases neurogenesis whereas prolonged 1B-
AR stimulation is neurodegenerative. The lack of subtype selective ligands makes the validation of these receptors as genuine
targets for treating epilepsy, Parkinsons disease and Alzheimers disease difficult. We have engineered thermostabilized 1A-AR
and 1B-AR proteins that have enabled us to probe and compare the protein structures of these receptors. Furthermore we are
able to conduct novel drug screening campaigns to identify subtype selective 1-AR compounds. In 2015, projects will be
offered focused on identifying new 1-AR binding compounds with fragment screening as a starting point for structure based
drug design. Students will be trained in techniques including protein structure analysis, computational ligand docking, protein
expression and purification, robotic ligand binding assays, cell-based GPCR assays, nuclear magnetic resonance spectroscopy and
pharmacological analysis. Ultimately, new 1-AR binding compounds may prove to be promising drug candidates for treating
epilepsy and neurodegenerative diseases.
1.
2.
3.
4.
5.
Scott, D. J., Kummer, L., Egloff, P., Bathgate, R. A. & Pluckthun, A. Improving the apo-state detergent stability of NTS1
with CHESS for pharmacological and structural studies. Biochim Biophys Acta, In Press, (2014).
Egloff, P., Hillenbrand, M., Klenk, C., Batyuk, A., Heine, P., Balada, S., Schlinkmann, K. M., Scott, D. J., Schutz, M. &
Pluckthun, A. Structure of signaling-competent neurotensin receptor 1 obtained by directed evolution in Escherichia coli.
Proc Natl Acad Sci U S A 111, E655-662, (2014).
Yong, K. & Scott, D. J. Engineering Stabilised G Protein-coupled Receptors for Biochemical and Structural Studies, in
Australian Biochemist Vol. 44 (2013).
Scott DJ, Kummer L, Tremmel D, Plckthun A, Stabilizing membrane proteins through protein engineering, Current
Opinion in Chemical Biology, 17, 427-435.
Supervisor(s):
Dr Daniel Scott and A/Prof. Paul Gooley (Dept. of Biochemistry and molecular biology)
Campus:
Parkville
Contact details:
90357584
Email:
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Projects
Neuropeptides - Designing allosteric modulators of the neurotensin receptor 1 (NTS1) as
potential drugs for schizophrenia.
Neurotensin (NT) is a 13-residue peptide expressed in the central nervous (CNS) gastro-intestinal and cardiovascular systems. NT
acts as a neuromodulator of classical neurotransmitters such as dopamine and glutamate in the mammalian CNS by activating
the G protein-coupled receptor (GPCR) NTS1. Preclinical studies have demonstrated a remarkable similarity between the
behavioural effects of centrally administered NT and peripherally administered antipsychotics. Brain NT concentrations are
increased following antipsychotic treatment and untreated schizophrenia patients have been shown to have low cerebrospinal
levels of NT. Thus NTS1 agonists, or positive allosteric modulators to enhance endogenous NT signalling, are considered to have
potential for the treatment of schizophrenia, which affects approximately 1% of the US and Australian populations. Using our
engineered NTS1 proteins, we have identified an allosteric binding site in NTS1 which plays an important role in receptor
activation by NT. Using structure based drug design, ligands that bind to this allosteric site will be conceived and tested for
allosteric activity on NTS1 expressing cells. Students will be trained in techniques including protein structure analysis,
computational ligand docking, protein expression and purification, robotic ligand binding assays, cell-based GPCR assays, nuclear
magnetic resonance spectroscopy and pharmacological analysis. Ultimately, allosteric modulators of NTS1 may prove to be drug
candidates for treating schizophrenia.
1.
2.
3.
4.
5.
Scott, D. J., Kummer, L., Egloff, P., Bathgate, R. A. & Pluckthun, A. Improving the apo-state detergent stability of NTS
with CHESS for pharmacological and structural studies. Biochim Biophys Acta, In Press, (2014).
Egloff, P., Hillenbrand, M., Klenk, C., Batyuk, A., Heine, P., Balada, S., Schlinkmann, K. M., Scott, D. J., Schutz, M. &
Pluckthun, A. Structure of signaling-competent neurotensin receptor 1 obtained by directed evolution in Escherichia coli.
Proc Natl Acad Sci U S A 111, E655-662, (2014).
Yong, K. & Scott, D. J. Engineering Stabilised G Protein-coupled Receptors for Biochemical and Structural Studies, in
Australian Biochemist Vol. 44 (2013).
Scott DJ, Kummer L, Tremmel D, Plckthun A, Stabilizing membrane proteins through protein engineering, Current
Opinion in Chemical Biology, 17, 427-435.
Supervisor(s):
biology)
Dr Daniel Scott, A/Prof. Ross Bathgate, A/Prof. Paul Gooley (Dept. of Biochemistry and molecular
Campus:
Parkville
Contact details:
90357584
Email:

