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
Neuroscience xxx (2015) xxxxxx
EDITORIAL
THE HIPPOCAMPUS IN AGING AND DISEASE: FROM PLASTICITY
TO VULNERABILITY
T. BARTSCH a* AND P. WULFF b!
a field imaging, Alzheimers disease, aging.
Department of Neurology, Memory Disorders and Plasticity
Group, University Hospital Schleswig-Holstein, Kiel, Germany
b
Institute of Physiology, Neurophysiology, University of
Kiel, Olshausenstrasse 40, 24098 Kiel, Germany
AbstractThe hippocampus has a pivotal role in learning
and in the formation and consolidation of memory and is
critically involved in the regulation of emotion, fear, anxiety,
and stress. Studies of the hippocampus have been central to
the study of memory in humans and in recent years, the
regional specialization and organization of hippocampal
functions have been elucidated in experimental models
and in human neurological and psychiatric diseases. The
hippocampus has long been considered a classic model
for the study of neuroplasticity as many examples of synap-
tic plasticity such as long-term potentiation and -depression
have been identified and demonstrated in hippocampal cir-
cuits. Neuroplasticity is the ability to adapt and reorganize
the structure or function to internal or external stimuli and
occurs at the cellular, population, network or behavioral
level and is reflected in the cytological and network architec-
ture as well as in intrinsic properties of hippocampal
neurons and circuits. The high degree of hippocampal neu-
roplasticity might, however, be also negatively reflected in
the pronounced vulnerability of the hippocampus to delete-
rious conditions such as ischemia, epilepsy, chronic stress,
neurodegeneration and aging targeting hippocampal
structure and function and leading to cognitive deficits.
Considering this framework of plasticity and vulnerability,
we here review basic principles of hippocampal anatomy
and neuroplasticity on various levels as well as recent find-
ings regarding the functional organization of the hippocam-
pus in light of the regional vulnerability in Alzheimers
disease, ischemia, epilepsy, neuroinflammation and aging.
This article is part of a Special Issue entitled:
Hippocampus. ! 2015 IBRO. Published by Elsevier Ltd. All
rights reserved.
*Corresponding author. Tel: +49-0-431-597-8550; fax: +49-0-431-
597-8502.
E-mail addresses: t.bartsch@neurologie.uni-kiel.de (T. Bartsch),
p.wul@physiologie.uni-kiel.de (P. Wul).
!
Tel: +49-431-880-2806; fax:+49-431-880-4580.
Abbreviations: Ab, amyloid-beta; AD, Alzheimers disease; DG,
dentate gyrus; EAE, experimental autoimmune encephalomyelitis;
EC, entorhinal cortex; IL-1b, interleukin-1 beta; LTD, long-term
depression; LTP, long-term potentiation; MS, multiple sclerosis; MTL,
medial temporal lobe; NFT, neurofibrillary tangle; ROS, reactive
oxygen species; TLE, temporal lobe epilepsy.
http://dx.doi.org/10.1016/j.neuroscience.2015.07.084
0306-4522/! 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
1
Key words: hippocampus, vulnerability, neuroplasticity, sub-
INTRODUCTION
The hippocampus is widely regarded as being in the
center of a brain network supporting encoding,
consolidation and retrieval of memory and, being central
to the study of human memory, has been implicated in
episodic and semantic long-term memory, novelty
detection, sleep-dependent memory consolidation,
pattern discrimination, spatial navigation and the binding
of temporally and spatially distributed representations
(Bartsch, 2012). Beyond these cognitive functions, the
hippocampus is also involved in the regulation of emotion,
fear, anxiety, and stress. The hippocampus has an
intriguing cyto- and network architecture and it has been
suggested that the particular circuit arrangement in dier-
ent subregions of the hippocampus subserves dierential
mnemonic operations (Kesner and Rolls, 2015). Indeed,
in recent years, a dierential and complex modular orga-
nization of hippocampal anatomy and function emerged
(Strange et al., 2014). Also, the concept of a regional
specialization and organization of hippocampal functions
has been increasingly studied in humans using high-
resolution MR subfield imaging indeed showing that
mnemonic operations can be attributed to subnetworks
and subregions of the hippocampus (Bakker et al.,
2008; Mueller et al., 2011) (Chetelat, this issue).
The hippocampus has long been considered as a
classic example for the study of functional
neuroplasticity as many models of synaptic plasticity
such as long-term potentiation (LTP) and -depression
(LTD), and spike-timing-dependent plasticity have been
observed in hippocampal circuits and are thought to be
fundamental to learning and memory (Bliss and
Schoepfer, 2004; Pastalkova et al., 2006). Neuroplasticity
is considered the ability to adapt and reorganize the
structure or function to internal or external stimuli and
occurs on the cellular, population, network or behavioral
level (Cramer et al., 2011). Neuroplastic mechanisms
are reflected in the cyto- and network architecture and
are mirrored in the intrinsic properties of hippocampal
neurons and circuits. Structural plasticity in hippocampal
neurons and circuits includes modifications of dendritic
tree size and spines, synapse number as well as the
2 T. Bartsch, P. Wul / Neuroscience xxx (2015) xxxxxx
formation of new neurons (Leuner and Gould, 2010). Cel-
lular neuroplasticity is not confined to physiology but also
present in the context of progressive pathology, such as
neurodegeneration in Alzheimers disease (AD) in
humans and is increasingly studied (Mufson et al.,
2015). On a network level, neuroplasticity in hippocampal
circuits drives changes in connectivity, structural modifi-
cations and behavioral outcome (Finke et al., 2013a;
Ryan et al., 2015).
