Bartsch (2015)

NSC 16481 No.
of Pages 16
7 August 2015
Please cite this article in press as: Bartsch T, Wulff P. The hippocampus in aging and disease: From plasticity to vulnerability. Neuroscience (2015),
http://dx.doi.org/10.1016/j.neuroscience.2015.07.084
1
Neuroscience xxx (2015) xxx–xxx
2 EDITORIAL
3 THE HIPPOCAMPUS IN AGING AND DISEASE: FROM PLASTICITY

4 TO VULNERABILITY
5 T. BARTSCH a* AND P. WULFF b Key words: hippocampus, vulnerability, neuroplasticity,
a subfield imaging, Alzheimer’s disease, aging.
6 Department of Neurology, Memory Disorders and Plasticity
11
7 Group, University Hospital Schleswig-Holstein, Kiel, Germany
b
8 Institute of Physiology, Neurophysiology, University of
9 Kiel, Olshausenstrasse 40, 24098 Kiel, Germany
INTRODUCTION 12
10 Abstract—The hippocampus has a pivotal role in learning

The hippocampus is widely regarded as being in the 13
and in the formation and consolidation of memory and is center of a brain network supporting encoding, 14
critically involved in the regulation of emotion, fear, anxiety, consolidation and retrieval of memory and, being central 15
and stress. Studies of the hippocampus have been central to to the study of human memory, has been implicated in 16
the study of memory in humans and in recent years, the episodic and semantic long-term memory, novelty 17
regional specialization and organization of hippocampal detection, sleep-dependent memory consolidation, 18
functions have been elucidated in experimental models pattern discrimination, spatial navigation and the binding 19
and in human neurological and psychiatric diseases. The of temporally and spatially distributed representations 20
hippocampus has long been considered a classic model (Bartsch, 2012). Beyond these cognitive functions, the 21
for the study of neuroplasticity as many examples of synap-
hippocampus is also involved in the regulation of emotion, 22
tic plasticity such as long-term potentiation and -depression
have been identified and demonstrated in hippocampal cir-
fear, anxiety, and stress. The hippocampus has an 23
cuits. Neuroplasticity is the ability to adapt and reorganize intriguing cyto- and network architecture and it has been 24
the structure or function to internal or external stimuli and suggested that the particular circuit arrangement in differ- 25
occurs at the cellular, population, network or behavioral ent subregions of the hippocampus subserves differential 26
level and is reflected in the cytological and network architec- mnemonic operations (Kesner and Rolls, 2015). Indeed, 27
ture as well as in intrinsic properties of hippocampal neu- in recent years, a differential and complex modular orga- 28
rons and circuits. The high degree of hippocampal nization of hippocampal anatomy and function emerged 29
neuroplasticity might, however, be also negatively reflected (Strange et al., 2014). Also, the concept of a regional spe- 30
in the pronounced vulnerability of the hippocampus to dele- cialization and organization of hippocampal functions has 31
terious conditions such as ischemia, epilepsy, chronic
been increasingly studied in humans using high- 32
stress, neurodegeneration and aging targeting hippocampal
structure and function and leading to cognitive deficits.
resolution MR subfield imaging indeed showing that mne- 33
Considering this framework of plasticity and vulnerability, monic operations can be attributed to subnetworks and 34
we here review basic principles of hippocampal anatomy subregions of the hippocampus (Bakker et al., 2008; 35
and neuroplasticity on various levels as well as recent find- Mueller et al., 2011) (Chetelat, this issue). 36
ings regarding the functional organization of the hippocam- The hippocampus has long been considered as a 37
pus in light of the regional vulnerability in Alzheimer’s classic example for the study of functional 38
disease, ischemia, epilepsy, neuroinflammation and aging. neuroplasticity as many models of synaptic plasticity 39
This article is part of a Special Issue entitled: such as long-term potentiation (LTP) and -depression 40
Hippocampus. Ó 2015 Published by Elsevier Ltd. on behalf (LTD), and spike-timing-dependent plasticity have been 41
of IBRO.
observed in hippocampal circuits and are thought to be 42
fundamental to learning and memory (Bliss and 43
Schoepfer, 2004; Pastalkova et al., 2006). 44
*Corresponding author. Tel: +49-0-431-597-8550; fax: +49-0-431- Neuroplasticity is considered the ability to adapt and reor- 45
597-8502. ganize the structure or function to internal or external 46
E-mail addresses: t.bartsch@neurologie.uni-kiel.de (T. Bartsch), p. stimuli and occurs on the cellular, population, network or 47
wulff@physiologie.uni-kiel.de (P. Wulff).

Tel: +49-431-880-2806; fax:+49-431-880-4580.
behavioral level (Cramer et al., 2011). Neuroplastic mech- 48
Abbreviations: Ab, amyloid-beta; AD, Alzheimer’s disease; DG, anisms are reflected in the cyto- and network architecture 49
dentate gyrus; EAE, experimental autoimmune encephalomyelitis; and are mirrored in the intrinsic properties of hippocampal 50
EC, entorhinal cortex; IL-1b, interleukin-1 beta; LTD, long-term neurons and circuits. Structural plasticity in hippocampal 51
depression; LTP, long-term potentiation; MS, multiple sclerosis; MTL,
medial temporal lobe; NFT, neurofibrillary tangle; ROS, reactive neurons and circuits includes modifications of dendritic 52
oxygen species; TLE, temporal lobe epilepsy. tree size and spines, synapse number as well as the 53
0306-4522/Ó 2015 Published by Elsevier Ltd. on behalf of IBRO.
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2 T. Bartsch, P. Wulff / Neuroscience xxx (2015) xxx–xxx
54 formation of new neurons (Leuner and Gould, 2010). lucidum, stratum radiatum). The structure of this feed- 113
55 Cellular neuroplasticity is not confined to physiology but forward circuit with its limited redundancy may be critical 114
56 also present in the context of progressive pathology, such for learning and memory but may also contribute to its vul- 115
57 as neurodegeneration in Alzheimer’s disease (AD) in nerability during insults (Lavenex and Amaral, 2000). 116
58 humans and is increasingly studied (Mufson et al., Learning and memory processes within hippocampal cir- 117
59 2015). On a network level, neuroplasticity in hippocampal cuits are regulated by synaptic plasticity mechanisms that 118
60 circuits drives changes in connectivity, structural modifi- require activation of specific molecular cascades (Aksoy- 119
61 cations and behavioral outcome (Finke et al., 2013a; Aksel and Manahan-Vaughan, 2015). For example, the 120
62 Ryan et al., 2015). induction of LTP in the CA1 region involves postsynaptic 121
63 This high degree of hippocampal plasticity, however, calcium ion entry via NMDA receptors with subsequent 122
64 is accompanied by the pronounced vulnerability of the activation of protein kinases (Aksoy-Aksel and 123
65 hippocampus to deleterious conditions such as Manahan-Vaughan, 2015). 124
66 ischemia, epilepsy, neuroinflammation, chronic stress, The hippocampus receives large amounts of sensory 125
67 neurodegeneration and aging suggesting that the information from neocortical structures, which is 126
68 instrinsic properties of hippocampal neurons and circuits integrated in several recurrent subnetworks with distinct 127
69 that are critical for neuroplasticity such as glutamatergic computational operations (van Strien et al., 2009). The 128
70 excitability may also predispose to metabolic injuries DG with its three layers (molecular, granular, and polymor- 129
71 occurring in the process of various neurological and phic layers) consists mainly of granule cells and receives 130
72 psychiatric diseases (Bartsch et al., 2015). This view is polymodal input form the EC. The axons of the DG granule 131
73 reflected in the suggestion by Bruce McEwen that ‘the cells form the mossy fiber system and project to CA3 132
74 plasticity of the hippocampus is the reason for its vulner- (Amaral et al., 2007). Mossy fibers also project back onto 133
75 ability’ (McEwen, 1994). granule cells, thus forming a recurrent network. In addition 134
76 In this special issue of Neuroscience: ‘The the DG receives information from the contralateral hip- 135
77 hippocampus in aging and disease: from plasticity to pocampus via commissural projections (Amaral et al., 136
78 vulnerability’, we will review basic principles of 2007). Axon collaterals of CA3 pyramidal neurons synapse 137
79 hippocampal anatomy and neuroplasticity on various onto other CA3 neurons, forming a recurrent autoassocia- 138
80 levels as well as recent findings regarding its functional tive network whereas CA3 neurons projecting back to the 139
81 organization with respect to regional vulnerability, which dentate network form a heteroassociative network 140
82 is critical for the understanding of neurocognitive (Lisman, 1999). CA1 pyramidal neurons receive informa- 141
83 diseases (Bartsch, 2012). tion which has been pre-processed in the subnetworks of 142
the DG and CA3, but also receives direct projections from 143
the EC suggesting that the function of CA1 neurons 144
84 HIPPOCAMPAL ANATOMY includes comparing new information from the EC with 145
stored information via CA3 in terms of mismatch, error 146
85 Encoding, consolidation and retrieval of mnemonic and novelty detection (Lisman and Otmakhova, 2001). 147
86 information is critically dependent on a large reciprocal Besides the structural layout of connectivity of these 148
87 network of regions that includes neocortical association hippocampal circuits, it is believed that mnemonic 149
88 regions, subcortical nuclei, the medial temporal lobe information is represented and processed by spatio- 150
89 (MTL), parahippocampal areas and the hippocampal temporal patterns of firing in groups of neurons, also 151
90 formation (Fig. 1). The hippocampus is considered the referred to as cell assemblies involving fast oscillatory 152
91 central node in this circuit. It receives input from almost dynamics in various frequency bands (e.g. theta, sharp- 153
92 all neocortical association areas via perirhinal and wave ripples, slow oscillations and gamma oscillations) 154
93 parahippocampal cortices and finally through the that are synchronized and temporally coordinated within 155
94 entorhinal cortex (EC) (van Strien et al., 2009). The hip- and across cortical regions (Wulff et al., 2009; Battaglia 156
95 pocampus is a three-layered allocortical structure that is et al., 2011; Buzsaki and Moser, 2013). 157
96 reciprocally connected to other cortical and subcortical
97 areas (Figs. 1 and 2). The principal neurons of the hip-
98 pocampus are organized in layers and receive unidirec- NEUROPLASTICITY AND THE HIPPOCAMPUS 158
99 tional polymodal input from the EC, where layer II
159
100 neurons project via the perforant path to granule cells in
101 the dentate gyrus (DG) (Strange et al., 2014). The trisy- ‘‘Neuroplasticity can be broadly defined as the ability of the 160
102 naptic pathway from the DG to CA3 via mossy fibers nervous system to respond to intrinsic and extrinsic stimuli 161
103 and onward to CA1 via Schaffer collaterals is the principal by reorganizing its structure, function and connections; can 162
104 feed-forward circuit involved in the processing of informa- be described at many levels, from molecular to cellular to sys- 163
105 tion through the hippocampus (Fig. 2). Additionally, layer tems to behavior; and can occur during development, in 164
106 III neurons from the EC directly project to CA1 neurons response to the environment, in support of learning, in 165
107 via the temporoammonic path (perforant path to CA1). response to disease, or in relation to therapy. Such plasticity 166
108 CA1 pyramidal cells -the major output relay neurons – can be viewed as adaptive when associated with a gain in 167
function or as maladaptive when associated with negative 168
109 project via the subicular complex back to deep layers of
consequences such as loss of function or increased injury, 169
110 the EC and to various subcortical and cortical areas
points illustrated by animal models and some human studies.’’ 170
111 (Murray et al., 2011). The regions CA1–CA3 are sepa-
112 rated into four layers (pyramidal, stratum oriens, stratum (Cramer et al., 2011). 171
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T. Bartsch, P. Wulff / Neuroscience xxx (2015) xxx–xxx 3
Fig. 1. (A) Principal anatomy of the hippocampal memory systems and the brain regions involved in learning and memory. (B) Connectivity map of
critical memory structures of the temporal lobe system, diencephalic nuclei and neocortical association areas highlighting the reciprocal information
flow. Abbreviations: Ant, anterior thalamic nuclei; CA, cornu ammonis; DG, dentate gyrus; EC, entorhinal cortex; MB, mamillary bodies; Med, medial
thalamic nuclei; MTT, mamillothalamic tract (bundle of Vicq d’Azyr); SN, septal nuclei.
reciprocal interaction between neural structure and 176

function (Kolb and Muhammad, 2014). Neuroplasticity 177
can occur on various functional and structural levels from 178
changes in membrane excitability, synaptic plasticity to 179
changes in dendritic and axonal structure (Kolb and 180
Gibb, 2014). Neuroplasticity can also occur as structural 181
and functional adaptations and reorganization of neuronal 182
populations, which is reflected in modifications of recruit- 183
ment and strength of connectivity of networks and circuits. 184
Finally, neuroplasticity can occur on a phenomenological 185
level mirrored in changes and modifications of cognitive 186
and behavioral strategies (Cramer et al., 2011) (Fig. 4). 187
Neuroplasticity can show a time- and age-dependency 188
and can result in positive adaptive or negative (maladap- 189
tive) effects (Kolb and Gibb, 2014). 190
The hippocampus has long been considered a classic 191
example for the study of neuroplasticity as many 192
paradigms of synaptic plasticity such as LTP and LTD, 193
EPSP-spike potentiation and spike-timing-dependent 194
Fig. 2. (A) Intrinsic anatomy of the hippocampus depicting the
trisynaptic pathway as the principal feed forward neural circuit
plasticity, which are thought to represent cellular 195
involved in the processing of information through the hippocampus. correlates of learning and memory, have been identified 196
(B) Flow diagram of the information flow through the hippocampus and demonstrated in hippocampal circuits. Similarly, 197
highlighting the parallel processing of information as well as the structural plasticity in response to external stimulation 198
reciprocal auto- and heteroassociative networks of the DG and CA3.
such as modifications of dendritic tree size, number of 199
Abbreviations: CA, cornu ammonis; DG, dentate gyrus; EC, entorhi-
nal cortex. dendritic spines and number of synapses as well as the 200
formation of new neurons have been demonstrated in 201
the hippocampus (Leuner and Gould, 2010). 202
172 Neuroplasticity is the ability of the brain or brain Mechanisms of plasticity in the hippocampus are also 203
173 structures to adapt in response to intrinsic or extrinsic affected during the early stages of AD during which neu- 204
174 stimuli such as changes in the environment, rodegenerative changes of extracellular amyloid-beta 205
175 development or lesions and consists in principle of a (Ab) deposition and intracellular neurofibrillary tangle 206
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Fig. 3. High-resolution MR-imaging of the hippocampus with an analysis of hippocampal subfields.