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Projects
Neuropeptides - Studies on G protein-coupled receptors; structure, function and drug
development
The largest single class of drug targets is the G Protein-Coupled Receptor (GPCR) family, which were targets for 13 of the top 50
prescription drugs sold in the U.S.A. in 2010 (26%). Modern GPCR drug development is encumbered by a lack of information
about the molecular structure underlying GPCR function and the reliance on cell-based assays that are prone to false positives in
drug screening. The fundamental importance of GPCRs is highlighted by the 2012 Nobel Prize in Chemistry awarded to Kobilka
and Lefkowitz for their research into the molecular mechanisms of GPCR function. Our group uses a multidisciplinary approach
to study GPCR function and is targeting numerous important GPCRs for drug development.
One class of receptors we are studying are the relaxin family peptide receptors RXFP1-4. The ligands for these GPCRs are the
peptides relaxin (RXFP1), insulin-like peptide 3 (INSL3) (RXFP2), relaxin-3 (RXFP3), and INSL5 (RXFP4). Relaxin is a hormone and
growth factor that induces its effects by regulating collagen turnover, stimulating tissue growth and angiogenesis and inducing
blood vessel dilatation. It recently passed a successful Phase III clinical trial for the treatment of acute heart failure being
performed by Novartis (Switzerland). INSL3 is essential for germ cell maturation and drugs targeting its receptor RXFP2 have
considerable potential as fertility regulators in both males and females. INSL5 is a gut hormone that has potential roles in
appetite regulation and we are working with Takeda Cambridge to develop compounds targeting its receptor RXFP4 which may
be useful for treating feeding disorders. Relaxin-3 is a specific neuropeptide which our laboratory recently discovered and has
potential roles in regulating behaviours which are perturbed in mental illnesses including anxiety, depression, sleep disorders,
and memory deficits. Hence drugs targeting the relaxin-3 receptor RXFP3 may be potential therapeutics to treat these mental
illnesses. We are working with pharmaceutical industry partners (eg. Takeda and Novartis) to determine the biological roles of
the peptides and to develop drugs targeting their receptors.
We are using various molecular and pharmacological techniques to map the native ligand binding sites of these receptors and
determine the mechanisms of receptor activation as well their cell signalling characteristics. A complete understanding of the
mechanism of ligand binding and activation is required to design drugs targeting these receptors. Furthermore in collaboration
with Dr Daniel Scott and A/Prof Paul Gooley (Bio21) we are utilizing various biochemical techniques to study the receptor
structures. The ability to probe these receptors using biochemical and structural approaches enhances our understanding of
how they function and will lead to the discovery and optimisation of novel therapeutics. We are therefore studying ligand
interactions with receptor domains using soluble protein constructs and NMR. Additionally, we are one of the only laboratories
in the world using protein engineering techniques to generate stabilised GPCRs that can be readily applied to standard
biochemical methods after they have been removed from the cell membrane (see Projects from Dr Daniel Scott). We are using
these stabilised receptors to probe the structure and dynamics of GPCRs with X-ray crystallography and NMR as well as protein
interaction analysis and screening to investigate how these receptors bind to natural ligands and drugs.
Project Overview
Honours, Masters and PhD projects are available to study the molecular pharmacology of these novel GPCRs. Candidates will
undergo training in various techniques including molecular cloning, site-directed mutagenesis, cell biology, cell signalling,
protein chemistry, protein engineering, fluorescence activated cell sorting (FACS) and confocal microscopy.
1.
2.
3.
4.
5.
Kong RCK, Petrie EJ, Mohanty B, Ling J, Lee JCY, Gooley PR and Bathgate RAD (2013) RXFP1 utilises hydrophobic moieties
on a signalling surface of the LDLa module to mediate receptor activation. Journal of Biological Chemistry 288: 28138-
28151 2.
Bathgate RAD, Oh MHY, Ling WJJ, Kaas Q, Hossain MA, Gooley PR and Rosengren KJ (2013) Elucidation of relaxin-3
binding interactions in the extracellular loops of RXFP3. Frontiers in Endocrinology. 4: Article 13
Bathgate RAD, et al. (2012) Relaxin Family Peptides and Their Receptors. Physiological Reviews. 93: 405480
Scott DJ, Rosengren KJ and Bathgate RAD (2012) Determining the factors that govern INSL3 binding specificity to RXFP2.
Molecular Endocrinology. 26: 1896-1906
Callander GE, Thomas WG and Bathgate RAD (2009) Prolonged RXFP1 and RXFP2 signaling can be explained by poor
internalization and a lack of arrestin recruitment. American Journal of Physiology, Cell Physiology 296: C1058-66
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Projects
Supervisor(s):
Associate Professor Ross Bathgate
Campus:
Parkville
Contact details:
9035-6735
Email:
bathgate@florey.edu.au
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Projects
Neurophysiology Characterisation of the onset and progression of tauopathy in the
pontomedullary brainstem nuclei of mice undergoing neurodegeneration
Swallowing disorders that increase the risk of aspiration and subsequent pneumonia are prevalent in the elderly and patients
suffering neurological diseases, such as Alzheimers disease. Swallowing disorders are often attributed to weakening of the aging
upper airway and digestive tract musculature; however, disturbed neural coordination of breathing and swallowing is
increasingly evident in such diseases. Recent research in our laboratory identified three key brainstem areas that are critically
involved in the coordination of swallowing and breathing: 1) Nucleus of the solitary tract (NTS), which generates a phasic or
rhythmic command to produce sequential swallowing in response to sensory stimuli; 2) Nucleus ambiguus (NA), which contains
the laryngeal motoneurons innervating the vocal folds; and 3) Klliker-Fuse nucleus (KF), which provides tonic drive for the
laryngeal adductors and completely seals the trachea during, and between, swallows.
PROJECT 1 This project examines the underlying brainstem pathology linking dementia and swallowing dysfunction in an
established mouse model of neurodegeneration. The onset and progression of tauopathy and neurofibrillary tangle-related
morphology will be characterised in the brainstem of mice undergoing neurodegeneration, with particular focus on the NTS, NA
and KF. The project also aims to identify the neurochemical profile of neurons in these brainstem regions that are susceptible to
tauopathy.
PROJECT 2 Using adult born stem cells to replace neurons lost as a consequence of disease has the potential to be of great
benefit to sufferers of neurodegenerative disorders. However, despite the extensive research efforts that have gone into
examining the biology and therapeutic potential of adult stem cells, the precise cues that modulate the birth of neurons in the
adult brain remain unknown. This project examines whether: a) the rate of stem cell division; b) migration of newly born cells;
and c) the positioning and phenotype of newly born cells in the olfactory bulb and dentate gyrus, are altered in an established
model of neurodegeneration. Techniques include: immunohistochemistry, and stereology.
Supervisor(s):
Dr Davor Stanic and A/Prof Mathias Dutschmann
Campus:
Parkville
Contact details:
83440182
Email:
davor.stanic@florey.edu.au
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Projects
Neurophysiology Characterisation of the onset and progression of tauopathy in the
pontomedullary brainstem nuclei of mice undergoing neurodegeneration
Dementia is the single greatest cause of disability in Australians over 65 years old. Recent data suggests that dementia-causing
neuropathology starts within the brainstem, where it may subtly affect vital autonomic functions - much earlier than the onset
of cognitive deficits. Olfaction is impaired during the early stages of dementia-related diseases. Olfaction is strongly linked to
sniffing, an exploratory behaviour that utilises respiratory motor outputs that are normally controlled by brainstem neuronal
circuits. Before we can understand how dementia-causing neuropathology affects sniffing and therefore olfaction, it is
important to understand the basic neural circuitry that elaborates sniffing.
In this project, the aim is to elicit and characterise sniffing and other upper airway behaviours in the in situ preparation of
rodents, a premier tool for studying central respiratory control. Techniques involved will include electrophysiology (nerve
recordings) and immunohistochemistry.
Supervisor(s):
Dr. Tara Bautista, Dr. Mathias Dutschmann
Campus:
Parkville
Contact details:
NA
Email:
tara.bautista@florey.edu.au or mathias.dutschmann@florey.edu.au
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Projects
Neurophysiology Inhale-swallow-exhale: neurotransmitters that prevent food going down
the wrong pipes
Swallowing disorders are common in the elderly and in patients with neurodegenerative diseases such as Parkinsons and
Alzheimers diseases. These are linked to an increased risk of aspiration and consequent aspiration pneumonia. Growing
evidence points to pathophysiological alterations to the centrally-mediated coordination of swallowing and breathing as an
important contributor to the increased risk of aspiration in such conditions. Our research group recently published a pioneering
study on the novel use of the in situ brainstem rodent preparation for the study of swallowing.
This project will characterise the neurotransmitters utilised in the central control of the swallowing reflex and its coordination
with breathing, as an important first step in identifying potential drug therapies for treating swallowing disorders. Techniques
involved will include immunohistochemistry and retrograde tracing of neuronal pathways using a rodent model.
Supervisor(s):
Dr. Tara Bautista, Dr. Mathias Dutschmann, Dr. Davor Stanic
Campus:
Parkville
Contact details:
NA
Email:
tara.bautista@florey.edu.au or mathias.dutschmann@florey.edu.au
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Projects
Neurophysiology - Synaptic gating mechanisms involving inhibitory interneurons in the nucleus
of the solitary tract.
The nucleus of the solitary tract (NTS) is the first central site to receive viscerosensory afferent input and is involved in mediating
autonomic reflexes (e.g. baroreflex). Autonomic reflexes are highly flexible and dynamic. For example during exercise, where
both blood pressure and heart rate both remain high over sustained periods, the baroreflex seemingly decoupled during this
period. This project aims to determine the synaptic mechanisms underlying reflex strength and flexibility. Specifically, how
inhibitory synaptic gating mechanisms affect synaptic transmission between viscerosensory afferents and NTS neurons utilizing a
channelrhodopsin 2 expressing mouse line. We are looking for a high achieving, intelligent and highly motived student to join
our team. The successful student will learn advanced techniques including immunohistochemistry and slice electrophysiology. If
you have a genuine interest in neuroscience research and want more information about the project (and honours in general) we
would welcome an obligation-free, informal chat. Figure. Using optogenetics to study the inhibitory network within NTS. A.
Experimental concept. B. Horizontal medulla slice from a Sst-ChR2-yfp mouse. C. LED pulse evokes Inhibitory post synaptic
currents in NTS neurons.
1.
McDougall SJ, Andresen MC. Low-fidelity GABA transmission within a dense excitatory network of the solitary tract
nucleus. J Physiol. 2012 Nov 15;590:5677-89. http://www.ncbi.nlm.nih.gov/pubmed/22946100
https://www.youtube.com/watch?v=I64X7vHSHOE
Supervisor(s):
Stuart McDougall & Andrew Allen
Campus:
Parkville
Contact details:
03 8344 0416
Email:
stuart.mcdougall@florey.edu.au
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Projects
Neurophysiology - Unravelling the role of chemokines in central control of the cardiovascular
system
The brain controls the cardiovascular system via a complex network spanning a number of specialised brain structures. We are
particularly interested in an area known as the paraventricular nucleus of the hypothalamus or PVN. While the projections from
the PVN to other brain centres that control the heart and blood vessels are well documented, the neurotransmitters and
signalling molecules utilised by these projections are less well known. In this project, we will determine the function of a new
class of neuromodulators called chemokines. Chemokines are well known for their role in mounting an inflammatory response in
the periphery but the recent discovery that chemokines might also act as a signalling molecule within the brain opens up an
exciting avenue of research. This project will investigate the role of a specific chemokine known as CCL2 and its cognate
receptor CCR2 in signalling to PVN neurones that project to another vitally important cardiovascular centre called the RVLM.
This project will be relatively demanding and involve using a number of different techniques including electrophysiology if time
permits. The successful completion of the project will increase our understanding of some of the fundamental mechanisms
underpinning central cardiovascular regulation and control. In this project we will be asking the following questions: 1. What is
the distribution pattern of CCL2 and CCR2 within PVN and how many of these cells project to the RVLM. 2. How do PVN
neurones react to exogenously applied CCL2? Techniques involved: *small animal surgery (microinjection of neuronal tracers
into the PVN) *tissue sectioning *immunohistochemistry (DAB and fluorescence) *microscopy (light, fluorescence, confocal) *in
vitro electrophysiology (if time permits)
The brain controls the cardiovascular system via a complex network spanning a number of specialised brain structures. We are
particularly interested in an area known as the paraventricular nucleus of the hypothalamus or PVN. While the projections from
the PVN to other brain centres that control the heart and blood vessels are well documented, the neurotransmitters and
signalling molecules utilised by these projections are less well known. In this project, we will determine the function of a new
class of neuromodulators called chemokines. Chemokines are well known for their role in mounting an inflammatory response in
the periphery but the recent discovery that chemokines might also act as a signalling molecule within the brain opens up an
exciting avenue of research. This project will investigate the role of a specific chemokine known as CCL2 and its cognate receptor
CCR2 in signalling to PVN neurones that project to another vitally important cardiovascular centre called the RVLM. This project
will be relatively demanding and involve using a number of different techniques including electrophysiology if time permits. The
successful completion of the project will increase our understanding of some of the fundamental mechanisms underpinning
central cardiovascular regulation and control. In this project we will be asking the following questions: 1. What is the
distribution pattern of CCL2 and CCR2 within PVN and how many of these cells project to the RVLM. 2. How do PVN neurones
react to exogenously applied CCL2? Techniques involved: *small animal surgery (microinjection of neuronal tracers into the
PVN) *tissue sectioning *immunohistochemistry (DAB and fluorescence) *microscopy (light, fluorescence, confocal) *in vitro
electrophysiology (if time permits)
Supervisor(s):
Dr Song Yao
Campus:
Parkville
Contact details:
8344 0182
Email:
song.yao@florey.edu.au
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Projects
Neurophysiology - Reinnervating the kidneys
Background: Destroying the nerves supplying the kidneys (renal denervation) using radiofrequency power transfer catheters is
being trialled as a novel treatment in patients with drug-resistant hypertension, chronic kidney disease and heart failure. The
renal nerves surrounding the renal artery are destroyed via heat generated at the tip of the catheter, which is transferred across
the artery wall. Our laboratory has shown a significant reduction in the number of nerves 1 week following renal denervation in
sheep using the same catheter used in human patients. Further, we have shown regrowth of the nerves 5.5 and 11 months after
the procedure. However, these initial studies only investigated the function of the nerves under anaesthesia and the
immunohistochemcial evidence of nerve regrowth in kidney tissue. The current project will investigate the function of the renal
nerves in conscious sheep in the first 6-8 weeks after denervation. The results of this study are likely to have a marked impact on
the catheter-based denervation field. Specific aims: Investigate the changes in urine output, renin release and responses to
cardiovascular challenges, such as changes in blood pressure, blood volume and ion balance in the first 6-8 weeks following
renal denervation in conscious sheep Using immunohistochemical techniques, determine the levels of reinnervation 6-8 weeks
after renal denervation Specific skills: Techniques expected to be mastered during this honours project include chronic
recordings of cardiovascular variables in conscious large animals, quantitative immunohistochemistry, data analysis and
statistical methods. There is the potential for publication for motivated students.
Supervisor(s):
Dr Lindsea Booth and Prof Clive May
Campus:
Parkville
Contact details:
83440182
Email:
lindsea.booth@florey.edu.au
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Projects
Stroke - A Very Early Rehabilitation Trial in China (AVERT China)
AVERT China aims to test whether a culturally acceptable version of a rehabilitation intervention is effective in improving
outcome for patients affected by stroke in China. Health care settings and practices in China and other countries vary from
Australian and UK health care settings where the AVERT phase 3 trial is predominantly being trialled. To help with the
generalization of the trial results, a global approach is required. It is important to determine if the results can be replicated in
countries such as China where health care practices differ. AVERT China aims to address the main question: Does very early
mobilisation result in a greater proportion of patients walking 50 metres unassisted post stroke? Secondary analyses will include
functional outcome (mRS), safety (serious adverse events post stroke), and cost of care post stroke. The study aims to recruit
300 patients and will take place over 3 years with start-up and active recruitment occurring over 2 years. Individual patient
involvement in the trial is for three months. Participants will receive protocolled rehabilitation treatment whilst in hospital post
stroke and will be followed up at 3 months by a blinded assessor. This project will involve liaison with trial teams in China and
involve a training and management component. An understanding of basic Chinese language and Chinese work culture will be
beneficial in this role.
1.
World Health Organization. The World Health Report 2003. Geneva, Switzerland, 2003. Bonita R. Epidemiology of
stroke. Lancet 1992;339:342-344. Wolfe C. The impact of stroke. British Medical Bulletin 2000;56:275-286.
Supervisor(s):
A/Prof Julie Bernhardt
Campus:
Austin
Contact details:
+61 3 9035 7072
Email:
j.bernhardt@florey.edu.au
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Projects
Stroke - Exploring the therapeutic potential of progranulin for the treatment of stroke
Background: Progranulin is a secreted protein that was recently shown to be important in protecting the brain from atrophy
associated with frontotemporal dementia. Our previous research focussed on progranulin in stroke. We demonstrated that
progranulin-deficient mice have a worse outcome after stroke, revealing an important and previously unrecognised role of
progranulin in the ischaemic brain (Jackman et al., J Neurosci (2013) 33:19579). We demonstrated that the structure of the
blood brain barrier (BBB) was altered in progranulin-deficient mice. Specifically, the overlap of endothelial cells - which forms
the primary site of the BBB - was shorter and less complex (Figure 1). This caused the BBB to become leaky in progranulin-
deficient mice and thereby increase injury after stroke. These findings, combined with evidence that progranulin is down-
regulated in the brain after stroke and our preliminary data that progranulin can rapidly decrease BBB permeability in vitro (see
accompanying project), suggests that increasing levels of progranulin could represent an effective treatment for stroke. As we
are yet to define the mechanism by which progranulin promotes barrier integrity, the second component of this study will be to
explore the mechanism of these BBB stabilising effects, with particular focus on select proteins such as VE-cadherin, -catenin
and their association with the actin cytoskeleton.