This high degree of hippocampal plasticity, however,
is accompanied by the pronounced vulnerability of the
hippocampus to deleterious conditions such as
ischemia, epilepsy, neuroinflammation, chronic stress,
neurodegeneration and aging suggesting that the
instrinsic properties of hippocampal neurons and circuits
that are critical for neuroplasticity such as glutamatergic
excitability may also predispose to metabolic injuries
occurring in the process of various neurological and
psychiatric diseases (Bartsch et al., 2015). This view is
reflected in the suggestion by Bruce McEwen that the
plasticity of the hippocampus is the reason for its vulner-
ability (McEwen, 1994).
In this special issue of Neuroscience: The
hippocampus in aging and disease: from plasticity to
vulnerability, we will review basic principles of
hippocampal anatomy and neuroplasticity on various
levels as well as recent findings regarding its functional
organization with respect to regional vulnerability, which
is critical for the understanding of neurocognitive
diseases (Bartsch, 2012).
HIPPOCAMPAL ANATOMY
Encoding, consolidation and retrieval of mnemonic
information is critically dependent on a large reciprocal
network of regions that includes neocortical association
regions, subcortical nuclei, the medial temporal lobe
(MTL), parahippocampal areas and the hippocampal
formation (Fig. 1). The hippocampus is considered the
central node in this circuit. It receives input from
almost all neocortical association areas via perirhinal
and parahippocampal cortices and finally through the
entorhinal cortex (EC) (van Strien et al., 2009). The hip-
pocampus is a three-layered allocortical structure that is
reciprocally connected to other cortical and subcortical
areas (Figs. 1 and 2). The principal neurons of the hip-
pocampus are organized in layers and receive unidirec-
tional polymodal input from the EC, where layer II
neurons project via the perforant path to granule cells in
the dentate gyrus (DG) (Strange et al., 2014). The trisy-
naptic pathway from the DG to CA3 via mossy fibers
and onward to CA1 via Schaer collaterals is the principal
feed-forward circuit involved in the processing of informa-
tion through the hippocampus (Fig. 2). Additionally, layer
III neurons from the EC directly project to CA1 neurons
via the temporoammonic path (perforant path to CA1).
CA1 pyramidal cells -the major output relay neurons
project via the subicular complex back to deep layers of
the EC and to various subcortical and cortical areas
(Murray et al., 2011). The regions CA1CA3 are sepa-
rated into four layers (pyramidal, stratum oriens, stratum
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
lucidum, stratum radiatum). The structure of this feed-
forward circuit with its limited redundancy may be critical
for learning and memory but may also contribute to its vul-
nerability during insults (Lavenex and Amaral, 2000).
Learning and memory processes within hippocampal
circuits are regulated by synaptic plasticity mechanisms
that require activation of specific molecular cascades
(Aksoy-Aksel and Manahan-Vaughan, 2015). For exam-
ple, the induction of LTP in the CA1 region involves post-
synaptic calcium ion entry via NMDA receptors with
subsequent activation of protein kinases (Aksoy-Aksel
and Manahan-Vaughan, 2015).
The hippocampus receives large amounts of sensory
information from neocortical structures, which is
integrated in several recurrent subnetworks with distinct
computational operations (van Strien et al., 2009). The
DG with its three layers (molecular, granular, and polymor-
phic layers) consists mainly of granule cells and receives
polymodal input form the EC. The axons of the DG granule
cells form the mossy fiber system and project to CA3
(Amaral et al., 2007). Mossy fibers also project back onto
granule cells, thus forming a recurrent network. In addition
the DG receives information from the contralateral hip-
pocampus via commissural projections (Amaral et al.,
2007). Axon collaterals of CA3 pyramidal neurons synapse
onto other CA3 neurons, forming a recurrent autoassocia-
tive network whereas CA3 neurons projecting back to the
dentate network form a heteroassociative network
(Lisman, 1999). CA1 pyramidal neurons receive informa-
tion which has been pre-processed in the subnetworks of
the DG and CA3, but also receives direct projections from
the EC suggesting that the function of CA1 neurons
includes comparing new information from the EC with
stored information via CA3 in terms of mismatch, error
and novelty detection (Lisman and Otmakhova, 2001).
Besides the structural layout of connectivity of these
hippocampal circuits, it is believed that mnemonic
information is represented and processed by spatio-
temporal patterns of firing in groups of neurons, also
referred to as cell assemblies involving fast oscillatory
dynamics in various frequency bands (e.g. theta, sharp-
wave ripples, slow oscillations and gamma oscillations)
that are synchronized and temporally coordinated within
and across cortical regions (Wul et al., 2009; Battaglia
et al., 2011; Buzsaki and Moser, 2013).
NEUROPLASTICITY AND THE HIPPOCAMPUS
Neuroplasticity can be broadly defined as the ability of the
nervous system to respond to intrinsic and extrinsic stimuli
by reorganizing its structure, function and connections; can
be described at many levels, from molecular to cellular to sys-
tems to behavior; and can occur during development, in
response to the environment, in support of learning, in
response to disease, or in relation to therapy. Such plasticity
can be viewed as adaptive when associated with a gain in
function or as maladaptive when associated with negative
consequences such as loss of function or increased injury,
points illustrated by animal models and some human studies.
