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applied to one type of neuroblastoma and two hereditary neuromuscular disorders. This research is led by George Karpati of McGill University, Montreal, Canada, and involved basic, clinical and social scientists from six Canadian institutions and three international collaborators. The INMHA support was provided in collaboration with three other CIHR institutes (those for Cancer Research, Human Development, Child and Youth Health, and Musculoskeletal Health and Arthritis) and two NGOs (Neuroscience Canada Partnership and Muscular Dystrophy Association of Canada). Artificial eyes and hearing aids are also the domain of regenerative medicine and are crucial research areas for the INMHA, considering their ever increasing prevalence associated with longer life expectancies and new lifestyles. It is essential that the INMHA is internationally prominent, and we intend to promote exchanges of personnel and to develop joint research initiatives with various countries. As a first step, the INMHA has already agreed to support

post-doctoral positions for young Japanese scientists interested in training in Canada (taking advantage of a JapanCanada Neuroscience initiative developed in the mid-1990s). Our Japanese colleagues will offer similar opportunities to Canadian trainees by broadening topics to include mental health and addiction. Discussion is also underway with colleagues in Israel, and a joint scientific meeting is being planned for later this year to formalize our collaboration. Various sister institutes at the NIH were recently visited and we certainly wish to develop strong links and joint funding initiatives with our American colleagues. We have just finalized a partnership agreement with the Fogarty International Center. We have also initiated discussions with members of the European Community. In summary, the first year of the existence of the INMHA has been both exciting and challenging. It is most humbling to serve as the first Scientific Director of the integrated Institute of Neurosciences, Mental Health and Addiction, especially in the light of a long tradition of Canadian excellence in brain

research, (pioneers include Wilder Penfield, Donald Hebb, Herbert Jasper and Heinz Lehmann, to name but a few). As an active, committed scientist, I truly want the Canadian experiment to be a success and even a model for others. With the support of Canadian neuroscientists, I am confident that it will be.
References 1 Murray, J.L. and Lopez, D. (1996) The Global Burden of Disease: a Comparative Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Harvard School of Public Health, Cambridge MA, USA 2 de la Fuente-Fernandez, R. et al. (2001) Expectation and dopamine release: mechanism of the placebo effect in Parkinsons Disease. Science 293, 11641166 3 Meaney, M.J. (2001) Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu. Rev. Neurosci. 24, 11611192

Rmi Quirion Institute of Neurosciences, Mental Health and Addiction, Douglas Hospital Research Centre, McGill University, 6875 Blvd Lasalle, Verdun, Quebec, Canada H4H 1R3. e-mail: quirem@douglas.mcgill.ca

Historical Perspective

A bugs smell research into insect olfaction

Bill S. Hansson
The olfactory system has become an important model system for neurobiological function and sensory processing. In insects, odours play a vital role in all aspects of life. From the late 1950s until very recently, research into the structure and function of the insect olfactory system has often preceded similar investigations in vertebrates and has been important in the formulation of general principles.

Imagine a warm summer night. A female moth sits on a twig of a potential host plant and releases a perfume irresistible for the male, a sex pheromone [1]. But she releases it in a deviously low amount, thus attracting only males with an adequate olfactory sensitivity and avoiding detection by unwanted eavesdroppers. Although the female produces only homeopathic concentrations of attractive odour, the male (Fig. 1) can detect this odour and follow it to its source. He is also able to detect the odour of the host plant
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with almost as high a sensitivity as he detects that of the female, and to then integrate this odour information with the scent of the sexual attractant. A complex message describing a female who is both ready to mate and sitting on a suitable host plant is conveyed, and the male is strongly attracted from hundreds of metres away. How are odours detected with such an amazing sensitivity and specificity? How is the peripheral information represented in the brain? How is the entire odour mixture of an ecologically relevant situation represented? How is such a representation modified by experience? These are some of the questions that have been studied since Butenandt and co-workers identified the first moth pheromone from 500 000 pheromone glands of silk moth females in 1959 [2]. In the same era, Schneider performed electrophysiological recordings from peripheral receptor neurons on the antenna of a male moth (Fig. 1), getting

the first hint of the sensitivity and specificity displayed by the insect olfactory system [3]. Even today, one of the major points of research in insect olfaction is its strong neuroethological profile, and we usually know the behavioural significance of the stimuli applied in experiments.
A molecular revolution