Figure 1. Images of endothelial tight junctions in wild-type (WT) and progranulin deficient (PGRN-KO) mice obtained using
transmission electron microscopy.
Aims: The aim of this study is to establish if progranulin treatment at clinically relevant time points after stroke can attenuate
BBB permeability and improve post-stroke outcome. In addition, the contribution of VE-cadherin, -catenin and their
association with the cytoskeleton will be evaluated.
Method & Plan: Mice will be subjected to transient cerebral ischemia using the intraluminal filament model of middle cerebral
artery occlusion (MCAO) (Jackman et al., Meth Mol Biol (2011) 793:195). Mice will be treated with progranulin (100 ng,
intravenous) from between 0 24 hrs post stroke. Three days (72hrs) after stroke motor impairment will be evaluated in mice
using behavioural testing, including the Bederson score, wire-hanging and corner test. The degree of brain injury will then be
assessed by quantifying swelling in the brain, using the wet-dry technique and infarct volume, with cresyl violet staining. In
order to explore the mechanism of these effects, additional mice will be subjected to stroke and sacrificed within 1 hr of
progranulin treatment (allowing us to establish a causative role) to evaluate BBB integrity by quantifying leakage of fluorescent
dyes (Evans blue, FITC-dextran) into the brain using confocal microscopy. In addition, the expression of key BBB proteins, in
particular VE-cadherin and -catenin, will be assessed using Western blot, confocal microscopy & immune-electron microscopy.
Expected outcomes: We hypothesise that treatment with progranulin will rapidly attenuate ischaemic brain injury by
attenuating BBB permeability. Furthermore, we predict that the ability of progranulin to promote BBB integrity will relate to its
ability to preserve expression and endothelial cleft localisation of VE-cadherin, in addition to promoting its interaction with the
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Projects
actin cytoskeleton via -catenin. The ability of progranulin treatment to effectively reduce brain injury at extended time points
after stroke will greatly increase the therapeutic potential of this agent.
1.
2.
Jackman et al., J Neurosci (2013) 33:19579)