(Cramer et al., 2011).
 T. Bartsch, P. Wul / Neuroscience xxx (2015) xxxxxx 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 dAzyr); SN, septal nuclei.

reciprocal interaction between neural structure and

Fig. 2. (A) Intrinsic anatomy of the hippocampus depicting the
trisynaptic pathway as the principal feed forward neural circuit
involved in the processing of information through the hippocampus.
(B) Flow diagram of the information flow through the hippocampus
highlighting the parallel processing of information as well as the
reciprocal auto- and heteroassociative networks of the DG and CA3.
Abbreviations: CA, cornu ammonis; DG, dentate gyrus; EC, entorhi-
nal cortex.
Neuroplasticity is the ability of the brain or brain
structures to adapt in response to intrinsic or extrinsic
stimuli such as changes in the environment,
development or lesions and consists in principle of a
function (Kolb and Muhammad, 2014). Neuroplasticity
can occur on various functional and structural levels from
changes in membrane excitability, synaptic plasticity to
changes in dendritic and axonal structure (Kolb and
Gibb, 2014). Neuroplasticity can also occur as structural
and functional adaptations and reorganization of neuronal
populations, which is reflected in modifications of recruit-
ment and strength of connectivity of networks and circuits.
Finally, neuroplasticity can occur on a phenomenological
level mirrored in changes and modifications of cognitive
and behavioral strategies (Cramer et al., 2011) (Fig. 4).
Neuroplasticity can show a time- and age-dependency
and can result in positive adaptive or negative (maladap-
tive) eects (Kolb and Gibb, 2014).
The hippocampus has long been considered a classic
example for the study of neuroplasticity as many
paradigms of synaptic plasticity such as LTP and LTD,
EPSP-spike potentiation and spike-timing-dependent
plasticity, which are thought to represent cellular
correlates of learning and memory, have been identified
and demonstrated in hippocampal circuits. Similarly,
structural plasticity in response to external stimulation
such as modifications of dendritic tree size, number of
dendritic spines and number of synapses as well as the
formation of new neurons have been demonstrated in
the hippocampus (Leuner and Gould, 2010). Mechanisms
of plasticity in the hippocampus are also aected during
the early stages of AD during which neurodegenerative
changes of extracellular amyloid-beta (Ab) deposition
and intracellular neurofibrillary tangle (NFT) formation

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
4 T. Bartsch, P. Wul / Neuroscience xxx (2015) xxxxxx
accounts for molecular synaptic and intraneuronal remod-
eling (Mufson et al., 2015). Axonal sprouting is another
example of structural plasticity after damage that may
result in maladaptive hippocampal circuit reorganization.
On the molecular level, plasticity can be driven by
enhanced expression of plasticity-related genes, such
as BDNF, CaMKII, CREB as well as increased surface
expression of glutamatergic AMPA and NMDA receptors.
Activity-dependent neuroplastic mechanisms in the hip-
pocampus that are fundamental to learning and memory
such as LTP (Pastalkova et al., 2006) can be modified
by preceding synaptic activity. This type of regulatory
mechanism of plasticity itself by prior activity is called
metaplasticity and has been implicated not only in physi-
ological regulation but also in aging and disease mecha-
nisms (Hulme et al., 2013; Jones, 2015). On the
network level, plastic changes in the hippocampal mem-
ory system to a perturbation in terms of a network reorga-
nization has been shown in patients with hippocampal
damage where a recruitment of an extended
hippocampal-neocortical network compensating for hip-
pocampal dysfunction could be observed (Finke et al.,
2013a).
In this Special Issue of Neuroscience, the concept of
neuroplasticity has been applied to various neurological
and psychiatric diseases as well as aging including AD
(Mufson et al., 2015; de Flores et al., 2015a), depression
(Malykhin and Coupland, 2015), schizophrenia
(Tamminga and Suzanne Zukin, 2015) aging (Gray and
Barnes, 2015), epilepsy (Sierra et al., 2015; Blumcke
and Coras, 2015), neurodevelopmental disorders (van
der Marel et al., 2015), metabolic disorders (Stranahan,
2015), neuroinflammation (Barrientos et al., 2015; Heine
et al., 2015) including multiple sclerosis (MS) (Novkovic
et al., 2015).
REGIONAL SPECIALIZATION AND
ORGANIZATION OF HIPPOCAMPAL
FUNCTIONS
Hippocampal organization along the longitudinal axis
Earlier experimental models of hippocampal function
regarded the hippocampus as a unitary functional and
structural entity. With a greater refinement of
hippocampal circuit anatomy in recent years, however, a
regional specialization of hippocampal functions along
the longitudinal axis emerged (Small, 2002). Animal data
using behavioral lesion models, studies of intrahippocam-
pal connectivity and electrophysiological findings suggest
a dichotomic organization of hippocampal networks into
functional compartments such as the dorsal hippocampus
performing cognitive functions, in particular spatial pro-
cessing, and the ventral hippocampus being involved in
the regulation of stress, emotion, and aect (Moser and
Moser, 1998; Bannerman et al., 2004; Thompson et al.,
2008; Dong et al., 2009; Fanselow and Dong, 2010). This
distinction was partly derived from findings that the ventral
hippocampus has stronger connectivity with the amyg-
dala, hypothalamic and endocrine nuclei as well as the
critical role of the ventral hippocampus in the stress
response (Kjelstrup et al., 2002; Strange et al., 2014).