During the past ten years, immense progress has been made in the study of the vertebrate olfactory system. Since Buck and Axel revealed the first sequences of olfactory receptor proteins in the rat [4], the molecular revolution has provided useful research tools. The availability of information regarding receptor identity has allowed studies of morphology, physiology and behaviour that are based on molecular manipulations of the olfactory system. Indeed, the progress has been fascinating to observe. However, in many of these classical studies, I have found a tendency to forget the vast

0166-2236/02/$ see front matter 2002 Elsevier Science Ltd. All rights reserved. PII: S0166-2236(02)02140-9

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Fig. 2. (a) The moth antennal lobe. Axons from the insect antenna enter the lobe via the antennal nerve (AN). In the moth, and in other types of insects that use long distance, female-produced sex pheromones, two types of olfactory glomeruli are present: sexually isomorphic, so-called ordinary glomeruli (O), and the male-specific macroglomerular complex (MGC) that receive input exclusively from sex pheromone specific olfactory receptor neurons (ORNs). The glomeruli are flanked by groups of antennal lobe interneuron cell bodies (CBs). Each glomerulus of the MGC receives input from a specific type of ORN, tuned to one of the components involved in sexual communication (indicated by numbers 1 to 4). (b) Ethyl gallate stained section of the turnip moth (Agrotis segetum) antennal lobe. Note the very large, male-specific MGC. (c) Wholemount of the Drosophila melanogaster brain, with the bilaterally symmetrical VA1lm glomeruli, labelled by GFP within invading olfactory sensory neurons (yellow). Uninvaded glomeruli are red. Photograph courtesy of Leslie Vosshall. Scale bars, 100 m.

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Fig. 1. (a) A male Antheraea polyphemus moth aroused by the presence of female pheromone. Note the large antennae, which possess many olfactory sensilla that house olfactory receptor neurons (photograph by Richard G. Vogt). (b) Insect olfactory sensilla. The olfactory receptor neurons (ORNs) are housed within a cuticular hair, in which they are surrounded by the sensillum lymph (SL). Each hair is a self-contained unit, owing to a tight seal at the base accomplished by three types of accessory cell (AC). Odour molecules enter the hair through pores (P) in the cuticule (C). ORNs project their axons to the brain through the antennal nerve (AN). (c) Vertebrate olfactory mucosa. Here, the cilia of the ORNs swim in a common mucus layer (ML). ORN axons leave for the brain through the olfactory nerve (ON).

information available from studies performed in insects decades, or at least years, earlier. Highly sophisticated molecular tools were not used in insects until recently, but even so, several studies with direct bearing on recent results in vertebrates have been published.
Detecting the scent

Ever since the pioneering work of Schneider, olfactory receptor neurons (ORNs) have been accessible for investigations using electrophysiological methods. Prime targets of such investigations were the
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pheromone-detecting neurons in male moths. Studies revealed that these neurons have a remarkable sensitivity and specificity [5]. Using radiolabelled pheromone it was shown that a single pheromone molecule is sufficient to elicit a nerve impulse.[6] Structureactivity investigations demonstrated that the recognition of a pheromone molecule was highly specific. When 75 analogues to a specific pheromone molecule were investigated, it was clear that the electrophysiological activity observed from a certain molecule was directly proportional to the conformational energy needed to fit the analogue into the original receptor pocket (see Ref. [7] for details). From early studies, terms such as specialist ORNand generalist ORNwere coined, with the former exemplified by pheromone detectors and the latter by neurons involved in plant odour detection. Today, we know that there seems to be very few generalist ORNs. Instead, different degrees of specialization have been found, both in the pheromone and the non-pheromone detection systems [8]. Recently, the ultimate characterization of different ORNs was made possible by molecular characterization of the entire family of odorant receptor proteins in Drosophila [9,10]. In one sense, the insect olfactory system differs dramatically from that of vertebrates (Fig. 1). Olfactory hairs made up from the insect exoskeleton house dendrites of a few receptor neurons, and the lumen of each hair is isolated from those of others [11]. Thus, there is the