Jackman et al., Meth Mol Biol (2011) 793:195
Supervisor(s):
Dr Katherine Jackman, A/Prof David Howells
Campus:
Austin
Contact details:
03 9035 7398
Email:
katherine.jackman@florey.edu.au
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Projects
Stroke - The ability of progranulin to attenuate blood brain barrier (BBB) disruption in response
to pro-permeability agents
Background: Progranulin is a secreted protein that was recently shown to be important in protecting the brain from atrophy
associated with frontotemporal dementia. Our previous research explored its role in stroke and demonstrated that progranulin-
deficient mice have a worse outcome, revealing an important and previously unrecognised role of progranulin in the ischaemic
brain (Jackman et al., J Neurosci (2013) 33:19579). We demonstrated that the structure of the blood brain barrier (BBB) was
altered in progranulin-deficient mice such that the overlap of endothelial cells - which forms the primary site of the BBB - was
shorter and less complex. This caused the BBB to become leaky and thereby increase injury in response to stroke. Interestingly,
we also demonstrated a generalised weakness of the BBB in response to other agents that promote BBB disruption (platelet
derived growth factor-CC (PDGF-CC); Figure 1), suggesting that the benefits of progranulin may be extended to other conditions
associated with cerebrovascular permeability. However, it remains unclear whether progranulin can acutely regulate
generalised BBB integrity