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
Recent findings also indicate that markers of plasticity
such as LTP as well as the formation of new neurons in
the DG are dierentially organized in the dorsal and ven-
tral hippocampus thus (Wu and Hen, 2014; Opendak and
Gould, 2015). Furthermore, on a cellular level, this
dichotomic organization also correlates to a dierential
expression of NMDA and AMPA receptor subunits in the
dorsal and ventral hippocampus of the rat (Pandis et al.,
2006).
This dichotomic view of the functional organization is
currently being replaced by a more dierentiated concept
as some functional dierences are organized in a more
gradient-like way along the longitudinal axis. The
distribution of NMDA receptors, the connectivity to
cortical and subcortical structures, the size of so called
place fields suggest a gradual longitudinal axis
distribution whereas genomic expression analyses
demarcate CA1 and DG into three (ventral, intermediate
and dorsal) and CA3 into nine modules (Thompson
et al., 2008). This arrangement suggests a superimposed
pattern of gradient-like as well as a modular organization
along the anterior-posterior axis of the hippocampus
(Strange et al., 2014). However, it is currently unclear,
how the anatomical organization, in particular the molecu-
lar expression patterns, can be reconciled with a functional
modular organization along the anterior-posterior axis.
Functional subfield organization
The hippocampus is organized into dierent cytoar-
chitectonic subfields that include the cornu ammonis
fields (CA1CA4), the DG, and the subiculum.
Considering the intriguing anatomy of the hippocampal
subnetworks with its recurrent associative networks
embedded into the unidirectional trisynaptic pathway but
with parallel projections from the EC to the CA3 and
CA1 region, it has been suggested that these networks
perform dierential computations in dierent cognitive
tasks (Marr, 1971; OReilly and McClelland, 1994;
Kesner and Rolls, 2015). Using animal models, an activa-
tion of these hippocampal subnetworks has been corre-
lated with distinct cognitive or mnemonic operations
thereby reflecting distinct electrophysiological- and
neuroplastic-properties of subfield neurons (Chen et al.,
2009). For example, it has been argued that the DG dur-
ing encoding is involved in pattern separation a cogni-
tive function whereby a discrimination of similar and
overlapping neuronal patterns into more dissimilar pat-
terns is performed using minimal dierences in the given
cues (Guzowski et al., 2004; Yassa and Stark, 2011;
Neunuebel and Knierim, 2014). The separation of pat-
terns on the basis of similarity is thought to play a role
in the non-ambiguous and distinct representation of simi-
lar memories in the context of learning and memory, pre-
venting memory interference and allowing novelty
detection (Bakker et al., 2008). It is also thought that pat-
tern separation is impaired in aging and mild cognitive
impairment (Yassa et al., 2011). The autoassociative
CA3 circuitry is thought to be involved in binding of disso-
ciative representations and pattern completion, a mnemo-
nic function which allows the recall of a memory by only
partial or fragmented representation of cues that were
 T. Bartsch, P. Wul / Neuroscience xxx (2015) xxxxxx
Fig. 3. High-resolution MR-imaging of the hippocampus with an analysis of hippocampal subfields.
present during initial learning. Both operations are linked
together, as pattern separation in the DG is a prerequisite
for pattern completion in CA3 (Lisman, 1999). The CA3
network has also been implied in spatial rapid one-trial
learning and spatial sequence learning. The CA1 network
receives input from CA3 and the EC and has been
thought to be engaged in input integration and match-
mismatch detection between predictions from CA3 and
perceptual input from the EC and novelty detection
(Rolls and Kesner, 2006; Hunsaker and Kesner, 2013).
The CA1 region is also involved in the integration of tem-
poral and object representations. Behaviorally, it has
been shown that CA1 is critical for autobiographical
memory retrieval (Kesner and Hunsaker, 2009; Bartsch
et al., 2011). Furthermore, the CA1 subregion is involved
in our ability to learn a map-like representation of an envi-
ronment which is in accordance with the cognitive-map
theory, which suggests that allocentric spatial representa-
tions of locations are processed in the hippocampus
(Bartsch et al., 2010).
Only recently, with the emergence of high-field MR
scanning and new imaging protocols it has been
possible to shed light on the longitudinal organization of
the hippocampus and to correlate dierential
hippocampal subfield activation to dierent mnemonic
functions in humans (Fig. 3) (Small, 2002; Das et al.,
2012; Engvig et al., 2012; Poppenk et al., 2013). High-
resolution functional and volumetric imaging studies indi-
cate a dierential involvement of hippocampal subfields
in memory and learning showing that CA3 and the DG
are involved in patterns separation, memory encoding
and early retrieval, and an involvement of CA1 in late
retrieval, consolidation, spatial encoding, autobiographical
retrieval and recognition (Bakker et al., 2008; Suthana
et al., 2009; Mueller et al., 2011; Bonnici et al., 2012,
2013; Deuker et al., 2014). These high-resolution imaging
methods have been applied to neurological, neurodegen-
erative and psychiatric diseases as well as aging showing
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
5
dierential patterns of pathological changes (Mueller et al.,
2007; Mueller and Weiner, 2009). These imaging patterns
are currently evaluated in terms of developing imaging
biomarkers for disease and treatment outcomes
(Malykhin and Coupland, 2015; Sierra et al., 2015).