Fig. 4. Schematic overview of the various contributing factors, different scales and methodological and conceptual levels determining
neuroplasticity in the hippocampus.
207 (NFT) formation accounts for molecular synaptic and mechanisms in the hippocampus that are fundamental 216
208 intraneuronal remodeling (Mufson et al., 2015). Axonal to learning and memory such as LTP (Pastalkova et al., 217
209 sprouting is another example of structural plasticity after 2006) can be modified by preceding synaptic activity. 218
210 damage that may result in maladaptive hippocampal cir- This type of regulatory mechanism of plasticity itself by 219
211 cuit reorganization. On the molecular level, plasticity can prior activity is called metaplasticity and has been impli- 220
212 be driven by enhanced expression of plasticity-related cated not only in physiological regulation but also in aging 221
213 genes, such as BDNF, CaMKII, CREB as well as and disease mechanisms (Hulme et al., 2013; Jones, this 222
214 increased surface expression of glutamatergic AMPA issue). On the network level, plastic changes in the hip- 223
215 and NMDA receptors. Activity-dependent neuroplastic pocampal memory system to a perturbation in terms of 224
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225 a network reorganization has been shown in patients with et al., 2008). This arrangement suggests a superimposed 284
226 hippocampal damage where a recruitment of an extended pattern of gradient-like as well as a modular organization 285
227 hippocampal-neocortical network compensating for hip- along the anterior-posterior axis of the hippocampus 286
228 pocampal dysfunction could be observed (Finke et al., (Strange et al., 2014). However, it is currently unclear, 287
229 2013a). how the anatomical organization, in particular the molec- 288
230 In this Special Issue of Neuroscience, the concept of ular expression patterns, can be reconciled with a func- 289
231 neuroplasticity has been applied to various neurological tional modular organization along the anterior-posterior 290
232 and psychiatric diseases as well as aging including AD axis. 291
233 (Mufson et al., 2015; Chetelat, this issue), depression
234 (Malykhin and Coupland, 2015), schizophrenia Functional subfield organization 292
235 (Tamminga and Suzanne Zukin, 2015) aging (Barnes, this
236 issue), epilepsy (Sierra et al., 2015; Bluemcke, this issue), The hippocampus is organized into different 293
237 neurodevelopmental disorders (van der Marel et al., cytoarchitectonic subfields that include the cornu 294
238 2015), metabolic disorders (Stranahan, 2015), neuroin- ammonis fields (CA1–CA4), the DG, and the subiculum. 295
239 flammation (Barrientos et al., 2015; Heine et al., 2015) Considering the intriguing anatomy of the hippocampal 296
240 including multiple sclerosis (MS) (Novkovic et al., 2015). subnetworks with its recurrent associative networks 297
embedded into the unidirectional trisynaptic pathway but 298
with parallel projections from the EC to the CA3 and 299
241 REGIONAL SPECIALIZATION AND CA1 region, it has been suggested that these networks 300
242 ORGANIZATION OF HIPPOCAMPAL perform differential computations in different cognitive 301
243 FUNCTIONS tasks (Marr, 1971; O’Reilly and McClelland, 1994; 302
Kesner and Rolls, 2015). Using animal models, an activa- 303
244 Hippocampal organization along the longitudinal axis
tion of these hippocampal subnetworks has been corre- 304
245 Earlier experimental models of hippocampal function lated with distinct cognitive or mnemonic operations 305
246 regarded the hippocampus as a unitary functional and thereby reflecting distinct electrophysiological- and 306
247 structural entity. With a greater refinement of neuroplastic-properties of subfield neurons (Chen et al., 307
248 hippocampal circuit anatomy in recent years, however, a 2009). For example, it has been argued that the DG dur- 308
249 regional specialization of hippocampal functions along ing encoding is involved in pattern separation – a cogni- 309
250 the longitudinal axis emerged (Small, 2002). Animal data tive function whereby a discrimination of similar and 310
251 using behavioral lesion models, studies of intrahippocam- overlapping neuronal patterns into more dissimilar pat- 311
252 pal connectivity and electrophysiological findings suggest terns is performed using minimal differences in the given 312
253 a dichotomic organization of hippocampal networks into cues (Guzowski et al., 2004; Yassa and Stark, 2011; 313
254 functional compartments such as the dorsal hippocampus Neunuebel and Knierim, 2014). The separation of pat- 314
255 performing cognitive functions, in particular spatial pro- terns on the basis of ‘similarity’ is thought to play a role 315
256 cessing, and the ventral hippocampus being involved in in the non-ambiguous and distinct representation of simi- 316
257 the regulation of stress, emotion, and affect (Moser and lar memories in the context of learning and memory, pre- 317
258 Moser, 1998; Bannerman et al., 2004; Thompson et al., venting memory interference and allowing novelty 318
259 2008; Dong et al., 2009; Fanselow and Dong, 2010). detection (Bakker et al., 2008). It is also thought that pat- 319
260 This distinction was partly derived from findings that the tern separation is impaired in aging and mild cognitive 320
261 ventral hippocampus has stronger connectivity with the impairment (Yassa et al., 2011). The autoassociative 321
262 amygdala, hypothalamic and endocrine nuclei as well as CA3 circuitry is thought to be involved in binding of disso- 322
263 the critical role of the ventral hippocampus in the stress ciative representations and pattern completion, a mnemo- 323
264 response (Kjelstrup et al., 2002; Strange et al., 2014). nic function which allows the recall of a memory by only 324
265 Recent findings also indicate that markers of plasticity partial or fragmented representation of cues that were 325
266 such as LTP as well as the formation of new neurons in present during initial learning. Both operations are linked 326
267 the DG are differentially organized in the dorsal and ven- together, as pattern separation in the DG is a prerequisite 327
268 tral hippocampus thus (Wu and Hen, 2014; Opendak and for pattern completion in CA3 (Lisman, 1999). The CA3 328
269 Gould, 2015). Furthermore, on a cellular level, this network has also been implied in spatial rapid one-trial 329
270 dichotomic organization also correlates to a differential learning and spatial sequence learning. The CA1 network 330
271 expression of NMDA and AMPA receptor subunits in the receives input from CA3 and the EC and has been 331
272 dorsal and ventral hippocampus of the rat (Pandis et al., thought to be engaged in input integration and match- 332
273 2006). mismatch detection between predictions from CA3 and 333
274 This dichotomic view of the functional organization is perceptual input from the EC and novelty detection 334
275 currently being replaced by a more differentiated (Rolls and Kesner, 2006; Hunsaker and Kesner, 2013). 335
276 concept as some functional differences are organized in The CA1 region is also involved in the integration of tem- 336
277 a more gradient-like way along the longitudinal axis. The poral and object representations. Behaviorally, it has 337
278 distribution of NMDA receptors, the connectivity to been shown that CA1 is critical for autobiographical mem- 338
279 cortical and subcortical structures, the size of so called ory retrieval (Kesner and Hunsaker, 2009; Bartsch et al., 339
280 place fields suggest a gradual longitudinal axis 2011). Furthermore, the CA1 subregion is involved in our 340
281 distribution whereas genomic expression analyses ability to learn a map-like representation of an environ- 341
282 demarcate CA1 and DG into three (ventral, intermediate ment which is in accordance with the cognitive-map the- 342
283 and dorsal) and CA3 into nine modules (Thompson ory, which suggests that allocentric spatial 343
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344 representations of locations are processed in the hip- stronger reduction of ADC suggesting that the ischemic 403
345 pocampus (Bartsch et al., 2010). insult results in a stronger impairment of CA1 metabolism 404
346 Only recently, with the emergence of high-field MR compared to inflammation and epilepsy (Bartsch et al., 405
347 scanning and new imaging protocols it has been 2015). These results show that acute damage to the hip- 406
348 possible to shed light on the longitudinal organization of pocampus selectively affects the CA1 subregion, a region 407
349 the hippocampus and to correlate differential that is highly plastic. In contrast, CA3 and the DG are only 408
350 hippocampal subfield activation to different mnemonic marginally affected. The cellular mechanisms that lead to 409
351 functions in humans (Fig. 3) (Small, 2002; Das et al., a regional vulnerability to a glutamate- and calcium- 410
352 2012; Engvig et al., 2012; Poppenk et al., 2013). High- mediated excitotoxicity are possibly a reflection of 411
353 resolution functional and volumetric imaging studies indi- genomic-dependent regional differences in the distribu- 412
354 cate a differential involvement of hippocampal subfields tion of glutamatergic NMDA receptors in CA1 neurons 413
355 in memory and learning showing that CA3 and the DG that express considerably higher densities of NMDA 414
356 are involved in patterns separation, memory encoding NR2 subunits than do CA3 or DG neurons, as reported 415
357 and early retrieval, and an involvement of CA1 in late for rodents (Coultrap et al., 2005; Gee et al., 2006; 416
358 retrieval, consolidation, spatial encoding, autobiographi- Quintana et al., 2006; Newrzella et al., 2007; Butler 417
359 cal retrieval and recognition (Bakker et al., 2008; et al., 2010). Furthermore, regional differences in antioxi- 418
360 Suthana et al., 2009; Mueller et al., 2011; Bonnici et al., dant enzymes as well as inflammatory reactions may play 419
361 2012, 2013; Deuker et al., 2014). These high-resolution a role in enhanced vulnerability of the CA1 region (Wang 420
362 imaging methods have been applied to neurological, neu- and Michaelis, 2010; Michaelis, 2012). Interestingly, hip- 421
363 rodegenerative and psychiatric diseases as well as aging pocampal interneurons are believed to be more resistant 422
364 showing differential patterns of pathological changes to the impact of transient ischemia than larger pyramidal 423
365 (Mueller et al., 2007; Mueller and Weiner, 2009). These neurons (Harry and Lefebvre d’Hellencourt, 2003; 424
366 imaging patterns are currently evaluated in terms of Avignone et al., 2005). 425
367 developing imaging biomarkers for disease and treatment
368 outcomes (Malykhin and Coupland, 2015; Sierra et al., Aging and the hippocampus 426
369 2015).