possibility to provide single or few ORNs with a specific chemical environment. Indeed, this is the case: extensive studies of the chemical composition of sensillum lymph have demonstrated the presence of different odorant binding proteins (OBPs) and ligand degrading enzymes [12]. Elegant immunocytochemical studies have shown that different OBPs are located in different morphological types of sensilla, also indicating a physiological function for OBP [13]. The close colocalization of specific types of ORN opens up other possibilities. In male moths, ORNs detecting an attractive pheromone component are often colocalized with a cell specifically tuned to a behavioural antagonist [14]. This colocalization is most probably the morphological basis for the tremendous capability to discriminate between odour plumes in which both the attractive molecule and its antagonist are released from the same source, and those in which the molecules are released from different sources. The moth can detect time differences in the arrival of the different odour molecules on the sensillum surface at the millisecond scale and use this information to determine whether the molecules were emitted together [14].
Olfactory maps in the brain

In all organisms possessing an olfactory system, the ORNs project axons directly to the CNS: in insects, the axons terminate in the antennal lobe (AL; Fig. 2) and in vertebrates they terminate in the

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Fig. 3. Optical recording from the moth antennal lobe. (a) Photograph of the male Helicoverpa zea antennal lobe before optical recording. (b) After application of a Ca2+-sensitive dye, antennal olfactory receptor neurons were stimulated with the main pheromone component Z11-hexadecenyl acetate. The activity spot, shown by false colour coding (red indicating higher calcium concentrations), coincides with the location of the main part of the male-specific macroglomerular complex. White lines indicate the outlines of the antennal lobe. Scale bar, 50 m.

of ORN axon projections into the antennal lobe showed that ORNs detecting sex pheromone molecules all targeted the MGC [17]. From further investigations, based on activity-dependent staining of neurons, it became clear that ORNs detecting different pheromone components targeted different glomeruli of the MGC [18]. This was the first proof that glomeruli constitute functional units. Similar experiments have now been performed in vertebrates [19] and Drosophila [20,21] using elegant molecular techniques; the results suggest that ORNs expressing a certain receptor all terminate in the same glomerulus (Fig. 2). A dream for the early investigators of odour representation in the AL was to be able to see this information entering the AL in real time. Methods for optical imaging of neural activity, primarily imaging of Ca2+ release, were developed in insects during the late 1990s [22]. Such methods have provided new and interesting insights into how different odours are coded over the glomerular array, and into how different receptor proteins interact with a specific molecule (Fig. 3). Again, these results can be compared directly with experiments performed in vertebrates [23].
Encoding the blend (and when)

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olfactory bulb (OB). Another trait common to all olfactory systems is also that the ORNs terminate in spherical neuropil called glomeruli [15]. In insects, the AL generally contains 50100 glomeruli, whereas the mammalian OB contains thousands of glomeruli. This morphological organization triggered very early speculations regarding the functional significance of the glomeruli [16]. Were they functional units, each receiving input from a certain type of ORN? Or were the peripheral olfactory organs mapped topographically in the glomerular array? These questions have now been answered. In the male moth, a large part of the AL is devoted to a large complex of glomeruli called the macroglomerular complex (MGC), which is not present in the female. Initial studies
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To understand how the complex odour image (e.g. that comprising the female moth and the host plant) is formed, it is essential to investigate central processing of olfactory information. The first intracellular recordings from moth antennal lobe neurons were performed in the early 1980s [24]. This opened up several new avenues, and since then processing in the AL has been elucidated extensively [25,26]. Owing to the relatively few glomeruli present in most insects, it has been possible to construct detailed maps of the AL, and to map innervation of the glomeruli by different types of AL interneurons in detail (Fig. 4). It has also been possible to study how odour information is integrated to allow the formation of a blend image, how coding of time (an important parameter for insect behaviour in an odour plume) is performed, and several other aspects of CNS coding. Dynamic processes among assemblies of AL neurons have also been shown to be important for olfactory coding [27]. The latest development in