REGIONAL VULNERABILITY OF THE
HIPPOCAMPUS
Acute damage to the hippocampus
For over 100 years it has been known that acute
pathological conditions, such as ischemia, hypo-
glycemia, epileptic seizures and other neurological
conditions can cause damage to the hippocampus
(Michaelis, 2012). This damage of the hippocampus is
most evident in CA1 hippocampal neurons and is a reflec-
tion of a selective vulnerability of the hippocampus to
acute conditions impairing the metabolic homeostasis of
CA1 pyramidal neurons to glutamate-dependent and
calcium-mediated mechanisms of neuronal cytotoxicity
(Schmidt-Kastner and Freund, 1991; Bartsch et al.,
2006, 2008). A brief episode of cerebral ischemia results
in the selective cell death of hippocampal CA1 neurons
whereas the DG, CA3, and most cortical neurons appear
to be more resistant. The structural changes in CA1 that
follow the insult are most prominent after a delay of
34 days and thus have been termed delayed neuronal
death (Pulsinelli et al., 1982; Schmidt-Kastner and
Freund, 1991; Kirino, 2000). The phenotype, evolution
and pattern of lesions in the hippocampal CA1 region in
acute neurological disorders was recently studied using
high-resolution MR-imaging (Bartsch et al., 2015). In
patients with hippocampal ischemia, neuroinflammation,
after status epilepticus and transient global amnesia, the
CA1 region was selectively aected compared to other
cornu ammonis (CA-) regions of the hippocampus. The
maximum impairment of CA1 cellular metabolism as
6 T. Bartsch, P. Wul / Neuroscience xxx (2015) xxxxxx
Fig. 4. Schematic overview of the various contributing factors, dierent scales and methodological and conceptual levels determining
neuroplasticity in the hippocampus.
measured by apparent diusion coecient (ADC) in MRI
was seen 48 h-72 h after the insult, irrespective of the nat-
ure of the insult. Hypoxic-ischemic insults led to a signifi-
cant stronger reduction of ADC suggesting that the
ischemic insult results in a stronger impairment of CA1
metabolism compared to inflammation and epilepsy
(Bartsch et al., 2015). These results show that acute dam-
age to the hippocampus selectively aects the CA1 sub-
region, a region that is highly plastic. In contrast, CA3
and the DG are only marginally aected. The cellular
mechanisms that lead to a regional vulnerability to a
glutamate- and calcium-mediated excitotoxicity are possi-
bly a reflection of genomic-dependent regional dierences
in the distribution of glutamatergic NMDA receptors in
CA1 neurons that express considerably higher densities
of NMDA NR2 subunits than do CA3 or DG neurons, as
reported for rodents (Coultrap et al., 2005; Gee et al.,
2006; Quintana et al., 2006; Newrzella et al., 2007;
Butler et al., 2010). Furthermore, regional dierences in
antioxidant enzymes as well as inflammatory reactions
may play a role in enhanced vulnerability of the CA1
region (Wang and Michaelis, 2010; Michaelis, 2012).
Interestingly, hippocampal interneurons are believed to
be more resistant to the impact of transient ischemia than
larger pyramidal neurons (Harry and Lefebvre
dHellencourt, 2003; Avignone et al., 2005).
Aging and the hippocampus
Neuroplasticity mechanisms in the hippocampus sub-
serving cognitive functions are also subject to aging
processes and it has been suggested that neuroplastic
mechanisms are particularly vulnerable during aging
(Burke and Barnes, 2006). Interestingly, principal cell
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
numbers, dendritic branching, and dendritic spine density
are not substantially reduced during the aging process
(West et al., 1994; Lister and Barnes, 2009). Also, bio-
physical properties of hippocampal neurons such as the
resting membrane potential, membrane time constant,
input resistance, threshold to action potential are largely
preserved over the lifespan (Burke and Barnes, 2010).
There are, however, observations of synaptic loss in the
layer II entorhinal cortical input to the granule cells in
the DG (Burke and Barnes, 2010). This change in con-
nectivity may aect the function of hippocampal subnet-
works for example during pattern separation (Burke and
Barnes, 2010). Synaptic plasticity such as the induction
and maintenance of LTP in line with alterations in
Ca2+ homeostasis changes with age (Lister and
Barnes, 2009). Along these lines, subregion-specific
changes in the expression of genes subserving the regu-
lation of neuroplasticity such as LTP have been observed
in the aging hippocampus (Burger, 2010). Furthermore,
cognitive changes during aging can also be attributed to
changes in the neural dynamics of hippocampal circuits,
e.g. in place cell maintenance, stability and plasticity
during remapping and pattern separation processes
(Burke and Barnes, 2010). Neurogenesis in the DG also
decreases with age, which may contribute to the changes
in neuroplasticity over the lifespan (Olariu et al., 2007). In
humans, histo-pathological studies confirm that CA1 does
not show a pronounced cell loss during aging, an obser-
vation that was confirmed in high-resolution subfield
imaging (La Joie et al., 2010) whereas other imaging stud-
ies did show an eect of aging on subfield volume
(Mueller and Weiner, 2009; Shing et al., 2011; Wisse
et al., 2014), probably depending on study cohort and
imaging methodology.