Figure 1. Image of BBB permeability in response to intrastriatal injection with pro-permeability agent platelet derived growth
factor-CC (PDGF-CC) in wild-type (+/+) and progranulin deficient mice (+/- & -/-).
Aims: The aim of this study is to explore the influence of progranulin on BBB disruption occurring in response to intra-striatal
injection with pro-permeability agents.
Method & Plan: These experiments will be performed in 1) C57Bl/6 mice treated with progranulin and 2) progranulin transgenic
mice in which progranulin deletion is induced during adulthood using tamoxifen inducible CreLox technology. Pro-permeability
agents (e.g. PDGF-CC, VEGF) will be injected directly into the striatum via stereotactic microinjection and at the same time, mice
will be injected with a fluorescent marker (Evans blue, FITC-dextran) to evaluate BBB disruption. The degree of BBB permeability
will be imaged and quantified using confocal microscopy. To complement these experiments, electron microscopic images of
the endothelial tight junctions (imaging not performed by student) will be analysed and complexity of tight junctions evaluated.
Expected outcomes: We hypothesise that progranulin treatment will attenuate BBB integrity, while genetic deletion of
progranulin in adulthood will increase BBB permeability and impair tight junction ultrastrucutre. Taken together, these findings
will support the ability of progranulin to rapidly regulate BBB integrity and function.
1.
Jackman et al., J Neurosci (2013) 33:19579
Supervisor(s):
Dr Katherine Jackman, A/Prof David Howells
Campus:
Austin
Contact details:
03 9035 7398
Email:
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Projects
Stroke - Stratifying stroke patients in rehabilitation and recovery trials.
Key questions in stroke rehabilitation research are who responds to rehabilitation interventions, who doesnt and why? The
heterogeneity of the stroke population is well known. Most commonly, rehabilitation researchers approach this problem by
applying highly selective entry criteria for trials. These criteria are largely based on clinical judgment. This approach, while
reasonable, fails to advance our understanding. If the characteristics of individual responders and non-responders were
identified, this would fundamentally change the focus of rehabilitation research and practice. The absence of large, prospective,
long term studies of stroke patients undergoing rehabilitation in which patients and interventions are well characterised, has
hampered efforts to address this important question. We have access to a potential pool of over 2000 stroke patients whose
characteristics and interventions are well characterised. Using pooled data from the control arms of trials or from observational
studies where baseline assessment occurred within 72 hours of stroke onset, we will determine the characteristics of patients
exhibiting different recovery profiles over the course of the first year post stroke. These data represent the natural history of
recovery. Using classification clustering, we will determine sub-groups of patients who exhibit distinct profiles. Using data from
the treatment arms of trials well conduct exploratory decision analysis to interrogate whether patient subgroups (eg, no, slow,
fast recovery) respond to treatment. The outcome of this project will be development of a clinical stratification tool for use in
future clinical trials.
1.
2.
Bernhardt, J., H. Dewey, et al. (2006). "A Very Early Rehabilitation Trial (AVERT)." International Journal of Stroke 1: 169-
171.
Ceglowski, R., L. Churilov, et al. (2006). "Combining Data Mining and Discrete Event Simulation for a value-added view of
a hospital emergency department." J Oper Res Soc 58(2): 246-254.
Supervisor(s):
A/Prof Julie Bernhardt; Prof Leonid Churilov
Campus:
Austin
Contact details:
390357072
Email:
j.bernhardt@unimelb.edu.au
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Projects
Stroke - Cerebral Haemodynamics and Orthostatic Response to Upright position in acute
ischaemic Stroke (CHORUS)
Stroke is the leading cause of adult disability and mortality in Australia. The majority of strokes are ischaemic in nature and occur
when a blood vessel to the brain is occluded, usually by a clot. Cerebral blood flow in acute ischaemic stroke is highly dynamic,
and factors that either impair or promote cerebral blood flow during the acute phase may directly affect the infarct size and
associated clinical deficit. Lowering the head of the bed in the early hours of stroke may theoretically assist flow to the ischaemic
tissue. Conversely, there is growing support for early mobilisation after stroke with the potential to reduce cerebral blood flow
and decrease infarct size. Currently there is no consensus and no clinical guidelines on the safety of early upright posture when
caring for acute stroke patients. Against a backdrop of a number of large, international clinical trials that are studying the effects
of early activity (AVERT) or bed rest for 24 hours (HEADpost) to improve recovery, further evaluation of the extent and clinical
relevance of orthostatic changes in cerebral blood flow in acute ischaemic stroke using transcranial Doppler ultrasound is
warranted. The project will involve patient contact, learning about the application and interpretation of TCD and data analysis.
The project could be extended to include further examination of the physiological effects of early activity and exercise. This
would be suitable for a PhD candidate.
1.
2.
3.
4.
5.
Bernhardt, J., H. Dewey, et al. (2007). "A Very Early Rehabilitation Trial (AVERT): Phase II safety and feasability results."
Internal Medicine Journal 37(Suppl. 1): A9.
Schwarz, S., D. Georgiadis, et al. (2002). "Effects of body position on intracranial pressure and cerebral perfusion in
patients with large hemispheric stroke." Stroke 33(2): 497-501.
Wojner-Alexander, A. W., Z. Garami, et al. (2005). "Heads down: Flat positioning improves blood flow velocity in acute
ischemic stroke." Neurology 64(8): 1354-1357.
Hunter, A., S. Snodgrass, et al. (2012). "HOBOE (Head-of-Bed Optimization of Elevation) Study: Association of Higher
Angle With Reduced Cerebral Blood Flow Velocity in Acute Ischemic Stroke." Physical Therapy 91(10): 1503-1512.
Olavarra, V. V., H. Arima, et al. (2014). "Head position and cerebral blood flow velocity in acute ischemic stroke: A
systematic review and meta-analysis." Cerebrovascular diseases (Basel, Switzerland) 37(6): 401-408.
Supervisor(s):
A/Prof Julie Bernhardt; Prof Brian Chambers
Campus:
Austin
Contact details:
390357072
Email:
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Projects
Stroke - Improving outcome assessment in stroke rehabilitation trials (Project 2)
Stroke rehabilitation is a multi-faceted process that typically involves a team approach. Post stroke interventions may address a
range of impairments, functional deficits and challenges of participation. For that reason, the development of agreed standards
for measuring outcome after stroke has been challenging and there is currently no universally accepted or adopted measure
that is used in clinical trials. The absence of agreement about how we should measure outcome after stroke has hampered our
ability to pool results across trials (e.g. meta-analysis) to build the evidence base, and/or foster development of new treatments.
Most commonly used outcome measures are ordinal in nature, however these scales are limited in their usefulness. Currently
no outcome measures exist in stroke rehabilitation that can effectively measure change. The development of a utility measure
will provide a common language that can be used clinically to track outcome, and as a measure of outcome in stroke
rehabilitation research. Health utilities are cardinal values that reflect the individuals preferences for different health outcomes.
They are measured on an interval scale with zero reflecting states of health equivalent to death and one reflecting perfect
health. Fitting utility weighted functions to an ordinal measure allows data analysis on an interval scale enabling use as a
measure of change. The aim of this project is to build on current efforts to improve the standards of outcome assessment by
developing utility measures for existing ordinal scales. The work has the potential to have global impact.
1.
2.
Ali M, English C, Bernhardt J, Sunnerhagen KS, Brady M, on behalf of the VISTA-Rehab Collaboration (2013). "More
outcomes than trials: A call for consistent data collection across stroke rehabilitation trials." International Journal of
Stroke 8: 18-24.
Arnesen T, Trommald M (2005). Are QALYs based on time trade-off comparable? A systematic review of TTO
methodologies. Health Economics 14:39-53. Baker K, Cano SJ, Playford D (2011). Outcome measurement in stroke: a
scale selection strategy. Stroke 42:1787-94.
Supervisor(s):
A/Prof Julie Bernhardt; Professor Leonid Churilov; Dr Sharon Hakkenes
Campus:
Austin
Contact details:
390357072
Email:
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Projects
Stroke - Predicting gains from therapy from the anatomy of stroke injury
Therapy based interventions aim to improve recovery after stroke. A soon to be completed, large clinical trial (AVERT) has tested
whether commencing upright activity, with walking and standing training early after stroke, improves recovery at 3 and 12
months. In a subset of patients we have gathered imaging data that can be used to explore the biological substrates needed for
treatment gains. The purpose of this study is to interrogate early imaging data and explore the relationship between brain injury
and outcome in this well characterised population. The student undertaking this project will work with neurologists,
physiotherapists and a statistician to characterise brain injury, with particular focus on the white matter tracts most strongly
associated with motor recovery, and determine the extent to which the brain injury predicts recovery with and without early
task-specific intervention.
1.
Anatomy of Stroke Injury Predicts Gains From Therapy Jeff D. Riley, MD; Vu Le, MS; Lucy Der-Yeghiaian, MA, OTR/L; Jill
See, MPT; Jennifer M. Newton, PhD; Nick S. Ward, MD, FRCP; Steven C. Cramer, MD, Stroke. 2011;42:421-426
Supervisor(s):
Dr Bruce Campbell; A/Prof Julie Bernhardt; Dr Nawaf Yassi
Campus:
Austin
Contact details:
390357072
Email:
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Projects
Stroke - What is the minimum dose of exercise needed for stroke survivors?
International clinical guidelines recommend that stroke survivors accumulate at least 150 minutes a week of moderate to
vigorous physical activity for example taking a brisk walk for at least 30 minutes, 5 days a week. These guidelines are the same
as those for all healthy adults, and are based on research involving healthy, non-stroke participants. We know that people after
stroke have many barriers to exercise and adherence to these guidelines in this population is very low. The dose response
relationship between exercise and outcome is curvi-linear meaning that in people with very low level of activity may benefit
from very small increases in physical activity. However, we do not know what the minimum amount of increased activity is for
benefit to be seen. This project will use a dose escalating design to determine the minimum amount of increased physical
activity that is required to see clinically meaningful improvements in cardiovascular disease biomarkers, general health and
quality of life. This is a unique opportunity to work with a leading international expert on the effect of exercise on brain function
(Prof Kirk Erikson, University of Pittsburgh). The results of this work will inform future physical activity guidelines for stroke
survivors.
1.
2.
3.
Gordon NF, Gulanick M, Costa F, et al. Physical activity and exercise recommendations for stroke survivors: an American
Heart Association scientific statement from the Council on Clinical Cardiology, Subcommittee on Exercise, Cardiac
Rehabilitation, and Prevention; the Council on Cardiovascular Nursing; the Council on Nutrition, Physical Activity, and
Metabolism; and the Stroke Council. Circulation 2004;109(16):2031-41 doi:
10.1161/01.CIR.0000126280.65777.A4[published Online First: Epub Date]|.
English C, Manns PJ, Tucak C, Bernhardt J. Physical activity and sedentary behaviors in people with stroke living in the
community: a systematic review. Phys Ther 2014;94(2):185-96 doi: 10.2522/ptj.20130175[published Online First: Epub
Date]|.
Baert I, Feys H, Daly D, Troosters T, Vanlandewijck Y. Are patients 1 year post-stroke active enough to improve their
physical health? Disabil Rehabil 2012;34(7):574-80 doi: 10.3109/09638288.2011.613513[published Online First: Epub
Date]|.
Supervisor(s):
Dr Coralie English, A/Prof Julie Bernhardt, Prof Kirk Erikson (University of Pittsburgh Pittsburgh, USA)
Campus:
Austin
Contact details:
(08) 83022552
Email:
Coralie.english@unisa.edu.au
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Projects
Stroke - Increasing physical activity in stroke rehabilitation units towards an effective solution
For decades, studies conducted worldwide have found that patient activity levels in stroke rehabilitation units are extremely
low, with almost all activity occurring in physiotherapy sessions. This is a problem because we know that activity and task
practice is the key driver of improving motor recovery after stroke, whereas inactivity leads to cardiovascular and muscular
deconditioning, increased cardiovascular disease risk, reduction in mood and a host of other negative health consequences.
There is increasing national and international momentum to rethink the paradigm in which rehabilitation is provided. We need a
thorough understanding of the drivers and barriers to increasing patient activity in order to develop effective strategies to
increase activity. This project will employ mixed methods (qualitative and quantitative methods) to comprehensively assess the
barriers and enablers of physical activity from multiple stakeholder perspectives (stroke survivors, families, all staff on
rehabilitation units). The results of this study are likely to inform future iterations of the Stroke Clinical Guidelines for
rehabilitation.
1.
2.
3.
4.
English C, Bernhardt J and Hillier S (2014) Circuit class therapy and 7-day-week therapy increase physiotherapy time, but
not patient activity. Early results from the CIRCIT trial. Stroke Published online before print August 14, 2014, doi:
10.1161/STROKEAHA.114.006038
West T, Bernhardt J. Physical activity in hospitalised stroke patients. Stroke Research and Treatment 2012;2012:813765
doi: 10.1155/2012/813765[published Online First: Epub Date]|.
Sjholm A, Skarin M, Churliov L, Nilsson M, Bernhardt J, Lindn T. Sedentary behaviour and physical activity of people
with stroke in rehabilitation hospitals. Stroke Research and Treatment 2014;Article ID 591897, 7 pages doi:
http://dx.doi.org/10.1155/2014/591897[published Online First: Epub Date]|.
Skarin M, Sjoholm A, Nilsson A, Nilsson M, Bernhardt J, Linden T. A mapping study on physical activity in stroke
rehabilitation: establishing the baseline. J Rehabil Med 2013;45(10):997-1003 doi: 2340/16501977-1214[published
Online First: Epub Date]|.
Supervisor(s):
Dr Coralie English, A/Prof Julie Bernhardt
Campus:
Austin
Contact details:
(08) 83022552
Email:
Coralie.english@unisa.edu.au
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Projects
Stroke - Improving outcome assessment in stroke rehabilitation trials (Project 1)
Stroke rehabilitation is a multi-faceted process that typically involves a team approach. Post stroke interventions may address a
range of impairments, functional deficits and challenges of participation. For that reason, the development of agreed standards
for measuring outcome after stroke has been challenging and there is currently no universally accepted or adopted measure
that is used in all clinical trials. The absence of agreement about how we should measure outcome after stroke has hampered
our ability to pool results across trials (e.g. meta-analysis) to build the evidence base, and/or foster development of new
treatments. Against a backdrop of global initiatives to develop core outcome sets for clinical practice, it is time we turn o ur
attention to developing a core dataset for use in rehabilitation based clinical trials. The aim of this PhD project is to develop the
framework, tools and processes to obtain global agreement for a core set of outcome measures to be used in rehabilitation
clinical trials. The work will have a global impact.
1.
2.
Ali, M., C. English, et al. (2013). "More outcomes than trials: A call for consistent data collection across stroke
rehabilitation trials." International Journal of Stroke 8: 18-24. ICHOM (2011). "Why we do it: The Mission of ICHOM."
Retrieved 20 August, 2014, from http://www.ichom.org/why-we-do-it/.
Williamson PR, Clarke M. The COMET (Core Outcome Measures in Effectiveness Trials) Initiative: its role in improving
Cochrane Reviews [editorial]. Cochrane Database Syst Rev. 2012 Apr13;5:ED000041 SORCan (2011). What is Outcomes
Research? Retrieved 20 August, 2014, http://sorcan.ca/outcomes-research/
Supervisor(s):
A/Prof Julie Bernhardt; Professor Leonid Churilov; Dr Coralie English
Campus:
Austin
Contact details:
390357072
Email:
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Projects
Stroke - Testing for contamination of standard care in a trial of acute stroke rehabilitation
Clinical trials of rehabilitation-based interventions are complex. Therapists delivering experimental interventions cannot be
blinded to treatment group and treatments are often visible to other patients and staff within the hospital environment. This
increases the risk of contamination of usual care control with the intervention under trial. The uptake of the intervention into
the usual care or control arm of a trial can derail the entire trial. Rehabilitation researchers are trying to develop methods for
monitoring contamination in clinical trials. The AVERT trial is an international trial of early rehabilitation, is approaching final
recruitment. We implemented, in two high recruiting sites, a model of tracking standard care over time using intermittent
observation. In this project, the student will interrogate the data accumulated over the course of the trial to examine whether
usual care practices changed with time. The student will learn techniques of behavioural mapping (structured observation) and
work with datasets in excel and access. This project will contribute to our thinking about current methods of controlling and
measuring contamination in clinical trials.
1.
2.
Bernhardt, J., H. Dewey, et al. (2006). "A Very Early Rehabilitation Trial (AVERT)." International Journal of Stroke 1: 169-
171.
Craig, P., P. Dieppe, et al. (2008). "Developing and evaluating complex interventions: the new Medical Research Council
guidance." BMJ 337: a1655.
Supervisor(s):
A/Prof Julie Bernhardt, Prof Leonid Churilov, Dr Coralie English
Campus:
Austin
Contact details:
390357072
Email:
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Projects
Stroke - Identifying super-responders to exercise training after stroke: A biomarker approach
Stroke survivors experience significant disability and motor impairment, resulting in reduced independence and capacity to
complete activities of daily living. We believe early and intensive rehabilitation can drive the recovery process, and imperative to
this recovery is the exercise-induced changes in neural plasticity and associated changes in motor function. Why some stroke
survivors make a full recovery whilst others experience significant residual impairment is poorly understood, but a stroke
survivors genetic profile is a likely contributor factor. There is emerging evidence to suggest genetic variants influence exercise
training adaptability, and genetic factors are strongly implicated in the neural changes that take place during stroke recovery.
This project aims to assess the influence a stroke survivors genetic profile has on their recovery and has important implications
for the planning of rehabilitation programs and for stroke survivors. This study will run as part of a larger feasibility trial and
patients will be recruited from the acute stroke units of the Austin Hospital in Melbourne.
1.
2.
3.
Cramer SC, Procaccio V and for the GAIN Americas and GAIN International Study Investigators. Correlation between
genetic polymorphisms and stroke recovery: analysis of the GAIN Americas and GAIN international studies. Eur J Neurol.
2012;19(5):718-24. Epub 2012/01/04.
Stinear C. Prediction of recovery of motor function after stroke. Lancet Neurology. 2010;9(12):1228-32. Epub
2010/11/03.
Whiteley W, Chong WL, Sengupta A, Sandercock P. Blood markers for the prognosis of ischemic stroke: a systematic
review. Stroke. 2009;40(5):e380-9. Epub 2009/03/17.
Supervisor(s):
Dr Liam Johnson, Dr Toby Cumming, Associate Professor Julie Bernhardt
Campus:
Austin
Contact details:
03 9035 7390
Email:
liam.johnson@florey.edu.au
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Projects
Stroke - The impact of psychological factors on engagement in stroke rehabilitation
It remains a puzzle why some stroke survivors show great benefits from rehabilitation while others do not. It is widely assumed
that psychological issues such as depression, apathy and fatigue limit participation in rehabilitation and thus contribute to
poorer recovery after stroke. Yet there is very little evidence to support this assumption. To take one example, the suggestion of
a relationship between post-stroke fatigue and poorer engagement in rehabilitation is based on an opinion article (Michael,
2002) and a very small pilot study (Morley et al., 2005). This project will investigate the effects of depression, anxiety, apathy,
cognitive impairment and fatigue on active participation in stroke rehabilitation. Engagement in rehabilitation will not be
quantified with crude measures such as length of inpatient stay or number of therapy sessions; it will involve measuring
movement with accelerometer-based devices during therapy sessions. Results from the project will be used to identify
strategies to increase the efficacy of rehabilitation in stroke survivors with psychological problems
1.
Michael, K. (2002). "Fatigue and stroke." Rehabilitation Nursing Journal 27(3): 89-94. Morley, W., K. Jackson, et al.
(2005). "Post-stroke fatigue: an important yet neglected symptom." Age & Ageing 34(3).
Supervisor(s):
Dr Toby Cumming, A/Prof Julie Bernhardt
Campus:
Austin
Contact details:
390357152
Email:
tcumming@unimelb.edu.au
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Projects
Stroke - Improving recovery early after stroke: Can we make the hospital environment more
stimulating?
Many stroke survivors report being inactive, isolated and bored during their hospital stay. Stroke research in animals indicates
that exposure to an enriched environment, with opportunities for exercise, social interaction and sensory stimulation, results in
improved recovery (Janssen et al., 2010). We are interested in whether changes to the hospital environment can make the
inpatient stay more stimulating for stroke survivors, and therefore contribute to better recovery. This project will focus on
identifying what activities stroke survivors do in hospital, and what activities they would like to do. It will be a mixed methods
investigation, with both quantitative (development of the Everyday Activities Questionnaire, behavioural mapping) and
qualitative (in-depth interviews with stroke survivors) components. Findings will be used to identify activities that can be
introduced to the hospital environment to increase physical, cognitive and social stimulation in stroke survivors.
1.
Janssen, H., J. Bernhardt, et al. (2010). "An enriched environment improves sensorimotor function post-ischemic stroke."
Neurorehabil Neural Repair 24(9): 802-813.
Supervisor(s):
Dr Toby Cumming, Dr Julie Luker, A/Prof Julie Bernhardt
Campus:
Austin
Contact details:
390357152
Email:
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Projects
Stroke - The effect of blue light on post-stroke fatigue
Debilitating fatigue is a problem that is experienced by more than 50% of stroke survivors. We still understand very little about
why fatigue occurs, and lack interventions that can reduce post-stroke fatigue. One possibility is that exposure to short
wavelength (blue) light reduces fatigue by increasing arousal and alertness. A small study in traumatic brain injury showed that
patients randomised to a 4-week, 45-minutes per day schedule of blue light therapy had lower fatigue than patients exposed to
either longer wavelength (yellow) light or no light (Sinclair et al., 2014). This project will investigate whether exposure to blue
light can reduce fatigue in stroke survivors. Participants will be recruited from the acute stroke unit at the Austin Hospital, and
the 4-week intervention will begin once they are discharged. If found to be effective, this non-invasive, safe and inexpensive
treatment will be tested in a larger, Phase III randomised trial.
1.
Sinclair, K. L., J. L. Ponsford, et al. (2014). "Randomized Controlled Trial of Light Therapy for Fatigue Following Traumatic
Brain Injury." Neurorehabilitation and Neural Repair 28(4): 303-313.
Supervisor(s):
Dr Toby Cumming, A/Prof Julie Bernhardt
Campus:
Austin
Contact details:
390357152
Email:
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Projects
Stroke - The rationality (or otherwise) of medical decision-making
Health care decisions often involve a choice between an active intervention and inactive medical management. For example,
patients with carotid stenosis decide whether to (a) have surgical removal of plaque (endarterectomy), or to (b) not have
surgery and continue with appropriate medications and vascular risk factor control. The psychology underlying such a medical
decision has not been explored. According to Kahneman & Tversky (1982), we have more regret regarding a negative outcome if
we perceive it to be the result of our action, as opposed to our inaction. So we will regret a loss on the share market more if it
was the result of a decision to switch companies than if it resulted from an unchanged share portfolio. In medical decision-
making, however, we hypothesise that regret regarding a negative outcome (e.g., stroke) will be greater if we perceive it to be
the result of inaction (e.g., medical management), as opposed to action (e.g., surgery). In this study, we will devise m ock
medical scenarios and ask participants to make decisions based on risk and probability. Once we have divulged the medical
outcomes, we will ask participants to rate how satisfied they were with their decisions. Any bias found towards active
treatments will have important implications for medical decision-making, allowing for a more rational appraisal of the risks and
benefits of all treatment options.
1.
Kahneman, D. and A. Tversky (1982). "The psychology of preferences." Scientific American 246(1): 160-173.
Supervisor(s):
Dr Toby Cumming
Campus:
Austin
Contact details:
390357152
Email:
121 | P a g e