Neuroplasticity mechanisms in the hippocampus 427
subserving cognitive functions are also subject to aging 428
370 REGIONAL VULNERABILITY OF THE processes and it has been suggested that neuroplastic 429
371 HIPPOCAMPUS mechanisms are particularly vulnerable during aging 430
(Burke and Barnes, 2006). Interestingly, principal cell 431
372 Acute damage to the hippocampus
numbers, dendritic branching, and dendritic spine density 432
373 For over 100 years it has been known that acute are not substantially reduced during the aging process 433
374 pathological conditions, such as ischemia, (West et al., 1994; Lister and Barnes, 2009). Also, bio- 434
375 hypoglycemia, epileptic seizures and other neurological physical properties of hippocampal neurons such as the 435
376 conditions can cause damage to the hippocampus resting membrane potential, membrane time constant, 436
377 (Michaelis, 2012). This damage of the hippocampus is input resistance, threshold to action potential are largely 437
378 most evident in CA1 hippocampal neurons and is a reflec- preserved over the lifespan (Burke and Barnes, 2010). 438
379 tion of a selective vulnerability of the hippocampus to There are, however, observations of synaptic loss in the 439
380 acute conditions impairing the metabolic homeostasis of layer II entorhinal cortical input to the granule cells in 440
381 CA1 pyramidal neurons to glutamate-dependent and the DG (Burke and Barnes, 2010). This change in con- 441
382 calcium-mediated mechanisms of neuronal cytotoxicity nectivity may affect the function of hippocampal subnet- 442
383 (Schmidt-Kastner and Freund, 1991; Bartsch et al., works for example during pattern separation (Burke and 443
384 2006, 2008). A brief episode of cerebral ischemia results Barnes, 2010). Synaptic plasticity such as the induction 444
385 in the selective cell death of hippocampal CA1 neurons and maintenance of LTP in line with alterations in 445
386 whereas the DG, CA3, and most cortical neurons appear Ca2+ homeostasis changes with age (Lister and 446
387 to be more resistant. The structural changes in CA1 that Barnes, 2009). Along these lines, subregion-specific 447
388 follow the insult are most prominent after a delay of changes in the expression of genes subserving the regu- 448
389 3–4 days and thus have been termed ‘delayed neuronal lation of neuroplasticity such as LTP have been observed 449
390 death’ (Pulsinelli et al., 1982; Schmidt-Kastner and in the aging hippocampus (Burger, 2010). Furthermore, 450
391 Freund, 1991; Kirino, 2000). The phenotype, evolution cognitive changes during aging can also be attributed to 451
392 and pattern of lesions in the hippocampal CA1 region in changes in the neural dynamics of hippocampal circuits, 452
393 acute neurological disorders was recently studied using e.g. in place cell maintenance, stability and plasticity dur- 453
394 high-resolution MR-imaging (Bartsch et al., 2015). In ing remapping and pattern separation processes (Burke 454
395 patients with hippocampal ischemia, neuroinflammation, and Barnes, 2010). Neurogenesis in the DG also 455
396 after status epilepticus and transient global amnesia, the decreases with age, which may contribute to the changes 456
397 CA1 region was selectively affected compared to other in neuroplasticity over the lifespan (Olariu et al., 2007). In 457
398 cornu ammonis (CA-) regions of the hippocampus. The humans, histo-pathological studies confirm that CA1 does 458
399 maximum impairment of CA1 cellular metabolism as mea- not show a pronounced cell loss during aging, an obser- 459
400 sured by apparent diffusion coefficient (ADC) in MRI was vation that was confirmed in high-resolution subfield 460
401 seen 48 h-72 h after the insult, irrespective of the nature imaging (La Joie et al., 2010) whereas other imaging stud- 461
402 of the insult. Hypoxic-ischemic insults led to a significant ies did show an effect of aging on subfield volume 462
7 August 2015
463 (Mueller and Weiner, 2009; Shing et al., 2011; Wisse The functional relevance of this continuous generation 520
464 et al., 2014), probably depending on study cohort and of new cells has been extensively studied in the last 521
465 imaging methodology. years, in particular with regard to the structural integra- 522
tion into preexisting neural circuits within the hippocam- 523
pus with subsequent modifications of hippocampal 524
466 CHRONIC INFLUENCES ON THE
functions (Bergmann and Frisen, 2013). The process 525
467 HIPPOCAMPUS AND DURING AGING
of adult neurogenesis is subject to various internal 526
468 In chronic diseases such as neurodegenerative diseases, and external modulatory influences during physiological 527
469 chronic epilepsy or neuropsychiatric disorders, the time and pathophysiological states (Voss et al., 2013). It has 528
470 course of pathological changes is much slower than with been suggested that adult neurogenesis contributes to 529
471 e.g. acute ischemia and might be more complex as the plastic adaptation of learning and memory in com- 530
472 multiple pathological pathways overlap. Furthermore, in plex environments as an impairment of neurogenesis 531
473 contrast to acute lesions to the hippocampus, the correlates with reduced hippocampus-dependent mem- 532
474 regional vulnerability of the hippocampus may shift to ory performance (Drapeau et al., 2003). One process 533
475 other hippocampal structures such as the DG or the that has been suggested to play a role in adaptive 534
476 CA3 area (Small et al., 2011; Falkai et al., 2012). behavior is pattern separation, during which similar rep- 535
477 In AD, extracellular amyloid deposits consisting of Ab resentations are processed into distinct, dissimilar non- 536
478 protein and intra-neuronal NFTs composed of overlapping representations, a function that is required 537
479 hyperphosphorylated tau protein are a hallmark of the in discriminating similar experiences (Sahay et al., 538
480 cellular pathological process. The deposition of NFTs 2011; Yassa and Stark, 2011). Pattern separation as 539
481 leads to neurodegeneration and the hippocampal CA1 is well as its complementary function – pattern completion 540
482 one of the first structures affected before other subfields – are thought to be dependent on the neural circuity of 541
483 such as the subiculum, CA2, CA3 and CA4/DG are the DG and the hippocampal CA3 region (Deng et al., 542
484 included in the pathological process (West et al., 1994; 2010). It has further been suggested that impairments 543
485 Braak and Braak, 1995, 1996; Chetelat et al., 2008; of this pattern separation process contribute to the 544
486 Mufson et al., 2015). In some imaging studies, the integ- development of certain neuropsychiatric diseases such 545
487 rity of CA3/DG (Mueller et al., 2010) or CA2 subregions as anxiety disorders and depression and may be 546
488 was preserved (Wisse et al., 2014). Deficits in encoding caused by disturbed adult neurogenesis (Sahay and 547
489 were correlated with CA1 volume whereas deficits in Hen, 2007; Kheirbek et al., 2012). Impairment of hip- 548
490 retrieval were correlated with a disruption of a pocampal neurogenesis may thus contribute to cogni- 549
491 hippocampal-parietal-frontal network in aMCI (Fouquet tive deficits seen in depression. Besides the putative 550
492 et al., 2012). Apolipoprotein E4 status has an effect on role in pattern separation, adult neurogenesis is also 551
493 the volume of CA3 / DG in healthy controls and AD thought to play a role in encoding temporal context rep- 552
494 (Mueller and Weiner, 2009). In other studies, it could be resentation in the hippocampus and in the resolution of 553
495 shown that the volume of CA3/DG is associated to verbal memory representations (Aimone et al., 2014). 554
496 learning and early retrieval whereas CA1 atrophy is corre- Furthermore, neurogenesis is involved in the formation 555
497 lated with impaired consolidation/delayed retrieval of a developmental phenotype of individuality as a 556
498 (Mueller et al., 2007, 2011). reflection of a neuroplastic interaction between genetic 557
499 Accordingly, imaging studies suggest an association and environmental variations (Freund et al., 2013). 558
500 between CA1 and subiculum volume loss and the Although the relevance of adult neurogenesis for 559
501 development of later dementia and emphasize subfield enhancing neuroplasticity in the hippocampus has been 560
502 imaging as sensitive biomarker tool for the detection demonstrated in rodents, the functional relevance in 561
503 and study of early AD processes (de Flores et al., 2015). humans is not entirely clear (Lazarov et al., 2010; 562
Ming and Song, 2011). Adult neurogenesis in the hip- 563
pocampus is dynamically regulated and positively mod- 564
504 HIPPOCAMPAL NEUROPLASTICITY AND
ulated by various physiological influences such as 565
505 ADULT NEUROGENESIS physical exercise, enriched environment, diet and hip- 566
506 Plasticity in the central nervous system requires the pocampal learning, which facilitate cell proliferation, 567
507 adaptation of brain functions and neural circuits and it maturation and new neuron survival and modulates 568
508 has long been assumed that these plastic changes mechanisms of synaptic plasticity such as DG LTP 569
509 take place at hard-wired neural connections. It has (Brown et al., 2003; Voss et al., 2013; Aimone et al., 570
510 been shown, however, that new neuronal cells can be 2014). On the other side, influences such as aging 571
511 created in the adult mammalian hippocampus; these and stress reduce cell proliferation, survival, and neu- 572
512 new cells might play an important role in the lifelong ronal differentiation of the newly formed neurons 573
513 plasticity mechanisms of learning and adaptation (Opendak and Gould, 2015). Thus, hippocampal neuro- 574
514 (Ming and Song, 2011). Adult neurogenesis in mam- genesis was found to be altered in experimental mod- 575
515 mals is restricted to two brain areas – the olfactory els of neuropsychiatric diseases such as major 576
516 bulb and hippocampus, where neurons are generated depression, anxiety disorders, stroke, AD and epilepsy. 577
517 by neural stem cells throughout adult life. In humans, In these disease states, either a reduction of neuroge- 578
518 adult neurogenesis is thought to be restricted to the nesis by decreased stem cell activity or a reduction of 579
519 subgranular zone (SGZ) in the DG of the hippocampus. neuronal survival can be observed. Further, abnormal 580
7 August 2015
581 stem cell maturation could lead to aberrant integration influence of newly generated cells on hippocampal 642
582 into hippocampal circuits. The reduction of adult neuroplasticity highlights the potential of neurogenesis for 643
583 genesis in AD may at least partly be modulated by dis- neuroplastic intervention in aging and disease states 644
584 ease risk genes such as human presenillin (PS) (Lazarov et al., 2010; Ming and Song, 2011). 645
585 variants. In epilepsy, seizures lead to increased cell
586 proliferation but also to mis-migration of newly formed THE HIPPOCAMPUS AND THE REGULATION 646
587 neurons and altered circuit integration (Ming and OF STRESS 647
588 Song, 2011). Cerebral ischemia stimulates cell prolifer-
589 ation in the DG, thereby giving rise to newly generated Stress as a concept is defined as a multidimensional 648
590 neurons and supporting the activity-dependent role of construct consisting of (i) stress input with perception 649
591 adult neurogenesis in plasticity and compensation and appraisal of the stressor, (ii) the processing of 650
592 (Schwamm et al., 1998; Bueters et al., 2008; Miles stressful information and (iii) the stress response itself 651
593 and Kernie, 2008). Interestingly, the development of with the objective of restoring homeostasis through 652
594 hippocampal neural stem/progenitor cells can not only behavioral and physiological adaptations’ (de Kloet, 653
595 be directed toward the neuronal lineage but can be 2012). These changes in homeostatic regulation can lead 654
596 also directed toward the oligodendrocyte lineage, which from adaptive to maladaptive consequences at multiple 655
597 could result in the generation of human oligodendro- levels and are considered to contribute to various neu- 656
598 cytes, critical for remyelination processes in response ropsychiatric diseases in which deficits of hippocampal 657
599 to demyelinating lesions (Czepiel et al., 2015). With function such as cognitive impairment can be observed 658
600 regard to the mechanisms of plasticity following hip- (Dohring et al., 2014; Lucassen et al., 2014). The hip- 659
601 pocampal damage, it has been shown that – at least pocampal system with its circuitry is functionally and 660
602 in the structurally integrated in the stress responses to behav- 661
603 rat – global ischemia results in an almost complete loss ioral stressors including fear and anxiety. In the context 662
604 of CA1 neurons, which is reflected by robust deficits in of stress, the hippocampus is subject to an involvement 663
605 spatial memory. The reappearance of nearly 40% of by the hypothalamic–pituitary–adrenal axis, which influ- 664
606 the CA1 neurons within 90 days of the insult was asso- ences the hippocampus by the release of stress hor- 665
607 ciated with a restoration of hippocampal spatial memory mones (de Kloet et al., 2005; McEwen, 2007; Fanselow 666
608 function, which indicates that the newly formed neurons and Dong, 2010). Stress targets hippocampal function 667
609 that originate in the lateral periventricular region have on different levels via glucocorticoid receptor activation 668
610 the potential to restore hippocampal function (Bendel leading to various cellular and systemic effects on synap- 669
611 et al., 2005). Metabolic diseases such diabetic states tic plasticity, neuronal survival, hippocampal neurogene- 670
612 and high-caloric intake also impair hippocampal neuro- sis, hippocampal connectivity and memory (McEwen 671
613 genesis, synaptic plasticity and learning possibly via and Milner, 2007; Sandi and Pinelo-Nava, 2007; Segal 672
614 changes in glucocorticoid levels (Stranahan et al., et al., 2010; de Kloet, 2012). As an example, hippocampal 673
615 2008). Radiation and chemotherapy-induced damage LTP and LTD in CA1 can be affected by acute behavioral 674
616 to neural progenitor populations may lead to impaired stress (Howland and Wang, 2008). Stress may lead also 675
617 adult hippocampal neurogenesis and decreased sub- to cytotoxicity and metabolic vulnerability in CA1 neurons 676
618 cortical white matter integrity contributing to neurocog- due to glucocorticoid-enhanced glutamatergic transmis- 677
619 nitive deficits (Monje and Dietrich, 2012). sion with an increase of calcium influx (Joels, 2009). On 678