 T. Bartsch, P. Wul / Neuroscience xxx (2015) xxxxxx
CHRONIC INFLUENCES ON THE
HIPPOCAMPUS AND DURING AGING
In chronic diseases such as neurodegenerative diseases,
chronic epilepsy or neuropsychiatric disorders, the time
course of pathological changes is much slower than with
e.g. acute ischemia and might be more complex as
multiple pathological pathways overlap. Furthermore, in
contrast to acute lesions to the hippocampus, the
regional vulnerability of the hippocampus may shift to
other hippocampal structures such as the DG or the
CA3 area (Small et al., 2011; Falkai et al., 2012).
In AD, extracellular amyloid deposits consisting of Ab
protein and intra-neuronal NFTs composed of
hyperphosphorylated tau protein are a hallmark of the
cellular pathological process. The deposition of NFTs
leads to neurodegeneration and the hippocampal CA1 is
one of the first structures aected before other subfields
such as the subiculum, CA2, CA3 and CA4/DG are
included in the pathological process (West et al., 1994;
Braak and Braak, 1995, 1996; Chetelat et al., 2008;
Mufson et al., 2015). In some imaging studies, the integ-
rity of CA3/DG (Mueller et al., 2010) or CA2 subregions
was preserved (Wisse et al., 2014). Deficits in encoding
were correlated with CA1 volume whereas deficits in
retrieval were correlated with a disruption of a
hippocampal-parietal-frontal network in aMCI (Fouquet
et al., 2012). Apolipoprotein E4 status has an eect on
the volume of CA3/DG in healthy controls and AD
(Mueller and Weiner, 2009). In other studies, it could be
shown that the volume of CA3/DG is associated to verbal
learning and early retrieval whereas CA1 atrophy is corre-
lated with impaired consolidation/delayed retrieval
(Mueller et al., 2007, 2011).
Accordingly, imaging studies suggest an association
between CA1 and subiculum volume loss and the
development of later dementia and emphasize subfield
imaging as sensitive biomarker tool for the detection
and study of early AD processes (de Flores et al., 2015b).
HIPPOCAMPAL NEUROPLASTICITY AND
ADULT NEUROGENESIS
Plasticity in the central nervous system requires the
adaptation of brain functions and neural circuits and it
has long been assumed that these plastic changes take
place at hard-wired neural connections. It has been
shown, however, that new neuronal cells can be created
in the adult mammalian hippocampus; these new cells
might play an important role in the lifelong plasticity
mechanisms of learning and adaptation (Ming and Song,
2011). Adult neurogenesis in mammals is restricted to
two brain areas the olfactory bulb and hippocampus,
where neurons are generated by neural stem cells
throughout adult life. In humans, adult neurogenesis is
thought to be restricted to the subgranular zone (SGZ) in
the DG of the hippocampus. The functional relevance
of this continuous generation of new cells has been
extensively studied in the last years, in particular with
regard to the structural integration into preexisting
neural circuits within the hippocampus with subsequent
Please cite this article in press as: Bartsch T, Wulff P. The hippocampus in aging and disease: From plasticity to vulnerability. Neuroscience (2015),
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7
modifications of hippocampal functions (Bergmann and
Frisen, 2013). The process of adult neurogenesis is sub-
ject to various internal and external modulatory influences
during physiological and pathophysiological states (Voss
et al., 2013). It has been suggested that adult neurogene-
sis contributes to the plastic adaptation of learning and
memory in complex environments as an impairment of
neurogenesis correlates with reduced hippocampus-
dependent memory performance (Drapeau et al., 2003).
One process that has been suggested to play a role in
adaptive behavior is pattern separation, during which sim-
ilar representations are processed into distinct, dissimilar
non-overlapping representations, a function that is
required in discriminating similar experiences (Sahay
et al., 2011; Yassa and Stark, 2011). Pattern separation
as well as its complementary function pattern completion
are thought to be dependent on the neural circuity of the
DG and the hippocampal CA3 region (Deng et al., 2010). It
has further been suggested that impairments of this pat-
tern separation process contribute to the development of
certain neuropsychiatric diseases such as anxiety disor-
ders and depression and may be caused by disturbed
adult neurogenesis (Sahay and Hen, 2007; Kheirbek
et al., 2012). Impairment of hippocampal neurogenesis
may thus contribute to cognitive deficits seen in depres-
sion. Besides the putative role in pattern separation, adult
neurogenesis is also thought to play a role in encoding
temporal context representation in the hippocampus and
in the resolution of memory representations (Aimone
et al., 2014). Furthermore, neurogenesis is involved in
the formation of a developmental phenotype of individual-
ity as a reflection of a neuroplastic interaction between
genetic and environmental variations (Freund et al.,
2013). Although the relevance of adult neurogenesis for
enhancing neuroplasticity in the hippocampus has been
demonstrated in rodents, the functional relevance in
humans is not entirely clear (Lazarov et al., 2010; Ming
and Song, 2011). Adult neurogenesis in the hippocampus
is dynamically regulated and positively modulated by var-
ious physiological influences such as physical exercise,
enriched environment, diet and hippocampal learning,
which facilitate cell proliferation, maturation and new neu-
ron survival and modulates mechanisms of synaptic plas-
ticity such as DG LTP (Brown et al., 2003; Voss et al.,
2013; Aimone et al., 2014). On the other side, influences
such as aging and stress reduce cell proliferation, survival,
and neuronal dierentiation of the newly formed neurons