Projects
Stroke - The effect of exercise training early after stroke
Following a stroke, physical therapy aimed towards improving motor control and developing movement strategies begins, but
typically ignores the stroke survivors reduced aerobic fitness and muscle strength. Such physical deconditioning is a likely
contributor to what is commonly described as profound motor and functional incapacity experienced after stroke. There is
good evidence to indicate the physiologically adaptive capacity of stroke survivors remains intact, and we have found that very
early rehabilitation for stroke survivors is safe and feasible, and can fast-track functional recovery and mobility. But it remains to
be seen if an exercise training program, including aerobic exercise and progressive resistance training, can be tolerated by stroke
survivors early after a stroke, and if such training can lead to improved physical, functional and psychosocial outcomes. This
project aims to establish if a short-term exercise training program in a small group of stroke survivors can be safely undertaken
and improve CRF, muscle strength and function. This study will run as part of a larger feasibility trial and patients will be
recruited from the acute stroke unit of the Austin Hospital in Melbourne.
1.
2.
3.
4.
Bernhardt J, Dewey H, Thrift A, Collier J, Donnan G. A very early rehabilitation trial for stroke (AVERT): phase II safety
and feasibility. Stroke. 2008;39(2):390-6. Epub 2008/01/05.
Billinger SA, Coughenour E, Mackay-Lyons MJ, Ivey FM. Reduced cardiorespiratory fitness after stroke: biological
consequences and exercise-induced adaptations. Stroke Research and Treatment. 2012;2012:959120. Epub 2011/08/31.
Cumming TB, Thrift AG, Collier JM, Churilov L, Dewey HM, Donnan GA, et al. Very early mobilization after stroke fast-
tracks return to walking: further results from the phase II AVERT randomized controlled trial. Stroke. 2011;42(1):153-8.
Epub 2010/12/15.
Stoller O, de Bruin ED, Knols RH, Hunt KJ. Effects of cardiovascular exercise early after stroke: systematic review and
meta-analysis. BMC Neurology. 2012;12:45. Epub 2012/06/26.
Supervisor(s):
Dr Liam Johnson, Dr Toby Cumming, Associate Professor Julie Bernhardt
Campus:
Austin
Contact details:
390357390
Email:
liam.johnson@florey.edu.au
122 | P a g e