Fig. 4. (a) Horizontal section through the brain of the scarab beetle Pachnoda marginata showing falsecolour-coded prominent features of the insect brain. The antennal lobes and their glomeruli are in brown, the mushroom bodies are in blue, and the central complex is in green. (b) The section shown in (a) has been schematized and shows the antennal lobes (AL), the mushroom bodies [with their calyces (CA), peduncle (PED) and two lobes: the , or horizontal, lobe (), and the , or vertical, lobe ()], the central complex (CC), the protocerebral bridge (PB) and the optic tubercle (OT). From the antennal lobe, the two main pathways for olfactory projection neurons, the outer and inner antennocerebral tracts (OACT and IACT respectively) are shown. (c) A local interneuron of the P marginata . antennal lobe. This neuron is a type of periglomerular cell, but in contrast to those of vertebrates, it connects to more or less all glomeruli of the antennal lobe. (d) A projection neuron with dendrites in one of the antennal lobe glomeruli, its axon travelling through the IACT and its axonal branches in the mushroom-body calyces and the lateral protocerebrum. Scale bars, 100 m.

investigations of the AL is the use of multiunit recordings [28]. Blend interactions and dynamic changes in the response properties of neural assemblies seem to occur in the AL (Fig. 5) after repeated experiences of an odour and after associating odours with rewards.
Moving upstream

One of the ultimate challenges in investigations of sensory systems in general is to understand higher order

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Fig. 5. Neural-ensemble recording was used to examine population responses to odours in the moth antennal lobe. Temporal analysis of these ensemble responses revealed the underlying dynamics and combinatorial nature of odour-evoked network interactions [28]. (a) Responses to brief odour pulses are shown as raster plots for five different projection neurons (PNs), and the peri-event histogram (below rasters) illustrates how the overall activity of the ensemble was time-locked to the stimulus pulses. Each odour pulse evoked a discrete burst of spikes across the population, followed immediately by strong suppression (arrows) that helped to further synchronize the population response to each stimulus pulse. (b) Odour blends evoked network dynamics that could not be predicted from the responses to individual odours. Colour-surface plots depict the spatiotemporal patterns of odour-evoked spike activity recorded from an ensemble across two tracks of a multi-electrode recording probe (see probe map). Note how each odour evoked reproducible patterns of synchronous activity in different, but overlapping, combinations of neurons. The odour blend (A + B) evoked a strong response from the neuron recorded at one site, while simultaneously suppressing activity at all other recording sites. (c) Colour-coded matrices represent the complex patterns of neuronal synchrony evoked by two different odours (A or B) and their blend (A + B) at two concentrations. Colour scale represents the degree of spike synchrony calculated between each pair of neurons in the ensemble. The horizontal display beneath each matrix shows the mean firing rate for each neuron individually. The top two matrices reveal firing patterns in response to a control stimulus, and the lower matrices show how several of the six stimulus conditions evokes synchronous firing among different combinations of neurons in the ensemble. (d) Surface plots illustrate how the cross-correlations between two neurons changed as a function of time. Dynamic correlation analysis revealed that the temporal structure of the ensemble response was not modulated by oscillations, but by the intrinsic dynamics of the odour stimulus itself. Collectively, neural-ensemble recordings in moths show that network oscillations do not govern the temporal patterning of synchrony evoked by natural, intermittent pulses of odour. Adapted, with permission, from Ref. [28].