(Opendak and Gould, 2015). Thus, hippocampal neuroge-
nesis was found to be altered in experimental models of
neuropsychiatric diseases such as major depression, anx-
iety disorders, stroke, AD and epilepsy. In these disease
states, either a reduction of neurogenesis by decreased
stem cell activity or a reduction of neuronal survival can
be observed. Further, abnormal stem cell maturation could
lead to aberrant integration into hippocampal circuits. The
reduction of adult neurogenesis in AD may at least partly
be modulated by disease risk genes such as human pre-
senillin (PS) variants. In epilepsy, seizures lead to
increased cell proliferation but also to mis-migration of
newly formed neurons and altered circuit integration
(Ming and Song, 2011). Cerebral ischemia stimulates cell
8 T. Bartsch, P. Wul / Neuroscience xxx (2015) xxxxxx
proliferation in the DG, thereby giving rise to newly gener-
ated neurons and supporting the activity-dependent role of
adult neurogenesis in plasticity and compensation
(Schwamm et al., 1998; Bueters et al., 2008; Miles and
Kernie, 2008). Interestingly, the development of
hippocampal neural stem/progenitor cells can not only
be directed toward the neuronal lineage but can be also
directed toward the oligodendrocyte lineage, which could
result in the generation of human oligodendrocytes, critical
for remyelination processes in response to demyelinating
lesions (Czepiel et al., 2015). With regard to the mecha-
nisms of plasticity following hippocampal damage, it has
been shown that at least in the rat global ischemia
results in an almost complete loss of CA1 neurons, which
is reflected by robust deficits in spatial memory. The reap-
pearance of nearly 40% of the CA1 neurons within 90 days
of the insult was associated with a restoration of hip-
pocampal spatial memory function, which indicates that
the newly formed neurons that originate in the lateral
periventricular region have the potential to restore
hippocampal function (Bendel et al., 2005). Metabolic
diseases such diabetic states and high-caloric intake also
impair hippocampal neurogenesis, synaptic plasticity and
learning possibly via changes in glucocorticoid levels
(Stranahan et al., 2008). Radiation and chemotherapy-
induced damage to neural progenitor populations may
lead to impaired adult hippocampal neurogenesis and
decreased subcortical white matter integrity contributing
to neurocognitive deficits (Monje and Dietrich, 2012).
Only recently, the interconnection between adult
neural stem cell regulation and the immune system
acting on hippocampal function has been studied
(Carpentier and Palmer, 2009; Williamson and Bilbo,
2013; Barrientos et al., 2015). A plethora of literature
demonstrates the impact of an activated immune
response such as microglia and astrocyte activation, infil-
tration of T cells, cytokines, chemokines, prostaglandins
and reactive oxygen species (ROS) on hippocampal func-
tion (Novkovic et al., 2015). This immune activation in
inflammatory states such as during insult, injury and in
neurodegenerative diseases such as AD and aging may
lead to an impairment of hippocampal function including
hippocampal neurogenesis, cellular plasticity and learning
(Barrientos et al., 2012; Williamson and Bilbo, 2013).
In sum, adult neurogenesis in the hippocampus permits
long-term neuroplastic adaptation in hippocampal circuits
to complex environmental conditions. Considering the
positive and negative regulation of adult hippocampal
neurogenesis by diverse external stimuli such as
environmental factors, the influence of newly generated
cells on hippocampal plasticity highlights the potential of
neurogenesis for neuroplastic intervention in aging and
disease states (Lazarov et al., 2010; Ming and Song,
2011).
THE HIPPOCAMPUS AND THE REGULATION
OF STRESS
Stress as a concept is defined as a multidimensional
construct consisting of (i) stress input with perception
and appraisal of the stressor, (ii) the processing of
stressful information and (iii) the stress response itself
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
with the objective of restoring homeostasis through
behavioral and physiological adaptations (de Kloet,
2012). These changes in homeostatic regulation can lead
from adaptive to maladaptive consequences at multiple
levels and are considered to contribute to various neu-
ropsychiatric diseases in which deficits of hippocampal
function such as cognitive impairment can be observed
(Dohring et al., 2014; Lucassen et al., 2014). The hip-
pocampal system with its circuitry is functionally and
structurally integrated in the stress responses to behav-
ioral stressors including fear and anxiety. In the context
of stress, the hippocampus is subject to an involvement
by the hypothalamicpituitaryadrenal axis, which influ-
ences the hippocampus by the release of stress hor-
mones (de Kloet et al., 2005; McEwen, 2007; Fanselow
and Dong, 2010). Stress targets hippocampal function
on dierent levels via glucocorticoid receptor activation
leading to various cellular and systemic eects on synap-
tic plasticity, neuronal survival, hippocampal neurogene-
sis, hippocampal connectivity and memory (McEwen
and Milner, 2007; Sandi and Pinelo-Nava, 2007; Segal
et al., 2010; de Kloet, 2012). As an example, hippocampal
LTP and LTD in CA1 can be aected by acute behavioral
stress (Howland and Wang, 2008). Stress may lead also
to cytotoxicity and metabolic vulnerability in CA1 neurons
due to glucocorticoid-enhanced glutamatergic transmis-
sion with an increase of calcium influx (Joels, 2009). On
a structural level, stress may lead to altered dendritic
architecture in hippocampal circuits as it may induce a
retraction of CA3 pyramidal neuron dendrites and reduc-
tion of dendritic spine density as well as a loss of
synapses (de Kloet et al., 2005).