Projects
Stroke - Observing changes in bone density and structure, lean mass and glucose metabolism
after stroke for targeting of therapeutic exercise
Bone deterioration accelerates after stroke, contributing to a dramatically increased risk of bone fracture and worsened
outcomes for stroke survivors (Ramnemark 2000). Reduction of bone mass occurs predominantly in stroke affected limbs, and is
related to physical inactivity and muscle weakness. Impaired glucose metabolism, a risk factor for recurrent stroke and
cardiovascular disease, also occurs early (Allport 2008). The absence of longitudinal studies has limited our understanding of
when and what we should target for early intervention. We are currently investigating the timing and magnitude of changes in
volumetric bone mineral density, body composition, insulin and glucose levels and physical activity from early after stroke
(Borschmann et al 2013). This Masters of Philosophy project will build on our current study by examining the emergence of
long term skeletal and cardiovascular outcomes through completion of two year follow ups of participants. It will also involve
examining the translation of evidence based exercise programs from healthy adult populations to rehabilitation programs for
stroke survivors.
1.
2.
3.
Allport L, Baird T, Davis S. Hyperglycaemia and the ischaemic brain: continuous glucose monitoring and implications for
therapy. Current Diabetes Reviews. 2008; 4: 245-57.
Borschmann K, Pang MYC, Iuliano S, Churilov L, Brodtmann A, Ekinci EI, Bernhardt JA, 2013 Changes to volumetric bone
mineral density and bone strength after stroke: a prospective study. Int J Stroke. (online ahead of press)
Ramnemark A, Nilsson M, Borssen B, Gustafson Y. Stroke, a major and increasing risk factor for femoral neck fracture.
Stroke. 2000; 31(7): 1572-7.
Supervisor(s):
A/Prof Julie Bernhardt
Campus:
Austin
Contact details:
9035 7072
Email:
123 | P a g e

Projects
Stroke - Progranulin as a novel blood-brain barrier-protecting agent during ischaemic stroke: an
in vitro study.
BACKGROUNG: Ischaemic stroke, resulting from formation of an occlusive thrombus in the brain, is a major cause for death and
disability in western society. The only pharmacological agent approved to date for acute intervention during stroke is tissue-type
plasminogen activator (t-PA), a blood protease which generates the clot-busting enzyme plasmin. Unfortunately, in addition to
the damages caused by the ischaemic insult itself, t-PA also possesses a direct capacity to harm the unique capillaries of the
brain which form the blood-brain barrier (BBB). These properties may increase the risk for development of intracerebral
bleeding during t-PA treatment. Hence, a need arises to protect the BBB throughout the ischaemic event and the therapeutic
intervention. Previous work in vivo by Dr. Jackman has demonstrated that progranulin (PGRN), a ubiquitously expressed,
secreted growth factor, is a key regulator of BBB integrity. Indeed, progranulin protected the BBB against post-ischaemic
disruption and decreased brain injury in a mouse model of stroke (Jackman et al., J Neurosci, 2013). However, despite its
potential, the mechanism by which PGRN regulates barrier integrity is yet to be established. AIM: This honours project will
assess the potential of progranulin as a BBB-protecting agent during t-PA mediated disruption of the BBB using an in vitro
model. METHODOLOGY AND PLAN: We will utilise a human in vitro BBB model, where human brain endothelial cells (BECs)
are co-cultured on porous membranes together with human astrocytes (their natural in vivo counterparts). The BBB model will
be subjected to t-PA and plasmin stimulation under normal conditions or under oxygen-glucose deprivation (OGD, which mimics
stroke in vitro). Progranulin will be added in each of the conditions and permeability will be assessed 6 or 24 h later by passage
of fluorescent tracers via the cell monolayers. We will also assess the effect of progranulin on permeability of BECs mono-
cultures (without astrocytes). This will allow us to test if progranulin affects the injured BECs directly or via cross-talk with
astrocytes, an important mechanistic question. Furthermore, we will generate primary BEC, neuron and astrocyte cultures from
brains of progranulin-deficient mice and wild-type littermates. We will then test how OGD, t-PA and plasmin modulate cell
viability, tight-junction structure, signaling pathways and overall cell morphology. Finally, we will perform rescue experiments,
attempting to reverse changes observed in progranulin-deficient cultures by addition of the recombinant PGRN protein. During
the project we will place special emphasis on cell imaging and advanced microscopy. EXPECTED OUTCOME: We aim to gain a
deeper insight into the mechanisms which link progranulin to BBB protection during stroke. Findings from this study will be
translated to in vivo rodent models of stroke. Ultimately, we believe that the protective effects of progranulin on BBB integrity
could be harnessed to improve the safety and effectiveness of stroke treatment. LOCATION OF PROJECT: Project will be
conducted at Monash University, ACBD, located at the Alfred Hospital.
1.
Jackman et al., "Progranulin deficiency promotes post-ischemic blood-brain barrier disruption" (2013) J Neurosci, 33(50):
19579.
Supervisor(s):
Dr. Katherine Jackman, Dr. Be'eri Niego (Monash University, ACBD), A/Prof David Howells & Prof.
Robert Medcalf (Monash University, ACBD)
Campus:
Parkville
Contact details:
(03) 90357398
Email:
124 | P a g e