620 Only recently, the interconnection between adult a structural level, stress may lead to altered dendritic 679
621 neural stem cell regulation and the immune system architecture in hippocampal circuits as it may induce a 680
622 acting on hippocampal function has been studied retraction of CA3 pyramidal neuron dendrites and reduc- 681
623 (Carpentier and Palmer, 2009; Williamson and Bilbo, tion of dendritic spine density as well as a loss of 682
624 2013; Barrientos et al., 2015). A plethora of literature synapses (de Kloet et al., 2005). 683
625 demonstrates the impact of an activated immune
626 response such as microglia and astrocyte activation, NEUROINFLAMMATION IN THE HIPPOCAMPUS 684
627 infiltration of T cells, cytokines, chemokines, prostaglan-
628 dins and reactive oxygen species (ROS) on hippocam- The role of neuroinflammatory mechanisms in 685
629 pal function (Novkovic et al., 2015). This immune hippocampal function and dysfunction has only recently 686
630 activation in inflammatory states such as during insult, been recognized. Neuroinflammatory states can 687
631 injury and in neurodegenerative diseases such as AD significantly contribute to the vulnerability of the 688
632 and aging may lead to an impairment of hippocampal hippocampus leading to cognitive impairment. This does 689
633 function including hippocampal neurogenesis, cellular not only pertain to pathological inflammatory states such 690
634 plasticity and learning (Barrientos et al., 2012; as during generalized inflammation or sepsis but also 691
635 Williamson and Bilbo, 2013). during dysregulation in autoimmunity as in MS and 692
636 In sum, adult neurogenesis in the hippocampus limbic encephalitis (Kayser and Dalmau, 2014; Kostic 693
637 permits long-term neuroplastic adaptation in et al., 2015). Peripheral inflammatory responses in the 694
638 hippocampal circuits to complex environmental hippocampus result in an interleukin-1 beta (IL-1b) activa- 695
639 conditions. Considering the positive and negative tion with subsequent T and B lymphocyte proliferation and 696
640 regulation of adult hippocampal neurogenesis by diverse stimulation of natural killer cell activity. IL-1b facilitates the 697
641 external stimuli such as environmental factors, the production of other cytokines such as TNFa and 698
interleukin-6 (IL-6), which acts on neural activity in the 699
7 August 2015
700 hippocampus (Baier et al., 2009; Tan et al., 2014). An et al., 1988). In patients with cognitive deficits, selective 758
701 aggravated glutamate excitotoxicity may lead to further and progressive hippocampal atrophy was observed 759
702 deleterious effects in hippocampal neurons (Semmler that was focused on the CA1 subregion (Sicotte et al., 760
703 et al., 2013; Tan et al., 2014; Michels et al., 2015). 2008). This hippocampal atrophy in turn was associated 761
704 Increasing evidence suggests that neuroimmune signal- with deficits in memory encoding and retrieval (Sicotte 762
705 ing and neuroinflammation is also present in a wide spec- et al., 2008; Anderson et al., 2010). MS patients with 763
706 trum of pathophysiological processes such as during depressive symptoms have smaller volume in CA2, 764
707 neurodegeneration in AD (Heneka et al., 2015). CA3 and DG but show elevated cortisol levels (Gold 765
708 Neuroimmune signaling encompasses microglia and et al., 2010, 2014). Besides reduction in hippocampal 766
709 astrocyte activation, T-cell infiltration and messengers volume, connectivity of the hippocampus as measured 767
710 such as cytokines, ROS and prostaglandins. using resting-state functional connectivity between the 768
711 The influence of the immune system is not restricted to hippocampus and anterior cingulate gyrus, thalamus 769
712 states of an activated immune system. The idea has been and prefrontal cortex was decreased reflecting impair- 770
713 put forward that a basal level of neuroimmune interaction ments of large-scale cognitive networks (Roosendaal 771
714 in the hippocampus is also functionally relevant and et al., 2008, 2010). The plasticity in hippocampal mem- 772
715 present in physiological states and during development ory networks in MS patients with cognitive deficits was 773
716 (Williamson and Bilbo, 2013). For example, a role for recently studied (Hulst et al., 2012). In an episodic 774
717 cytokines has been observed in hippocampal learning, memory fMRI task, hypoactivation of hippocampus- 775
718 LTP and neurogenesis (Baier et al., 2009; Braun et al., dependent networks was observed in MS patients with 776
719 2013; Williamson and Bilbo, 2013). It has further been sug- cognitive deficits compared to controls. However, hyper- 777
720 gested that hippocampal-neuroimmunological interactions activation in the hippocampal-cingulate memory system 778
721 via neuroimmune signaling molecules including chemoki- during encoding was seen in MS patients without cogni- 779
722 nes and cytokines contribute to the homeostatic balance tive deficits. This different activation pattern was inter- 780
723 of vulnerability, plasticity and resilience mechanisms in preted as functional adaptation within the hippocampal 781
724 the hippocampus (Williamson and Bilbo, 2013). memory system before cognitive deficits become clini- 782
725 Alterations of the neuro-immune signature such as cally relevant. 783
726 microglial sensitization seems to be a hallmark of a On a cellular level, hippocampal demyelination and 784
727 normal aging process resulting in facilitated and inflammation are robust findings in post-mortem 785
728 exaggerated neuroinflammatory response in the aging specimens (Geurts et al., 2007). Most demyelination 786
729 brain to an immune challenge (Barrientos et al., 2015). lesions are chronic with subpial or subependymal loca- 787
730 This neuroinflammatory response is further enhanced by tion. Whereas Papadopoulos et al. reported neuronal 788
731 a dysregulated neuroendocrine response in the aged ani- cell loss in the CA1 and CA3-2 regions of approxi- 789
732 mal leading to higher cortisol levels. Notably, these neu- mately 30% (Papadopoulos et al., 2009), Dutta et al., 790
733 roimmunological responses seem to be most prominent reported only minor neuronal cell loss (Dutta et al., 791
734 in the hippocampal formation (Barrientos et al., 2015). 2010). However, the latter study showed a significant 792
735 These mechanisms may lead to long lasting elevations decrease in synaptic density in the demyelinated hip- 793
736 in pro-inflammatory cytokines in the hippocampus result- pocampus (Dutta et al., 2010). Synaptophysin-positive 794
737 ing in impaired plasticity and cognitive deficits pre-synaptic terminals in CA1 and DG were reduced 795
738 (Barrientos et al., 2015). possibly due to demyelination-associated synaptic prun- 796
ing. In comparison to motor cortex, levels of proteins 797
involved in axonal transport, synaptic plasticity, neu- 798
739 MS
ronal survival and glutamatergic neurotransmission 799
740 MS is an inflammatory and demyelinating disease that were altered in the hippocampus. This suggests that 800
741 affects the central nervous system and is commonly the molecular machinery associated with neuroplasticity 801
742 associated with white-matter damage. (such as LTP) may be impaired in MS (Dutta et al., 802
743 Neuroinflammation is mediated by microglia activation 2010; Novkovic et al., 2015). Experimentally, inflamma- 803
744 and acts against myelin, the neuropathological tory changes in MS can be modeled using experimen- 804
745 hallmark of the disease process in MS. However, tal autoimmune encephalomyelitis (EAE), an 805
746 activation of the neuroinflammatory cascade also established animal model of MS that shows acute or 806
747 causes neuronal and synaptic damage leading to gray chronically relapsing inflammatory and demyelinating 807
748 matter demyelination, atrophy and degeneration autoimmune processes (Novkovic et al., 2015). EAE 808
749 (Wegner and Stadelmann, 2009). The majority of MS leads to microglia-mediated neuroinflammation, 809
750 patients exhibits a clinically relevant cognitive dysfunc- demyelination, loss of hippocampal CA1 neurons and 810
751 tion during the course of the disease including learning behavioral deficits in a spatial learning task (Peruga 811
752 and memory difficulties suggesting involvement of the et al., 2011). 812
753 hippocampal memory system (Sicotte et al., 2008; The inflammatory changes in EAE also affect synaptic 813
754 Sacco et al., 2015). Indeed, human imaging studies plasticity in the hippocampus as LTP in CA1 is 814
755 have shown that the cognitive deficits are at least partly compromised possibly due to enhanced IL-1b release 815
756 dependent on the distribution of demyelinating lesions in from infiltrating lymphocytes or activated microglia 816
757 the hippocampus of severely-affected patients (Brainin (Nistico et al., 2014; Novkovic et al., 2015 #1748). Also, 817
7 August 2015
818 a certain role of the complement system has been attrib- mesial or hippocampal structures can be observed in the 876
819 uted to the synaptic changes in demyelinated hippocampi later stages (Urbach et al., 2006; Bien et al., 2007). 877
820 (Michailidou et al., 2015). Notably, remyelination of the
821 hippocampal neurons reversed these alterations (Dutta CHEMOTHERAPY, COGNITIVE IMPAIRMENT 878
822 et al., 2013).
AND HIPPOCAMPAL TOXICITY 879
Modern therapeutic options targeting cancer cells can 880

have also effects on the cognitive domain including 881
823 IMMUNE-MEDIATED NEUROINFLAMMATORY learning and memory, attention, executive, processing 882
824 LIMBIC ENCEPHALITIS AND HIPPOCAMPAL speed as well as mood that are clinically relevant and 883
825 FUNCTION add to the morbidity of patients (Seigers et al., 2013). In 884
recent years, putative key elements of this CNS toxicity 885
826 In the last decade, a new entity of inflammatory diseases of chemotherapy have been identified on a cellular level 886
827 was recognized that typically affects the limbic system and it has been suggested that neurotoxic effects act on 887
828 including the medial temporal lobe system and the neural function and plasticity (Monje and Dietrich, 2012). 888
829 hippocampus (Varley et al., 2015). The limbic encephalitis Key elements include a direct cellular toxicity, alterations 889
830 is considered an autoimmune encephalitis as antibodies in cellular metabolism, facilitation of oxidative stress and 890
831 targeting cell-surface or intracellular antigens can be induction of pro-inflammatory processes leading to myelin 891
832 detected. In paraneoplastic limbic encephalitis, onconeu- toxicity, disruption of neurogenesis (Kaiser et al., 2014). 892
833 ral (paraneoplastic) antibodies, such as anti-Hu, anti- Thus, modern chemotherapeutic substances exert their 893
834 Ma2 (anti-Ta), CRMP5/CV2 and ANNA-3 target intracellu- neurotoxic effect via several modes of action. 894
835 lar antigens (Irani et al., 2014). On the other side, antibod- Considering the role of the hippocampus in learning and 895
836 ies against neuronal surface antigens attack voltage- memory, its ability for plasticity and its vulnerability, an 896
837 gated potassium channels, glutamic acid decarboxylase impairment of neurogenesis has been suggested to be a 897
838 (GAD) and NMDA, AMPA and GABA(B) receptors and key element in the deleterious effects of chemotherapy 898
839 thus directly interfere with synaptic transmission and neu- on hippocampal function (Kaiser et al., 2014; Dietrich 899
840 ronal plasticity (Irani et al., 2014). Antibodies are not et al., 2015). Experimentally, damage to neural progenitor 900
841 directly pathogenic and neuronal damage rather seems cell populations within germinal zones of the adult CNS 901
842 to be mediated by cytotoxic T cells (Irani et al., 2014). has been identified as one of the key concepts in 902
843 Patients with autoimmune limbic encephalitis present with chemotherapy-associated impairments of neuroplasticity 903
844 subacute memory disturbances that are accompanied by and learning and memory (Seigers et al., 2013). Some 904
845 various neuropsychiatric symptoms, such as disorienta- chemotherapies show a neurotoxic effect on glial progen- 905
846 tion, confusion, temporal lobe seizures and behavioral itor cells and post-mitotic oligodendrocytes, the myelin 906
847 abnormalities, that are suggestive of impaired limbic and forming cells of the CNS that constitute white matter 907
848 hippocampal structures. Memory impairment is particu- integrity (Dietrich et al., 2015). Experimentally, it could 908
849 larly pronounced in the episodic domain (Bartsch et al., be shown that chemotherapy leads to an impairment of 909
850 2010, 2011; Bettcher et al., 2014). For example, antibod- hippocampus-dependent learning and frontal-temporal 910
851 ies against NMDARs result in impaired hippocampal networks. In chemotherapy-treated patients, several 911
852 synaptic function and leads to memory disturbances, psy- human imaging studies suggest a reduction of hippocam- 912
853 chiatric symptoms and seizures (Hughes et al., 2010; pal volume accompanied by memory deficits, albeit there 913
854 Moscato et al., 2010; Bettcher et al., 2014). In patients with are also studies that did not find volume loss and memory 914
855 NMDA encephalitis, neuroinflammatory processes lead to deficits (Inagaki et al., 2007). 915
856 an impairment of hippocampal functional connectivity and
857 white matter integrity that correlated with individual mem-
858 ory impairment (Finke et al., 2013b). In mice, the human HIPPOCAMPAL DYSFUNCTION IN METABOLIC 916
859 NMDAR antibodies cause a decrease in the density of
DISEASES 917
860 total and synaptic NMDAR clusters and total NMDAR pro-
861 tein concentration in the hippocampus (Planagumà et al., In the last years, it has been shown that metabolic 918
862 2014). This suggests that these cell-surface antibodies influences on the cellular and systems level can 919
863 impair hippocampal NMDAR functions and synaptic plas- enhance or impair hippocampal plasticity (Fotuhi et al., 920
864 ticity thus providing a rationale for functional and neurode- 2012). It became clear that metabolic alterations in obe- 921
865 generative changes leading to cognitive deficits. sity and diabetes increase the likelihood of cognitive 922
866 Potassium channel complex antibody–associated decline and accelerate the conversion of cognitive impair- 923
867 encephalitis is the most common form of non- ment to dementia (Stranahan, 2015). A model of neu- 924
868 paraneoplastic limbic encephalitis. MR imaging shows a rocognitive impairment in obesity and diabetes has been 925
869 preferential affection of the hippocampus with an suggested emphasizing a bidirectional influence of the 926