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processing. How is odour information represented and processed in the cortex? In insects, several studies have centred on the function of an extremely dense and characteristic neuropil, that of the mushroom bodies (MB; Fig. 4). Several studies have shown the multi-modal character of processing that occurs at this level, and also its more detailed connectivity [29]. From different ablation studies, a picture of the MBs as important centres of memory formation has been formed [30]. Besides the MBs, several other areas of the protocerebrum have been shown to be involved in olfactory processing. These include the lateral protocerebrum and the lateral accessory lobes [30]. The degree of integration occurring at these levels seems to vary between species, according to whether blend-detectors make up a larger or smaller proportion of
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5 1.
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neurons investigated, and whether labelled lines (i.e. neurons carrying information regarding a specific odour molecule) pass straight through the entire brain to thoracic premotor centres [31]. The factors underlying the success of research in insect olfaction are mainly the relative accessibility of the system, both at a peripheral and a central level, and the availability of behaviourally active odours. Recently, the description of the entire Drosophila genome has added a new dimension. Together, these

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components have allowed us to form a detailed picture of the system, from antenna to wing muscles. From this vantage point we are now ready for the next 50 years of insect olfaction studies, a period that indeed promises to be as fruitful as the first.
References 1 Hartlieb, E. and Anderson, P. (1999) In Insect Olfaction (Hansson, B.S., ed.), pp. 315350, Springer-Verlag 2 Butenandt, A. et al. (1959) ber den Sexuallockstoff des Seidenspinners Bombyx mori. Reindarstellung und Konstitution. Z. Naturforsch. 14b, 283284

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3 Schneider, D. and Boeckh, J. (1962) Rezeptorptential und Nervenimpulse einzelner olfaktorischer Sensillen der Insektenantenne. Z. Vergl. Physiol. 45, 405412 4 Buck, L. and Axel, R. (1991) A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65, 175187 5 Todd, J.L. and Baker, T.C. (1999) In Insect Olfaction (Hansson, B.S., ed.), pp. 6797, Springer-Verlag 6 Kaissling, K.E. (1986) Peripheral mechanisms of pheromone reception in moths. Chem. Senses 21, 257268 7 Gustavsson, A-L. et al. (1997) Bioisosteric approach to elucidation of binding of the acetate group of a moth sex pheromone component to its receptor. J. Chem. Ecol. 23, 27552776 8 Hansson, B.S. (1995) Olfaction in Lepidoptera. Experientia 51, 10031027 9 Clyne, P.J. et al. (1999) A novel family of divergent seven-transmembrane proteins: candidate odorant receptors in Drosophila. Neuron 22, 327338 10 Vosshall, L.B. et al. (1999) A spatial map of olfactory receptor expression in the Drosophila antenna. Cell 96, 725736 11 Keil, T.A. (1999) In Insect Olfaction (Hansson, B.S., ed.), pp. 548, Springer-Verlag 12 Vogt, R.G. et al. (1999) Odorant binding protein diversity and distribution among the insect orders, as indicated by LAP, an OBP-related protein of the true bug Lygus lineolaris (Hemiptera, Heteroptera). Chem. Senses 24, 481495 13 Steinbrecht, R.A. et al. (1995) Immunolocalization of pheromone-binding protein and general odorant-binding protein in olfactory sensilla of the

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silk moths Antheraea and Bombyx. Cell Tissue Res. 282, 203217 Baker, T.C. et al. (1998) Moth uses fine tuning for odour resolution. Nature 393, 530 Hildebrand, J.G. (1997) Mechanisms of olfactory discrimination: converging evidence for common principles across phyla. Annu. Rev. Neurosci. 20, 595631 LeGros Clark, W.E. (1956) Inquiries into the anatomical basis of olfactory discrimination. Proc. R. Soc. London Ser. B 146, 299319 Koontz, M.A. and Schneider, D. (1987) Sexual dimorphism in neuronal projections from the antennae of silk moths (Bombyx mori, Antheraea polyphemus) and the gypsy moth (Lymantria dispar). Cell Tissue Res. 249, 3950 Hansson, B.S. et al. (1992) Functional specialization of olfactory glomeruli in a moth. Science 256, 13131315 Mombaerts, P. et al. (1996) Visualizing an olfactory sensory map. Cell 87, 675686 Gao, Q. et al. (2000) Convergent projections of Drosophila olfactory neurons to specific glomeruli in the antennal lobe. Nat. Neurosci. 3, 780785 Vosshall, L.B. et al. (2000) An olfactory sensory map in the fly brain. Cell 102, 147159 Galizia, C.G. et al. (1997) A semi-in-vivo preparation for optical recording of the insect brain. J. Neurosci. Methods 76, 6169 Korsching, S.I. (2001) Odor maps in the brains: spatial aspects of odor representation in sensory surface and olfactory bulb. Cell. Mol. Life Sci. 58, 520530 Matsumoto, S.G. and Hildebrand, J.G. (1981) Olfactory mechanisms in the moth Manduca