Projects
Stroke - Improving the quality of stroke care in Australia: exploring stroke care using data from
a national clinical quality stroke registry
In Australia, stroke is the second leading cause of death and the largest cause of adult disability. Recent advances in treatments
for acute stroke have resulted in improved survival and reduced disability, while well-coordinated multidisciplinary stroke care
has been shown to improve recovery. Essential to understanding where to focus efforts to improve stroke care is ensuring
reliable data are available. The Australian Stoke Clinical Registry (AuSCR) was established in 2009 to provide data on the
processes of care and outcomes for patients admitted to hospital with acute stroke and transient ischemic attack (TIA) The aim
is to contribute to the improvement of the quality of stroke care nationally. As of August 2014, there were 50 hospitals approved
to use AuSCR in Australia with ~20,000 registered cases and ~10,000 post stroke follow-up surveys. This large dataset (and
related linked data) provides several opportunities to explore varied aspects of acute stroke care and health outcomes. The
following research topics/questions would provide an honours project with potential publications as an outcome. 1. Do the
quality of care and outcomes differ for patients with transient ischaemic attack admitted to Australian hospitals compared with
patients with ischaemic stroke? For example: the frequency of re-admission rates. 2. Do the quality of care and outcomes differ
for patients with in-patient stroke admitted to Australian hospitals compared with patients admitted to hospital with acute
stroke? For example: the frequency of re-admission rates. 3. What are the causes of death from stroke in Australia and does this
vary by region and hospital? 4. What proportion of people discharged from hospital with stroke require support in the
community and does this differ by region and hospital? How many are able to access in-patient rehabilitation? What are the
differences in quality of life for those accessing different discharge venues? 5. What factors influence achieving greater health-
related quality of life (HR-QoL) within 180 days of stroke? Are Australian health outcomes for stroke similar to the outcome
profiles in other countries? Can any difference be explained by differences in access to evidence-based care? 6. Access to
prevention medication after acute hospital admission and risk of recurrent strokes or re-admissions: a national overview. 7.
Estimating Quality Adjusted Life Years (a measure of disease burden) for Australian stroke survivors based on 3 month post-
stroke outcome data (from AuSCR, using a health-related quality of life instrument - the EQ-5D)
8.
9.
Registry website: http://www.auscr.com.au

Lannin N, Anderson C, Lim J, Paice K, Price C, Faux S, Levi C, Donnan G, Cadilhac D (2013). Telephone follow-up was more
expensive but more efficient than postal in a national stroke registry. Journal of Clinical Epidemiology 66: 896-902.
10. Cadilhac DA, Sundararajan V, Andrew N, Kilkenny M, Flack F, Anderson P, Boyd J, Katzenellenbogen J, Thrift A.G. Using
linked data to more comprehensively measure the quality of care for stroke - understanding the issues. Australasian
Epidemiologist, accepted 21 May 2013
11. Cadilhac D, Lannin N, Anderson C, Levi C, Faux S, Price C, et al. Protocol and pilot data for establishing the Australian
Stroke Clinical Registry (AuSCR). Int J Stroke 5(3): 217-226, 2010.
Supervisor(s):
Assoc Prof Dominique Cadilhac
Campus:
Austin
Contact details:
(03) 9035 7032
Email:
dominique.cadilhac@florey.edu.au
125 | P a g e

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Epilepsy - Neuroanatomical determinants of susceptibility in a model of genetic epilepsy .................................................................... 39

Graduate Research at the Florey

Dr Terence Pang and Prof. Anthony Hannan

Dr Thibault Renoir and Prof. Anthony Hannan

Dr Emma Burrows and Prof. Anthony Hannan

Dr Emma Burrows, Dr Scott Kolbe, Prof. Anthony Hannan

Dr Emma Burrows, Dr Scott Kolbe, Prof. Anthony Hannan

Professor Andrew Lawrence & Dr Robyn Brown

Professor Andrew Lawrence, Dr Christina Perry & Dr Jee Hyun Kim

Professor Andrew Lawrence & Dr Stuart McDougall

Adam Vogel and Amy Brodtmann

Dr Jee Hyun Kim and Dr Heather Madsen

Dr Jee Hyun Kim and Dr Despina Ganella

Dr. Jhodie R. Duncan and Professor Andrew J. Lawrence

Dr. Jhodie R. Duncan and Professor Andrew J. Lawrence

Hannan AJ. Neurobiol. Dis. 2013; 57:1-4.

Dr Thibault Renoir and A/Prof. Anthony Hannan

Dr Emma Burrows, Dr Scott Kolbe and A/Prof. Anthony Hannan

Hill-Yardin EL, Hannan AJ. Behav. Neurosci. 2013 Aug;127:606-9.

Dr Emma Burrows and A/Prof. Anthony Hannan

Mo C, Renoir T, Pang TY, Hannan AJ. Behav. Brain Res. 2013;253C:318-322.

Dr Terence Pang and A/Prof. Anthony Hannan

Nithianantharajah J et al., (2013) Nat. Neurosci; 16, 16-24.

Dr Jason Howitt and Pof Seong-Seng Tan

Prof Seong-Seng Tan and Dr Jason Howitt

Prof Seong-Seng Tan and Dr Ulrich Putz

Prof Seong-Seng Tan and Dr Jason Howitt

Prof Seong_Seng Tan and Dr Jason Howitt

Prof Tony Paolini/Dr Amanda Paolini/Prof Graeme Jackson

Professor Tony Paolini/Prof Graeme Jackson

A/Professor Steve Petrou & A/Professor Chris Reid

Reid et al Brain 2014

A/Professor Steve Petrou & A/Professor Chris Reid

A/Prof Chris Reid, A/Professor Steve Petrou

A/Prof Chris Reid, A/Professor Steve Petrou, A/Prof Paul Adlard

Verena C Wimmer, Steven Petrou

Milligan et al Annals of Neurology 2014

Dr Carol Milligan & A/Professor Steve Petrou

Richards et al Neuroimage 2014

A/Professor Steve Petrou, Dr Verena Wimmer, Dr Kay Richards

Kay Richards, A/Professor Steve Petrou, A/Professor Chris Reid

A/Prof Steve Petrou

A/Professor Steve Petrou, A/Professor Chris Reid

Dr. Ben J. Gu, Prof. James Wiley

Dr. Ben J. Gu, Prof. James Wiley

Dr. Ben J. Gu, Dr. Tobias Merson, Prof. James Wiley

ben.gu@florey.edu.au; tmerson@unimelb.edu.au; james.wiley@florey.edu.au

Dr. Ben J. Gu, Dr. Tobias Merson, Prof. James Wiley

ben.gu@florey.edu.au; tmerson@unimelb.edu.au; james.wiley@florey.edu.au

Dr. Ben J. Gu, Prof. James Wiley

Dr. Ben J. Gu, Prof. James Wiley

Fernando Calamante, Alan Connelly

Fernando Calamante, Alan Connelly

Kevin Barnham, Laura Jacobson

Dr. Gawain McColl and Dr. Simon Drew

Dr. Gawain McColl