870 extension to the parahippocampal or fusiform gyrus and, metabolic condition on cellular mechanisms involved in 927
871 in some patients, to remote areas such as the thalamus. synaptic plasticity (Stranahan and Mattson, 2011). For 928
872 In many patients, the hippocampus is selectively example, a sedentary lifestyle, diabetes and obesity 929
873 affected. The hippocampi show prominent swelling in the may reduce adaptive cellular stress responses with oxida- 930
874 T2-weighted imaging typically seen within the first three tive stress, and inflammatory pathways leading to 931
875 months of disease onset. Typically, atrophic temporal- impaired synaptic plasticity, decreased neurogenesis 932
7 August 2015
933 and increased neurodegeneration (Fontan-Lozano et al., the CA3 principal cells into an epileptogenic population 992
934 2007; Stranahan, 2015). These mechanisms may lead promoting seizure initiation and/or propagation by 993
935 to enhanced vulnerability toward neurocognitive impair- increasing the net excitatory drive of dentate granule neu- 994
936 ment and AD. On the other hand, exercise and caloric rons (Kienzler et al., 2009; O’Dell et al., 2012). Other 995
937 restriction enhance neuroprotection, neurogenesis, and potential components of hippocampal epileptogenesis 996
938 synaptic plasticity via induction of adaptive cellular stress include, among others, molecular rearrangement/plastic- 997
939 responses, e.g. via BDNF (Stranahan and Mattson, ity of ion channel and neurotransmitter receptor expres- 998
940 2011). Some of the underlying mechanisms have been sion, neural injury, viral infections, as well as genetic 999
941 identified. Diabetic states and high-caloric intake seem variations, epigenetic modifications, neuroinflammation, 1000
942 to, at least partly, exert their effects via increased gluco- blood brain-barrier leakage, angiogenesis and endocrine 1001
943 corticoid receptor activation and impaired insulin and lep- influences. However, the precise role of these influences 1002
944 tin signaling (Stranahan et al., 2008; Stranahan and in the generation of epileptogenic networks remains 1003
945 Mattson, 2011). A link between diabetes and neurodegen- unclear (Pitkanen and Sutula, 2002; O’Dell et al., 2012). 1004
946 erative diseases such as Alzheimer’s has been suggested Hippocampal neurons are in particular vulnerable to 1005
947 as the insulin-degrading enzyme (IDE) is also involved in metabolic stress conditions and excitotoxicity in the wake 1006
948 the removal of beta-amyloid from the brain. It is thus of epileptic seizures leading to cell loss (Forster et al., 1007
949 conceivable that both conditions, diabetes and amyloid 2012; Bartsch et al., 2015; Sierra et al., 2015). This itself 1008
950 burden enhance each other by competing for the same may stimulate mechanisms of neural plasticity and further 1009
951 rescue pathway (Yang and Song, 2013). In addition, contribute to epileptogenesis. For example, it has been 1010
952 obesity-induced neuroinflammation has been linked to shown that during epileptogenesis, aberrant neuronal cir- 1011
953 impaired hippocampal function (Yang and Song, 2013; cuits are formed by adult-generated granule cells in the 1012
954 Erion et al., 2014). In sum, metabolic factors do show DG that itself are capable of inducing seizure activity 1013
955 an important influence on various cellular and systems (Pun et al., 2012). These results suggest that seizure– 1014
956 mechanisms involved in the regulation of hippocampal induced neurogenesis may play critical role in epileptoge- 1015
957 plasticity which may lead to an increased vulnerability in nesis in the hippocampus. In human patients, aspects of 1016
958 disease states. Along these lines the relevance of modifi- microstructural damage and plasticity in the hippocampus 1017
959 able environmental factors including cognitive activation, in epileptogenesis have begun to be studied using 1018
960 learning, life style factors, physical activity and metabolic MR-imaging aiming at identifying biomarkers of the 1019
961 factors on hippocampal function has been emphasized epileptogenic process, which are critical for the prognosis 1020
962 (Fotuhi et al., 2012). of epilepsy as well as for the assessment of possible 1021
treatment strategies (Sierra et al., 2015). 1022
963 THE HIPPOCAMPUS IN EPILEPSY

SLEEP AND HIPPOCAMPAL VULNERABILITY 1023
964 Epilepsy is a neurological disorder that is characterized by
965 recurrent seizures. Seizures are correlates of abnormal, The hippocampus plays a key role in sleep-dependent 1024
966 excessive or synchronous neuronal activity within the memory consolidation in animals and humans 1025
967 CNS. The human hippocampus in particular is capable (Diekelmann and Born, 2010). Consolidation of newly 1026
968 in generating epileptic seizures and to facilitate a formed memories refers to the process of stabilization of 1027
969 chronic increase of cellular excitability which in turn is a memory trace either by strengthening or reducing the 1028
970 thought to be the correlate of temporal lobe epilepsy susceptibility to interference. In humans, the hippocam- 1029
971 (TLE). TLE is a focal epilepsy characterized by seizures pus and adjacent cortical structures contribute to sleep- 1030
972 originating in or primarily involving temporal lobe dependent memory consolidation through interactions 1031
973 structures including the hippocampus (O’Dell et al., with distributed brain areas. According to a major hypoth- 1032
974 2012; Sloviter and Bumanglag, 2013). The disease esis of sleep-dependent memory consolidation of episo- 1033
975 course of TLE typically correlates with pathomorphologi- dic memory, neuronal activity associated with the 1034
976 cal neuronal changes termed hippocampal sclerosis encoding process during wakefulness becomes replayed 1035
977 (HS; syn. Ammon’s horn sclerosis) that manifest with seg- (reactivated) during ensuing sleep and thus mediates sys- 1036
978 mental neuronal cell loss in the pyramidal cell layer of the tem consolidation processes involving the redistribution of 1037
979 cornu ammonis CA1 and CA4 associated with reactive memories from an intermediate hippocampus-dependent 1038
980 astrogliosis (Cendes et al., 2014; Bluemcke, this issue). to a long-term hippocampus-independent store (Wilson 1039
981 It is difficult, however, to disentangle causes and conse- and McNaughton, 1994; Diekelmann and Born, 2010). 1040
982 quences of epileptogenesis and seizures in hippocampal This transfer is thought to be mediated by synchronous 1041
983 circuits. The current concept of TLE favors complex network pattern in the hippocampus during slow-wave 1042
984 multifactorial influences and mechanisms on different sleep (O’Neill et al., 2010). Sleep has also been impli- 1043
985 temporal scales and suggests a structural and functional cated in the regulation of plasticity as it has been sug- 1044
986 re-organization of neural circuits in CA3 and DG with gested that one of the critical functions of sleep is the 1045
987 aberrant maturation and ectopic migration within the restoration of synaptic homeostasis in terms of renormal- 1046
988 dentate circuitry. These alterations of synaptic circuitry ization of synaptic strength. This homeostatic regulation 1047
989 include aberrant mossy fiber sprouting, alterations in of synaptic strength is thought to increase neuronal 1048
990 dendritic branching, spine density and may lead to a signal-to-noise ratios and thus to facilitate the integration 1049
991 formation of recurrent excitatory collaterals that transform and consolidation of new memories (Tononi and Cirelli, 1050
7 August 2015
1051 2014). As described, many critical cognitive functions of regulated by NMDA receptors, metabotropic glutamate receptors 1108
1052 the hippocampus require specific brain states such as and voltage-gated calcium channels. Neuroscience. http:// 1109
dx.doi.org/10.1016/j.neuroscience.2015.03.014. 1110
1053 slow-wave sleep for the processing of mnemonic informa-
Amaral DG, Scharfman HE, Lavenex P (2007) The dentate gyrus: 1111
1054 tion. Thus, hippocampal function is very sensitive to a dis- fundamental neuroanatomical organization (dentate gyrus for 1112
1055 ruption of these processes by sleep deprivation and sleep dummies). Prog Brain Res 163:3–22. 1113
1056 loss leading to impaired formation of hippocampus- Anderson VM, Fisniku LK, Khaleeli Z, Summers MM, Penny SA, 1114
1057 dependent memories (Kreutzmann et al., 2015). Sleep Altmann DR, Thompson AJ, Ron MA, Miller DH (2010) 1115
1058 deprivation not only interrupts sleep-dependent cognitive Hippocampal atrophy in relapsing-remitting and primary 1116
1059 processing leading to impaired cognitive functioning, but progressive MS: a comparative study. Mult Scler 1117
16:1083–1090. 1118
1060 has widespread effects on synaptic plasticity mechanisms Avignone E, Frenguelli BG, Irving AJ (2005) Differential responses to 1119
1061 in the hippocampus (Prince and Abel, 2013). Short peri- NMDA receptor activation in rat hippocampal interneurons and 1120
1062 ods of sleep deprivation impair hippocampal plasticity by pyramidal cells may underlie enhanced pyramidal cell 1121
1063 affecting LTP, second-messenger signaling (cAMP- vulnerability. Eur J Neurosci 22:3077–3090. 1122
1064 protein kinase A (PKA)), adenosine, cellular transcription Baier PC, May U, Scheller J, Rose-John S, Schiffelholz T (2009) 1123
1065 factors (CREB), neurotrophic signaling (BDNF), and glu- Impaired hippocampus-dependent and -independent learning in 1124
IL-6 deficient mice. Behav Brain Res 200:192–196. 1125
1066 tamate receptor expression (Havekes et al., 2012).
Bakker A, Kirwan CB, Miller M, Stark CE (2008) Pattern separation in 1126
1067 Long-term sleep loss may lead to reduced hippocampal the human hippocampal CA3 and dentate gyrus. Science 1127
1068 cell proliferation and impaired neurogenesis thus impair- 319:1640–1642. 1128
1069 ing hippocampal plasticity and structural integrity on a Bannerman DM, Rawlins JN, McHugh SB, Deacon RM, Yee BK, Bast 1129
1070 longer time scale (Kreutzmann et al., 2015). Sleep depri- T, Zhang WN, Pothuizen HH, Feldon J (2004) Regional 1130
1071 vation after learning in humans also alters the connectivity dissociations within the hippocampus–memory and anxiety. 1131
Neurosci Biobehav Rev 28:273–283. 1132
1072 between brain regions as a shift from the hippocampo-
Barrientos RM, Frank MG, Watkins LR, Maier SF (2012) Aging- 1133
1073 neocortical network to an increased striatal navigation- related changes in neuroimmune-endocrine function: implications 1134
1074 related activity was observed (Orban et al., 2006). for hippocampal-dependent cognition. Horm Behav 62:219–227. 1135
Barrientos RM, Kitt MM, Watkins LR, Maier SF (2015) 1136
Neuroinflammation in the normal aging hippocampus. 1137
1075 CONCLUDING REMARKS
Neuroscience. http://dx.doi.org/10.1016/j.neuroscience.2015.03. 1138
1076 The research of the last decades has highlighted the 007. 1139
1077 multifaceted structure and function of the hippocampus Bartsch T (2012) The Clinical Neurobiology of the 1140
Hippocampus. Oxford, UK: Oxford University Press. 1141
1078 as a pivotal structure involved in cognitive and Bartsch T, Alfke K, Stingele R, Rohr A, Freitag-Wolf S, Jansen O, 1142
1079 behavioral regulation. These functions of the Deuschl G (2006) Selective affection of hippocampal CA-1 1143
1080 hippocampus are a reflection of the high degree of neurons in patients with transient global amnesia without long- 1144
1081 neuroplasticity and tightly linked to the instrinsic term sequelae. Brain 129:2874–2884. 1145
1082 properties of hippocampal neurons, circuits and neural Bartsch T, Alfke K, Wolff S, Rohr A, Jansen O, Deuschl G (2008) 1146
1083 populations. This particular degree of neuroplasticity Focal MR spectroscopy of hippocampal CA-1 lesions in transient 1147
global amnesia. Neurology 70:1030–1035. 1148
1084 may also be involved in the particular vulnerability and
Bartsch T, Dohring J, Rohr A, Jansen O, Deuschl G (2011) 1149
1085 susceptibility of the hippocampus to deleterious CA1 neurons in the human hippocampus are critical for 1150
1086 conditions such as ischemia, epilepsy, chronic stress autobiographical memory, mental time travel, and autonoetic 1151
1087 and neurodegeneration. From a clinical viewpoint, the consciousness. Proc Natl Acad Sci U S A 1152
1088 unique level of neuroplastic mechanisms in the 108:17562–17567. 1153
1089 hippocampus may be further explored with regard to Bartsch T, Döhring J, Reuter S, Finke C, Rohr A, Brauer H, Deuschl 1154
G, Jansen O (2015) Selective neuronal vulnerability of human 1155
1090 questions of resilience, regeneration and restoration
hippocampal CA1 neurons: lesion evolution, temporal course, and 1156
1091 to metabolic and behavioral stress that could lead to pattern of hippocampal damage in diffusion-weighted MR 1157
1092 therapeutic interventions on a cellular and systems level imaging. J Cereb Blood Flow Metab. 1158
1093 in neurological, neurodegenerative, and psychiatric Bartsch T, Schonfeld R, Muller FJ, Alfke K, Leplow B, Aldenhoff J, 1159
1094 diseases. Deuschl G, Koch JM (2010) Focal lesions of human hippocampal 1160
CA1 neurons in transient global amnesia impair place memory. 1161
Science 328:1412–1415. 1162
1095 Acknowledgments—T.B. has been supported by the German
Battaglia FP, Benchenane K, Sirota A, Pennartz CM, Wiener SI 1163
1096 Research Foundation SFB 654, FOR 2093, the German
(2011) The hippocampus: hub of brain network communication for 1164
1097 Cluster of Excellence Inflammation-at-Interfaces (ExC 306) and
memory. Trends Cognit Sci 15:310–318. 1165
1098 by the Faculty of Medicine, University of Kiel, Germany. Peer Bendel O, Bueters T, von Euler M, Ove Ogren S, Sandin J, von Euler 1166
1099 Wulff was supported by the Medical Research Council grant G (2005) Reappearance of hippocampal CA1 neurons after 1167
1100 G1100546, the German Research Foundation FOR 2143 and ischemia is associated with recovery of learning and memory. J 1168
1101 the Faculty of Medicine, University of Kiel, Germany. Cereb Blood Flow Metab 25:1586–1595. 1169
Bergmann O, Frisen J (2013) Neuroscience. Why adults need new 1170
brain cells. Science 340:695–696. 1171
1102 REFERENCES Bettcher BM, Gelfand JM, Irani SR, Neuhaus J, Forner S, Hess CP, 1172
Geschwind MD (2014) More than memory impairment in voltage- 1173
gated potassium channel complex encephalopathy. Eur J Neurol 1174
1103 Aimone JB, Li Y, Lee SW, Clemenson GD, Deng W, Gage FH (2014)
21:1301–1310. 1175
1104 Regulation and function of adult neurogenesis: from genes to
Bien CG, Urbach H, Schramm J, Soeder BM, Becker AJ, Voltz R, 1176
1105 cognition. Physiol Rev 94:991–1026.