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sexta: response characteristics and morphology of central neurons in the antennal lobes. Proc. R. Soc. London Ser. B 213, 249277 Hansson, B.S. and Christensen, T.A. (1999) In Insect Olfaction (Hansson, B.S., ed.), pp. 126164, Springer-Verlag Christensen, T.A. and White, J. (2000) In The Neurobiology of Taste and Smell (Finger, T.E. et al., eds.), pp. 201232, WileyLiss Laurent, G. and Davidowitz, H. (1994) Encoding of olfactory information with oscillating neural assemblies. Science 265, 18721875 Christensen, T.A. et al. (2000) Multi-unit recordings reveal context dependent modulation of synchrony in odor-specific neural ensembles. Nat. Neurosci. 3, 927931 Strausfeld, N.J. et al. (1998) Evolution, discovery, and interpretations of arthropod mushroom bodies. Learn. Mem. 5, 1137 de Belle, J.S. and Kanzaki, R. (1999) In Insect Olfaction (Hansson, B.S., ed.), pp. 243282, Springer-Verlag Lei, H. et al. (2001) Olfactory protocerebral pathways processing sex pheromone and plant odour information in the male moth Agrotis segetum. J. Comp. Neurol. 432, 356370

Bill S. Hansson Dept of Crop Science, Division of Chemical Ecology, Swedish University of Agricultural Sciences, PO Box 44, SE-230 53 Alnarp, Sweden. e-mail: bill.hansson@vv.slu.se

Book Review

Methusalahs brain
Functional Neurobiology of Aging edited by Patrick R. Hof and Charles V. Mobbs, Academic Press, 2001. 115.00/ US$169.95 (1100 pages) ISBN 0 123 51830 X

Aging is often referred to as the ultimate disease, the one that will inevitably kill every one of us. Human beings are probably the only living species on this planet that know about their unavoidable biological decline in late life. Although all parts of the body are affected by aging, it is the brain the organ that endows us with the ability to look into the future and its supplementary sensory systems whose deterioration with age inflicts some of the gravest and most distressful effects of old age.
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Neurobiological aging does not only affect cognitive, cerebral functions, but also, because the brain is the master control organ, the entire body. The subjects covered by Functional Neurobiology of Aging include cognitive impairments, motorneural control mechanisms and sensory systems. Research in recent years has provided a wealth of evidence that the functioning of nerve cells and the CNS as a whole is closely intertwined with the hormonal homeostatic complex. The brain is a pace-maker, as well as a controller of hormonal reactions and mechanisms while, at the same time, being an effector of many hormones. When any area of biology or medicine touches the molecular level, genes are not far away. So the Functional Neurobiology of Aging features molecules galore. As human beings, understanding the human nervous system and how it is affected by aging is at the heart of our curiosity and ambitions. However, animal models must be used, as human subjects are only available for experimental

studies using non-invasive imaging techniques. Three chapters of the book deal with what can only count as a small selection of what has already been learned using modern in vivo imaging techniques such MRI. Because primates are the model animals favoured by neurobiologists attempting to understand complex neurobiological functions by invasive experimentation (rather than by observation), the majority of chapters dealing with animal systems provide information gathered from primate models. Proper data processing within the brain relies on the input received from connecting sensory organs. Aging of these sensory organs contributes significantly to neurobiological aging by reducing or biasing the sensory information available for integrative action at higher levels. Functional Neurobiology of Aging brings together authoritative information on how sensory perception is altered by the aging of all senses, from the deterioration of vision and progressive age-related hearing loss to changes in smell and taste.