Vincent A, Elger CE (2007) Limbic encephalitis as a precipitating 1177
1106 Aksoy-Aksel A, Manahan-Vaughan D (2015) Synaptic strength at the
1107 temporoammonic input to the hippocampal CA1 region in vivo is
7 August 2015
1178 event in adult-onset temporal lobe epilepsy. Neurology Lorenz P, Schiff N, Sharma A, Shekim L, Stryker M, Sullivan EV, 1249
1179 69:1236–1244. Vinogradov S (2011) Harnessing neuroplasticity for clinical 1250
1180 Bliss T, Schoepfer R (2004) Neuroscience. Controlling the ups and applications. Brain 134:1591–1609. 1251
1181 downs of synaptic strength. Science 304:973–974. Czepiel M, Boddeke E, Copray S (2015) Human oligodendrocytes in 1252
1182 Bonnici HM, Chadwick MJ, Kumaran D, Hassabis D, Weiskopf N, remyelination research. Glia 63:513–530. 1253
1183 Maguire EA (2012) Multi-voxel pattern analysis in human Das SR, Avants BB, Pluta J, Wang H, Suh JW, Weiner MW, Mueller 1254
1184 hippocampal subfields. Front Hum Neurosci 6:290. SG, Yushkevich PA (2012) Measuring longitudinal change in the 1255
1185 Bonnici HM, Chadwick MJ, Maguire EA (2013) Representations of hippocampal formation from in vivo high-resolution T2-weighted 1256
1186 recent and remote autobiographical memories in hippocampal MRI. Neuroimage 60:1266–1279. 1257
1187 subfields. Hippocampus 23:849–854. de Flores R, La Joie R, Landeau B, Perrotin A, Mezenge F, de La 1258
1188 Braak H, Braak E (1995) Staging of Alzheimer’s disease-related Sayette V, Eustache F, Desgranges B, Chetelat G (2015) Effects 1259
1189 neurofibrillary changes. Neurobiol Aging 16:271–278. Discussion of age and Alzheimer’s disease on hippocampal subfields: 1260
1190 278–284. comparison between manual and FreeSurfer volumetry. Hum 1261
1191 Braak H, Braak E (1996) Evolution of the neuropathology of Brain Mapp 36:463–474. 1262
1192 Alzheimer’s disease. Acta Neurol Scand Suppl 165:3–12. de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from 1263
1193 Brainin M, Goldenberg G, Ahlers C, Reisner T, Neuhold A, Deecke L adaptation to disease. Nat Rev Neurosci 6:463–475. 1264
1194 (1988) Structural brain correlates of anterograde memory deficits de Kloet R (2012) Stress and the Hippocampus. In: The clinical 1265
1195 in multiple sclerosis. J Neurol 235:362–365. neurobiology of the hippocampus (Th. Bartsch, ed), pp 77–104. 1266
1196 Braun O, Dewitz C, Moller-Hackbarth K, Scheller J, Schiffelholz T, Oxford: Oxford University Press. 1267
1197 Baier PC, Rose-John S (2013) Effects of blockade of peripheral Deng W, Aimone JB, Gage FH (2010) New neurons and new 1268
1198 interleukin-6 trans-signaling on hippocampus-dependent and memories: how does adult hippocampal neurogenesis affect 1269
1199 independent memory in mice. J Interferon Cytokine Res learning and memory? Nat Rev Neurosci 11:339–350. 1270
1200 33:254–260. Deuker L, Doeller CF, Fell J, Axmacher N (2014) Human 1271
1201 Brown J, Cooper-Kuhn CM, Kempermann G, Van Praag H, Winkler J, neuroimaging studies on the hippocampal CA3 region – 1272
1202 Gage FH, Kuhn HG (2003) Enriched environment and physical integrating evidence for pattern separation and completion. 1273
1203 activity stimulate hippocampal but not olfactory bulb Front Cell Neurosci 8:64. 1274
1204 neurogenesis. Eur J Neurosci 17:2042–2046. Diekelmann S, Born J (2010) The memory function of sleep. Nat Rev 1275
1205 Bueters T, von Euler M, Bendel O, von Euler G (2008) Degeneration Neurosci 11:114–126. 1276
1206 of newly formed CA1 neurons following global ischemia in the rat. Dietrich J, Prust M, Kaiser J (2015) Chemotherapy, cognitive 1277
1207 Exp Neurol 209:114–124. impairment and hippocampal toxicity. Neuroscience. http:// 1278
1208 Burger C (2010) Region-specific genetic alterations in the aging dx.doi.org/10.1016/j.neuroscience.2015.06.016. 1279
1209 hippocampus: implications for cognitive aging. Front Aging Dohring J, Schmuck A, Bartsch T (2014) Stress-related factors in the 1280
1210 Neurosci 2:140. emergence of transient global amnesia with hippocampal lesions. 1281
1211 Burke SN, Barnes CA (2006) Neural plasticity in the ageing brain. Nat Front Behav Neurosci 8:287. 1282
1212 Rev Neurosci 7:30–40. Dong HW, Swanson LW, Chen L, Fanselow MS, Toga AW (2009) 1283
1213 Burke SN, Barnes CA (2010) Senescent synapses and hippocampal Genomic-anatomic evidence for distinct functional domains in 1284
1214 circuit dynamics. Trends Neurosci 33:153–161. hippocampal field CA1. Proc Natl Acad Sci U S A 1285
1215 Butler TR, Self RL, Smith KJ, Sharrett-Field LJ, Berry JN, Littleton 106:11794–11799. 1286
1216 JM, Pauly JR, Mulholland PJ, Prendergast MA (2010) Selective Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza PV, Abrous 1287
1217 vulnerability of hippocampal cornu ammonis 1 pyramidal cells to DN (2003) Spatial memory performances of aged rats in the water 1288
1218 excitotoxic insult is associated with the expression of polyamine- maze predict levels of hippocampal neurogenesis. Proc Natl Acad 1289
1219 sensitive N-methyl-D-asparate-type glutamate receptors. Sci U S A 100:14385–14390. 1290
1220 Neuroscience 165:525–534. Dutta R, Chang A, Doud MK, Kidd GJ, Ribuado MV, Young EA, Fox 1291
1221 Buzsaki G, Moser EI (2013) Memory, navigation and theta rhythm in RJ, Staugaitis SM, Trapp BD (2010) Demyelination causes 1292
1222 the hippocampal-entorhinal system. Nat Neurosci 16:130–138. synaptic alterations in hippocampi from multiple sclerosis 1293
1223 Carpentier PA, Palmer TD (2009) Immune influence on adult neural patients. Ann Neurol. 1294
1224 stem cell regulation and function. Neuron 64:79–92. Dutta R, Chomyk AM, Chang A, Ribaudo MV, Deckard SA, Doud MK, 1295
1225 Cendes F, Sakamoto AC, Spreafico R, Bingaman W, Becker AJ Edberg DD, Bai B, Li M, Baranzini SE, Fox RJ, Staugaitis SM, 1296
1226 (2014) Epilepsies associated with hippocampal sclerosis. Acta Macklin WB, Trapp BD (2013) Hippocampal demyelination and 1297
1227 Neuropathol 128:21–37. memory dysfunction are associated with increased levels of the 1298
1228 Chen PE, Errington ML, Kneussel M, Chen G, Annala AJ, Rudhard neuronal microRNA miR-124 and reduced AMPA receptors. Ann 1299
1229 YH, Rast GF, Specht CG, Tigaret CM, Nassar MA, Morris RG, Neurol 73:637–645. 1300
1230 Bliss TV, Schoepfer R (2009) Behavioral deficits and subregion- Engvig A, Fjell AM, Westlye LT, Skaane NV, Sundseth O, Walhovd 1301
1231 specific suppression of LTP in mice expressing a population of KB (2012) Hippocampal subfield volumes correlate with memory 1302
1232 mutant NMDA receptors throughout the hippocampus. Learn training benefit in subjective memory impairment. Neuroimage 1303
1233 Mem16:635–644. 61:188–194. 1304
1234 Chetelat G, Fouquet M, Kalpouzos G, Denghien I, De la Sayette V, Erion JR, Wosiski-Kuhn M, Dey A, Hao S, Davis CL, Pollock NK, 1305
1235 Viader F, Mezenge F, Landeau B, Baron JC, Eustache F, Stranahan AM (2014) Obesity elicits interleukin 1-mediated 1306
1236 Desgranges B (2008) Three-dimensional surface mapping of deficits in hippocampal synaptic plasticity. J Neurosci 1307
1237 hippocampal atrophy progression from MCI to AD and over 34:2618–2631. 1308
1238 normal aging as assessed using voxel-based morphometry. Falkai P, Gruber O, Schmitt A (2012) Schizophrenia. In: The clinical 1309
1239 Neuropsychologia 46:1721–1731. neurobiology of the hippocampus (Th. Bartsch, ed). Oxford: 1310
1240 Coultrap SJ, Nixon KM, Alvestad RM, Valenzuela CF, Browning MD Oxford University Press. 1311
1241 (2005) Differential expression of NMDA receptor subunits and Fanselow MS, Dong HW (2010) Are the dorsal and ventral 1312
1242 splice variants among the CA1, CA3 and dentate gyrus of the hippocampus functionally distinct structures? Neuron 65:7–19. 1313
1243 adult rat. Brain Res Mol Brain Res 135:104–111. Finke C, Bruehl H, Duzel E, Heekeren HR, Ploner CJ (2013a) Neural 1314
1244 Cramer SC, Sur M, Dobkin BH, O’Brien C, Sanger TD, Trojanowski correlates of short-term memory reorganization in humans with 1315
1245 JQ, Rumsey JM, Hicks R, Cameron J, Chen D, Chen WG, Cohen hippocampal damage. J Neurosci 33:11061–11069. 1316
1246 LG, deCharms C, Duffy CJ, Eden GF, Fetz EE, Filart R, Freund Finke C, Kopp UA, Scheel M, Pech LM, Soemmer C, Schlichting J, 1317
1247 M, Grant SJ, Haber S, Kalivas PW, Kolb B, Kramer AF, Lynch M, Leypoldt F, Brandt AU, Wuerfel J, Probst C, Ploner CJ, Pruss H, 1318
1248 Mayberg HS, McQuillen PS, Nitkin R, Pascual-Leone A, Reuter- Paul F (2013b) Functional and structural brain changes in anti-N- 1319
7 August 2015
1320 methyl-D-aspartate receptor encephalitis. Ann Neurol attributes or domains of memory. Neurosci Biobehav Rev 1391
1321 74:284–296. 37:36–58. 1392
1322 Fontan-Lozano A, Saez-Cassanelli JL, Inda MC, de los Santos- Inagaki M, Yoshikawa E, Matsuoka Y, Sugawara Y, Nakano T, 1393
1323 Arteaga M, Sierra-Dominguez SA, Lopez-Lluch G, Delgado- Akechi T, Wada N, Imoto S, Murakami K, Uchitomi Y (2007) 1394
1324 Garcia JM, Carrion AM (2007) Caloric restriction increases Smaller regional volumes of brain gray and white matter 1395
1325 learning consolidation and facilitates synaptic plasticity through demonstrated in breast cancer survivors exposed to adjuvant 1396
1326 mechanisms dependent on NR2B subunits of the NMDA receptor. chemotherapy. Cancer 109:146–156. 1397
1327 J Neurosci 27:10185–10195. Irani SR, Gelfand JM, Al-Diwani A, Vincent A (2014) Cell-surface 1398
1328 Forster A, Griebe M, Gass A, Kern R, Hennerici MG, Szabo K (2012) central nervous system autoantibodies: clinical relevance and 1399
1329 Diffusion-weighted imaging for the differential diagnosis of emerging paradigms. Ann Neurol 76:168–184. 1400
1330 disorders affecting the hippocampus. Cerebrovasc Dis Joels M (2009) Stress, the hippocampus, and epilepsy. Epilepsia 1401
1331 33:104–115. 50:586–597. 1402
1332 Fotuhi M, Do D, Jack C (2012) Modifiable factors that alter the size of Kaiser J, Bledowski C, Dietrich J (2014) Neural correlates of 1403
1333 the hippocampus with ageing. Nat Rev Neurol 8:189–202. chemotherapy-related cognitive impairment. Cortex 54:33–50. 1404
1334 Fouquet M, Desgranges B, La Joie R, Riviere D, Mangin JF, Landeau Kayser MS, Dalmau J (2014) Anti-NMDA receptor encephalitis, 1405
1335 B, Mezenge F, Pelerin A, de La Sayette V, Viader F, Baron JC, autoimmunity, and psychosis. Schizophr Res. 1406
1336 Eustache F, Chetelat G (2012) Role of hippocampal CA1 atrophy Kesner RP, Hunsaker MR (2009) The temporal attributes of episodic 1407
1337 in memory encoding deficits in amnestic mild cognitive memory. Behav Brain Res 215:299–309. 1408
1338 impairment. Neuroimage 59:3309–3315. Kesner RP, Rolls ET (2015) A computational theory of hippocampal 1409
1339 Freund J, Brandmaier AM, Lewejohann L, Kirste I, Kritzler M, Kruger function, and tests of the theory: new developments. Neurosci 1410
1340 A, Sachser N, Lindenberger U, Kempermann G (2013) Biobehav Rev 48:92–147. 1411
1341 Emergence of individuality in genetically identical mice. Science Kheirbek MA, Klemenhagen KC, Sahay A, Hen R (2012) 1412
1342 340:756–759. Neurogenesis and generalization: a new approach to stratify 1413
1343 Gee CE, Benquet P, Raineteau O, Rietschin L, Kirbach SW, Gerber and treat anxiety disorders. Nat Neurosci 15:1613–1620. 1414
1344 U (2006) NMDA receptors and the differential ischemic Kienzler F, Norwood BA, Sloviter RS (2009) Hippocampal injury, 1415
1345 vulnerability of hippocampal neurons. Eur J Neurosci atrophy, synaptic reorganization, and epileptogenesis after 1416
1346 23:2595–2603. perforant pathway stimulation-induced status epilepticus in the 1417
1347 Geurts JJ, Bo L, Roosendaal SD, Hazes T, Daniels R, Barkhof F, mouse. J Comp Neurol 515:181–196. 1418
1348 Witter MP, Huitinga I, van der Valk P (2007) Extensive Kirino T (2000) Delayed neuronal death. Neuropathology 1419
1349 hippocampal demyelination in multiple sclerosis. J Neuropathol 20(Suppl):S95–S97. 1420
1350 Exp Neurol 66:819–827. Kjelstrup KG, Tuvnes FA, Steffenach HA, Murison R, Moser EI, 1421
1351 Gold SM, Kern KC, O’Connor MF, Montag MJ, Kim A, Yoo YS, Moser MB (2002) Reduced fear expression after lesions of the 1422
1352 Giesser BS, Sicotte NL (2010) Smaller cornu ammonis 2– ventral hippocampus. Proc Natl Acad Sci U S A 99:10825–10830. 1423
1353 3/dentate gyrus volumes and elevated cortisol in multiple Kolb B, Gibb R (2014) Searching for the principles of brain plasticity 1424
1354 sclerosis patients with depressive symptoms. Biol Psychiatry and behavior. Cortex 58:251–260. 1425
1355 68:553–559. Kolb B, Muhammad A (2014) Harnessing the power of neuroplasticity 1426
1356 Gold SM, O’Connor MF, Gill R, Kern KC, Shi Y, Henry RG, for intervention. Front Hum Neurosci 8:377. 1427
1357 Pelletier D, Mohr DC, Sicotte NL (2014) Detection of altered Kostic M, Stojanovic I, Marjanovic G, Zivkovic N, Cvetanovic A (2015) 1428
1358 hippocampal morphology in multiple sclerosis-associated Deleterious versus protective autoimmunity in multiple sclerosis. 1429
1359 depression using automated surface mesh modeling. Hum Cell Immunol. 1430
1360 Brain Mapp 35:30–37. Kreutzmann JC, Havekes R, Abel T, Meerlo P (2015) Sleep 1431
1361 Guzowski JF, Knierim JJ, Moser EI (2004) Ensemble dynamics of deprivation and hippocampal vulnerability: changes in neuronal 1432
1362 hippocampal regions CA3 and CA1. Neuron 44:581–584. plasticity, neurogenesis and cognitive function. Neuroscience. 1433
1363 Harry GJ, Lefebvre d’Hellencourt C (2003) Dentate gyrus: alterations http://dx.doi.org/10.1016/j.neuroscience.2015.04.053. 1434
1364 that occur with hippocampal injury. Neurotoxicology 24:343–356. La Joie R, Fouquet M, Mezenge F, Landeau B, Villain N, Mevel K, 1435
1365 Havekes R, Vecsey CG, Abel T (2012) The impact of sleep Pelerin A, Eustache F, Desgranges B, Chetelat G (2010) 1436
1366 deprivation on neuronal and glial signaling pathways important Differential effect of age on hippocampal subfields assessed 1437
1367 for memory and synaptic plasticity. Cell Signal 24:1251–1260. using a new high-resolution 3T MR sequence. Neuroimage 1438
1368 Heine J, Pruess H, Bartsch T, Ploner CJ, Paul F, Finke C (2015) 53:506–514. 1439
1369 Imaging of autoimmune encephalitis – relevance for clinical Lavenex P, Amaral DG (2000) Hippocampal-neocortical interaction: a 1440
1370 practice and hippocampal function. Neuroscience. http:// hierarchy of associativity. Hippocampus 10:420–430. 1441
1371 dx.doi.org/10.1016/j.neuroscience.2015.05.037. Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, van Praag H 1442
1372 Heneka MT, Golenbock DT, Latz E (2015) Innate immunity in (2010) When neurogenesis encounters aging and disease. 1443
1373 Alzheimer’s disease. Nat Immunol 16:229–236. Trends Neurosci 33:569–579. 1444
1374 Howland JG, Wang YT (2008) Synaptic plasticity in learning and Leuner B, Gould E (2010) Structural plasticity and hippocampal 1445
1375 memory: stress effects in the hippocampus. Prog Brain Res function. Annu Rev Psychol 61(111–140):C111–C113. 1446
1376 169:145–158. Lisman JE (1999) Relating hippocampal circuitry to function: recall of 1447
1377 Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, Parsons memory sequences by reciprocal dentate-CA3 interactions. 1448
1378 TD, Lynch DR, Dalmau J, Balice-Gordon RJ (2010) Cellular and Neuron 22:233–242. 1449
1379 synaptic mechanisms of anti-NMDA receptor encephalitis. J Lisman JE, Otmakhova NA (2001) Storage, recall, and novelty 1450
1380 Neurosci 30:5866–5875. detection of sequences by the hippocampus: elaborating on the 1451
1381 Hulme SR, Jones OD, Abraham WC (2013) Emerging roles of SOCRATIC model to account for normal and aberrant effects of 1452
1382 metaplasticity in behaviour and disease. Trends Neurosci dopamine. Hippocampus 11:551–568. 1453
1383 36:353–362. Lister JP, Barnes CA (2009) Neurobiological changes in the 1454
1384 Hulst HE, Schoonheim MM, Roosendaal SD, Popescu V, Schweren hippocampus during normative aging. Arch Neurol 66:829–833. 1455
1385 LJ, van der Werf YD, Visser LH, Polman CH, Barkhof F, Geurts JJ Lucassen PJ, Pruessner J, Sousa N, Almeida OF, Van Dam AM, 1456
1386 (2012) Functional adaptive changes within the hippocampal Rajkowska G, Swaab DF, Czeh B (2014) Neuropathology of 1457
1387 memory system of patients with multiple sclerosis. Hum Brain stress. Acta Neuropathol 127:109–135. 1458
1388 Mapp 33:2268–2280. Malykhin NV, Coupland NJ (2015) Hippocampal neuroplasticity in 1459
1389 Hunsaker MR, Kesner RP (2013) The operation of pattern separation major depressive disorder. Neuroscience. http://dx.doi.org/ 1460
1390 and pattern completion processes associated with different 10.1016/j.neuroscience.2015.04.047. 1461
7 August 2015
1462 Marr D (1971) Simple memory: a theory for archicortex. Philos Trans native conditions and in response to ischemia. BMC Genomics 1532
1463 R Soc Lond B Biol Sci 262:23–81. 8:370. 1533
1464 McEwen B (1994) The plasticity of the hippocampus is the reason for Novkovic T, Shchyglo O, Gold R, Manahan-Vaughan D (2015) 1534
1465 its vulnerability. Semin Neurosci 6:239–246. Hippocampal function is compromised in an animal model of 1535
1466 McEwen BS (2007) Physiology and neurobiology of stress and multiple sclerosis. Neuroscience. http://dx.doi.org/10.1016/ 1536
1467 adaptation: central role of the brain. Physiol Rev 87:873–904. j.neuroscience.2015.03.008. 1537
1468 McEwen BS, Milner TA (2007) Hippocampal formation: shedding light O’Dell CM, Das A, Gt Wallace, Ray SK, Banik NL (2012) 1538
1469 on the influence of sex and stress on the brain. Brain Res Rev Understanding the basic mechanisms underlying seizures in 1539
1470 55:343–355. mesial temporal lobe epilepsy and possible therapeutic targets: 1540
1471 Michaelis E (2012) Selective Neuronal Vulnerability in the a review. J Neurosci Res 90:913–924. 1541
1472 Hippocampus: Relationship to Neurological Diseases and O’Neill J, Pleydell-Bouverie B, Dupret D, Csicsvari J (2010) Play it 1542
1473 Mechanisms for Differential Sensitivity of Neurons to Stress. In: again: reactivation of waking experience and memory. Trends 1543
1474 The clinical neurobiology of the hippocampus (Th. Bartsch, ed), Neurosci 33:220–229. 1544
1475 pp 54–76 Oxford: Oxford University Press. O’Reilly RC, McClelland JL (1994) Hippocampal conjunctive 1545
1476 Michailidou I, Willems JG, Kooi EJ, van Eden C, Gold SM, Geurts JJ, encoding, storage, and recall: avoiding a trade-off. 1546
1477 Baas F, Huitinga I, Ramaglia V (2015) Complement C1q–C3 Hippocampus 4:661–682. 1547
1478 associated synaptic changes in multiple sclerosis hippocampus. Olariu A, Cleaver KM, Cameron HA (2007) Decreased neurogenesis 1548
1479 Ann Neurol. in aged rats results from loss of granule cell precursors without 1549
1480 Michels M, Vieira AS, Vuolo F, Zapelini HG, Mendonca B, Mina F, lengthening of the cell cycle. J Comp Neurol 501:659–667. 1550
1481 Dominguini D, Steckert A, Schuck PF, Quevedo J, Petronilho F, Opendak M, Gould E (2015) Adult neurogenesis: a substrate for 1551
1482 Dal-Pizzol F (2015) The role of microglia activation in the experience-dependent change. Trends Cogn Sci 19:151–161. 1552
1483 development of sepsis-induced long-term cognitive impairment. Orban P, Rauchs G, Balteau E, Degueldre C, Luxen A, Maquet P, 1553
1484 Brain Behav Immun 43:54–59. Peigneux P (2006) Sleep after spatial learning promotes covert 1554
1485 Miles DK, Kernie SG (2008) Hypoxic-ischemic brain injury activates reorganization of brain activity. Proc Natl Acad Sci U S A 1555
1486 early hippocampal stem/progenitor cells to replace vulnerable 103:7124–7129. 1556
1487 neuroblasts. Hippocampus 18:793–806. Pandis C, Sotiriou E, Kouvaras E, Asprodini E, Papatheodoropoulos 1557
1488 Ming GL, Song H (2011) Adult neurogenesis in the mammalian brain: C, Angelatou F (2006) Differential expression of NMDA and 1558
1489 significant answers and significant questions. Neuron AMPA receptor subunits in rat dorsal and ventral hippocampus. 1559
1490 70:687–702. Neuroscience 140:163–175. 1560
1491 Monje M, Dietrich J (2012) Cognitive side effects of cancer therapy Papadopoulos D, Dukes S, Patel R, Nicholas R, Vora A, Reynolds R 1561
1492 demonstrate a functional role for adult neurogenesis. Behav Brain (2009) Substantial archaeocortical atrophy and neuronal loss in 1562
1493 Res 227:376–379. multiple sclerosis. Brain Pathol 19:238–253. 1563
1494 Moscato EH, Jain A, Peng X, Hughes EG, Dalmau J, Balice-Gordon Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, 1564
1495 RJ (2010) Mechanisms underlying autoimmune synaptic Sacktor TC (2006) Storage of spatial information by the 1565
1496 encephalitis leading to disorders of memory, behavior and maintenance mechanism of LTP. Science 313:1141–1144. 1566
1497 cognition: insights from molecular, cellular and synaptic studies. Peruga I, Hartwig S, Thone J, Hovemann B, Gold R, Juckel G, Linker 1567
1498 Eur J Neurosci 32:298–309. RA (2011) Inflammation modulates anxiety in an animal model of 1568
1499 Moser MB, Moser EI (1998) Functional differentiation in the multiple sclerosis. Behav Brain Res 220:20–29. 1569
1500 hippocampus. Hippocampus 8:608–619. Pitkanen A, Sutula TP (2002) Is epilepsy a progressive disorder? 1570
1501 Mueller SG, Chao LL, Berman B, Weiner MW (2011) Evidence for Prospects for new therapeutic approaches in temporal-lobe 1571
1502 functional specialization of hippocampal subfields detected by MR epilepsy. Lancet Neurol 1:173–181. 1572
1503 subfield volumetry on high resolution images at 4T. Neuroimage Poppenk J, Evensmoen HR, Moscovitch M, Nadel L (2013) Long-axis 1573
1504 56:851–857. specialization of the human hippocampus. Trends Cogn Sci 1574
1505 Mueller SG, Schuff N, Yaffe K, Madison C, Miller B, Weiner MW 17:230–240. 1575
1506 (2010) Hippocampal atrophy patterns in mild cognitive impairment Prince TM, Abel T (2013) The impact of sleep loss on hippocampal 1576
1507 and Alzheimer’s disease. Hum Brain Mapp 31:1339–1347. function. Learn Mem 20:558–569. 1577
1508 Mueller SG, Stables L, Du AT, Schuff N, Truran D, Cashdollar N, Pulsinelli WA, Brierley JB, Plum F (1982) Temporal profile of neuronal 1578
1509 Weiner MW (2007) Measurement of hippocampal subfields and damage in a model of transient forebrain ischemia. Ann Neurol 1579
1510 age-related changes with high resolution MRI at 4T. Neurobiol 11:491–498. 1580
1511 Aging 28:719–726. Pun RY, Rolle IJ, Lasarge CL, Hosford BE, Rosen JM, Uhl JD, 1581
1512 Mueller SG, Weiner MW (2009) Selective effect of age, Apo e4, and Schmeltzer SN, Faulkner C, Bronson SL, Murphy BL, Richards 1582
1513 Alzheimer’s disease on hippocampal subfields. Hippocampus DA, Holland KD, Danzer SC (2012) Excessive activation of mTOR 1583
1514 19:558–564. in postnatally generated granule cells is sufficient to cause 1584
1515 Mufson EJ, Mahady L, Waters D, Counts SE, Perez SE, DeKosky epilepsy. Neuron 75:1022–1034. 1585
1516 ST, Ginsberg SD, Ikonomovic MD, Scheff SW, Binder LI (2015) Quintana P, Stefano A, Hakkoum D, Muller D (2006) Glutamate 1586
1517 Hippocampal plasticity during the progression of Alzheimer’s receptor changes associated with transient anoxia/ 1587
1518 disease. Neuroscience. http://dx.doi.org/10.1016/ hypoglycaemia in hippocampal slice cultures. Eur J Neurosci 1588
1519 j.neuroscience.2015.03.006. 23:975–983. 1589
1520 Murray AJ, Sauer JF, Riedel G, McClure C, Ansel L, Cheyne L, Rolls ET, Kesner RP (2006) A computational theory of hippocampal 1590
1521 Bartos M, Wisden W, Wulff P (2011) Parvalbumin-positive CA1 function, and empirical tests of the theory. Prog Neurobiol 1591
1522 interneurons are required for spatial working but not for reference 79:1–48. 1592
1523 memory. Nat Neurosci 14:297–299. Roosendaal SD, Hulst HE, Vrenken H, Feenstra HE, Castelijns JA, 1593
1524 Neunuebel JP, Knierim JJ (2014) CA3 retrieves coherent Pouwels PJ, Barkhof F, Geurts JJ (2010) Structural and functional 1594
1525 representations from degraded input: direct evidence for CA3 hippocampal changes in multiple sclerosis patients with intact 1595
1526 pattern completion and dentate gyrus pattern separation. Neuron memory function. Radiology 255:595–604. 1596
1527 81:416–427. Roosendaal SD, Moraal B, Vrenken H, Castelijns JA, Pouwels PJ, 1597
1528 Newrzella D, Pahlavan PS, Kruger C, Boehm C, Sorgenfrei O, Barkhof F, Geurts JJ (2008) In vivo MR imaging of hippocampal 1598
1529 Schrock H, Eisenhardt G, Bischoff N, Vogt G, Wafzig O, Rossner lesions in multiple sclerosis. J Magn Reson Imaging 27:726–731. 1599
1530 M, Maurer MH, Hiemisch H, Bach A, Kuschinsky W, Schneider A Ryan TJ, Roy DS, Pignatelli M, Arons A, Tonegawa S (2015) 1600
1531 (2007) The functional genome of CA1 and CA3 neurons under Memory. Engram cells retain memory under retrograde amnesia. 1601
Science 348:1007–1013. 1602
7 August 2015
1603 Sacco R, Bisecco A, Corbo D, Della Corte M, d’Ambrosio A, Docimo allocentric encoding of spatial information. J Neurosci 1669
1604 R, Gallo A, Esposito F, Esposito S, Cirillo M, Lavorgna L, 292009:10512–10519. 1670
1605 Tedeschi G, Bonavita S (2015) Cognitive impairment and memory Tamminga CA, Suzanne Zukin R (2015) Schizophrenia: evidence 1671
1606 disorders in relapsing-remitting multiple sclerosis: the role of white implicating hippocampal GluN2B protein and REST epigenetics in 1672
1607 matter, gray matter and hippocampus. J Neurol. psychosis pathophysiology. Neuroscience. http://dx.doi.org/ 1673
1608 Sahay A, Hen R (2007) Adult hippocampal neurogenesis in 10.1016/j.neuroscience.2015.07.038. 1674
1609 depression. Nat Neurosci 10:1110–1115. Tan H, Cao J, Zhang J, Zuo Z (2014) Critical role of inflammatory 1675
1610 Sahay A, Wilson DA, Hen R (2011) Pattern separation: a common cytokines in impairing biochemical processes for learning and 1676
1611 function for new neurons in hippocampus and olfactory bulb. memory after surgery in rats. J Neuroinflammation 11:93. 1677
1612 Neuron 70:582–588. Thompson CL, Pathak SD, Jeromin A, Ng LL, MacPherson CR, 1678
1613 Sandi C, Pinelo-Nava MT (2007) Stress and memory: behavioral Mortrud MT, Cusick A, Riley ZL, Sunkin SM, Bernard A, Puchalski 1679
1614 effects and neurobiological mechanisms. Neural Plast RB, Gage FH, Jones AR, Bajic VB, Hawrylycz MJ, Lein ES (2008) 1680
1615 2007:78970. Genomic anatomy of the hippocampus. Neuron 60:1010–1021. 1681
1616 Schmidt-Kastner R, Freund TF (1991) Selective vulnerability of the Tononi G, Cirelli C (2014) Sleep and the price of plasticity: from 1682
1617 hippocampus in brain ischemia. Neuroscience 40:599–636. synaptic and cellular homeostasis to memory consolidation and 1683
1618 Schwamm LH, Koroshetz WJ, Sorensen AG, Wang B, Copen WA, integration. Neuron 81:12–34. 1684
1619 Budzik R, Rordorf G, Buonanno FS, Schaefer PW, Gonzalez RG Urbach H, Soeder BM, Jeub M, Klockgether T, Meyer B, Bien CG 1685
1620 (1998) Time course of lesion development in patients with acute (2006) Serial MRI of limbic encephalitis. Neuroradiology 1686
1621 stroke: serial diffusion- and hemodynamic-weighted magnetic 48:380–386. 1687
1622 resonance imaging. Stroke 29:2268–2276. van der Marel K, Bouet V, Meerhoff GF, Freret T, Boulouard M, 1688
1623 Segal M, Richter-Levin G, Maggio N (2010) Stress-induced dynamic Dauphin F, Klomp A, Lucassen PJ, Homberg JR, Dijkhuizen RM, 1689
1624 routing of hippocampal connectivity: a hypothesis. Hippocampus Reneman L (2015) Effects of long-term methylphenidate 1690
1625 20:1332–1338. treatment in adolescent and adult rats on hippocampal shape, 1691
1626 Seigers R, Schagen SB, Van Tellingen O, Dietrich J (2013) functional connectivity and adult neurogenesis. Neuroscience. 1692
1627 Chemotherapy-related cognitive dysfunction: current animal http://dx.doi.org/10.1016/j.neuroscience.2015.04.044. 1693
1628 studies and future directions. Brain Imaging Behav 7:453–459. van Strien NM, Cappaert NL, Witter MP (2009) The anatomy of 1694
1629 Semmler A, Widmann CN, Okulla T, Urbach H, Kaiser M, Widman G, memory: an interactive overview of the parahippocampal- 1695
1630 Mormann F, Weide J, Fliessbach K, Hoeft A, Jessen F, Putensen hippocampal network. Nat Rev Neurosci 10:272–282. 1696
1631 C, Heneka MT (2013) Persistent cognitive impairment, Varley J, Vincent A, Irani SR (2015) Clinical and experimental studies 1697
1632 hippocampal atrophy and EEG changes in sepsis survivors. J of potentially pathogenic brain-directed autoantibodies: current 1698
1633 Neurol Neurosurg Psychiatry 84:62–69. knowledge and future directions. J Neurol 262:1081–1095. 1699
1634 Shing YL, Rodrigue KM, Kennedy KM, Fandakova Y, Bodammer N, Voss MW, Vivar C, Kramer AF, van Praag H (2013) Bridging animal 1700
1635 Werkle-Bergner M, Lindenberger U, Raz N (2011) Hippocampal and human models of exercise-induced brain plasticity. Trends 1701
1636 subfield volumes: age, vascular risk, and correlation with Cogn Sci 17:525–544. 1702
1637 associative memory. Front Aging Neurosci 3:2. Wang X, Michaelis EK (2010) Selective neuronal vulnerability to 1703
1638 Sicotte NL, Kern KC, Giesser BS, Arshanapalli A, Schultz A, Montag oxidative stress in the brain. Front Aging Neurosci 2:12. 1704
1639 M, Wang H, Bookheimer SY (2008) Regional hippocampal Wegner C, Stadelmann C (2009) Gray matter pathology and multiple 1705
1640 atrophy in multiple sclerosis. Brain 131:1134–1141. sclerosis. Curr Neurol Neurosci Rep 9:399–404. 1706
1641 Sierra A, Grohn O, Pitkanen A (2015) Imaging microstructural West MJ, Coleman PD, Flood DG, Troncoso JC (1994) Differences in 1707
1642 damage and plasticity in the hippocampus during the pattern of hippocampal neuronal loss in normal ageing and 1708
1643 epileptogenesis. Neuroscience. http://dx.doi.org/10.1016/ Alzheimer’s disease. Lancet 344:769–772. 1709
1644 j.neuroscience.2015.04.054. Williamson LL, Bilbo SD (2013) Chemokines and the hippocampus: a 1710
1645 Sloviter RS, Bumanglag AV (2013) Defining ‘‘epileptogenesis’’ and new perspective on hippocampal plasticity and vulnerability. Brain 1711
1646 identifying ‘‘antiepileptogenic targets’’ in animal models of Behav Immun 30:186–194. 1712
1647 acquired temporal lobe epilepsy is not as simple as it might Wilson MA, McNaughton BL (1994) Reactivation of hippocampal 1713
1648 seem. Neuropharmacology 69:3–15. ensemble memories during sleep. Science 265:676–679. 1714
1649 Small SA (2002) The longitudinal axis of the hippocampal formation: Wisse LE, Biessels GJ, Heringa SM, Kuijf HJ, Koek DH, Luijten PR, 1715
1650 its anatomy, circuitry, and role in cognitive function. Rev Neurosci Geerlings MI (2014) Hippocampal subfield volumes at 7T in early 1716
1651 13:183–194. Alzheimer’s disease and normal aging. Neurobiol Aging 1717
1652 Small SA, Schobel SA, Buxton RB, Witter MP, Barnes CA (2011) A 35:2039–2045. 1718
1653 pathophysiological framework of hippocampal dysfunction in Wu MV, Hen R (2014) Functional dissociation of adult-born neurons 1719
1654 ageing and disease. Nat Rev Neurosci 12:585–601. along the dorsoventral axis of the dentate gyrus. Hippocampus 1720
1655 Stranahan AM (2015) Models and mechanisms for hippocampal 24:751–761. 1721
1656 dysfunction in obesity and diabetes. Neuroscience. http:// Wulff P, Ponomarenko AA, Bartos M, Korotkova TM, Fuchs EC, 1722
1657 dx.doi.org/10.1016/j.neuroscience.2015.04.045. Bahner F, Both M, Tort AB, Kopell NJ, Wisden W, Monyer H 1723
1658 Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson (2009) Hippocampal theta rhythm and its coupling with gamma 1724
1659 MP (2008) Diabetes impairs hippocampal function through oscillations require fast inhibition onto parvalbumin-positive 1725
1660 glucocorticoid-mediated effects on new and mature neurons. interneurons. Proc Natl Acad Sci U S A 106:3561–3566. 1726
1661 Nat Neurosci 11:309–317. Yang Y, Song W (2013) Molecular links between Alzheimer’s disease 1727
1662 Stranahan AM, Mattson MP (2011) Bidirectional metabolic regulation and diabetes mellitus. Neuroscience 250:140–150. 1728
1663 of neurocognitive function. Neurobiol Learn Mem 96:507–516. Yassa MA, Mattfeld AT, Stark SM, Stark CE (2011) Age-related 1729
1664 Strange BA, Witter MP, Lein ES, Moser EI (2014) Functional memory deficits linked to circuit-specific disruptions in the 1730
1665 organization of the hippocampal longitudinal axis. Nat Rev hippocampus. Proc Natl Acad Sci U S A 108:8873–8878. 1731
1666 Neurosci 15:655–669. Yassa MA, Stark CE (2011) Pattern separation in the hippocampus. 1732
1667 Suthana NA, Ekstrom AD, Moshirvaziri S, Knowlton B, Bookheimer Trends Neurosci 34:515–525. 1733
1668 SY (2009) Human hippocampal CA1 involvement during 1734

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3 THE HIPPOCAMPUS IN AGING AND DISEASE: FROM PLASTICITY

10 Abstract—The hippocampus has a pivotal role in learning

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reciprocal interaction between neural structure and 176

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Fig. 3. High-resolution MR-imaging of the hippocampus with an analysis of hippocampal subﬁelds.

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Modern therapeutic options targeting cancer cells can 880

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963 THE HIPPOCAMPUS IN EPILEPSY

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