NEUROINFLAMMATION IN THE HIPPOCAMPUS
The role of neuroinflammatory mechanisms in
hippocampal function and dysfunction has only recently
been recognized. Neuroinflammatory states can
significantly contribute to the vulnerability of the
hippocampus leading to cognitive impairment. This does
not only pertain to pathological inflammatory states such
as during generalized inflammation or sepsis but also
during dysregulation in autoimmunity as in MS and
limbic encephalitis (Kayser and Dalmau, 2014; Kostic
et al., 2015). Peripheral inflammatory responses in the
hippocampus result in an interleukin-1 beta (IL-1b) activa-
tion with subsequent T and B lymphocyte proliferation and
stimulation of natural killer cell activity. IL-1b facilitates the
production of other cytokines such as TNFa and
interleukin-6 (IL-6), which acts on neural activity in the hip-
pocampus (Baier et al., 2009; Tan et al., 2014). An aggra-
vated glutamate excitotoxicity may lead to further
deleterious eects in hippocampal neurons (Semmler
et al., 2013; Tan et al., 2014; Michels et al., 2015).
Increasing evidence suggests that neuroimmune signal-
ing and neuroinflammation is also present in a wide spec-
trum of pathophysiological processes such as during
neurodegeneration in AD (Heneka et al., 2015). Neuroim-
mune signaling encompasses microglia and astrocyte
activation, T-cell infiltration and messengers such as
cytokines, ROS and prostaglandins.
 T. Bartsch, P. Wul / Neuroscience xxx (2015) xxxxxx
The influence of the immune system is not restricted to
states of an activated immune system. The idea has been
put forward that a basal level of neuroimmune interaction
in the hippocampus is also functionally relevant and
present in physiological states and during development
(Williamson and Bilbo, 2013). For example, a role for
cytokines has been observed in hippocampal learning,
LTP and neurogenesis (Baier et al., 2009; Braun et al.,
2013; Williamson and Bilbo, 2013). It has further been sug-
gested that hippocampal-neuroimmunological interactions
via neuroimmune signaling molecules including chemoki-
nes and cytokines contribute to the homeostatic balance
of vulnerability, plasticity and resilience mechanisms in
the hippocampus (Williamson and Bilbo, 2013).
Alterations of the neuro-immune signature such as
microglial sensitization seems to be a hallmark of a
normal aging process resulting in facilitated and
exaggerated neuroinflammatory response in the aging
brain to an immune challenge (Barrientos et al., 2015).
This neuroinflammatory response is further enhanced by
a dysregulated neuroendocrine response in the aged ani-
mal leading to higher cortisol levels. Notably, these neu-
roimmunological responses seem to be most prominent
in the hippocampal formation (Barrientos et al., 2015).
These mechanisms may lead to long lasting elevations in
pro-inflammatory cytokines in the hippocampus resulting
in impaired plasticity and cognitive deficits (Barrientos
et al., 2015).
MULTIPLE SCLEROSIS
MS is an inflammatory and demyelinating disease
that aects the central nervous system and is
commonly associated with white-matter damage.
Neuroinflammation is mediated by microglia activation
and acts against myelin, the neuropathological hallmark
of the disease process in MS. However, activation of
the neuroinflammatory cascade also causes neuronal
and synaptic damage leading to gray matter
demyelination, atrophy and degeneration (Wegner and
Stadelmann, 2009). The majority of MS patients exhibits
a clinically relevant cognitive dysfunction during the
course of the disease including learning and memory dif-
ficulties suggesting involvement of the hippocampal mem-
ory system (Sicotte et al., 2008; Sacco et al., 2015).
Indeed, human imaging studies have shown that the
cognitive deficits are at least partly dependent on the
distribution of demyelinating lesions in the hippocampus
of severely-aected patients (Brainin et al., 1988). In
patients with cognitive deficits, selective and progressive
hippocampal atrophy was observed that was focused on
the CA1 subregion (Sicotte et al., 2008). This hippocam-
pal atrophy in turn was associated with deficits in memory
encoding and retrieval (Sicotte et al., 2008; Anderson
et al., 2010). MS patients with depressive symptoms have
smaller volume in CA2, CA3 and DG but show elevated
cortisol levels (Gold et al., 2010, 2014). Besides reduction
in hippocampal volume, connectivity of the hippocampus
as measured using resting-state functional connectivity
between the hippocampus and anterior cingulate
gyrus, thalamus and prefrontal cortex was decreased
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
9
reflecting impairments of large-scale cognitive networks
(Roosendaal et al., 2008, 2010). The plasticity in hip-
pocampal memory networks in MS patients with cognitive
deficits was recently studied (Hulst et al., 2012). In an epi-
sodic memory fMRI task, hypoactivation of hippocampus-
dependent networks was observed in MS patients with
cognitive deficits compared to controls. However,
hyperactivation in the hippocampal-cingulate memory
system during encoding was seen in MS patients without
cognitive deficits. This dierent activation pattern was
interpreted as functional adaptation within the hippocam-
pal memory system before cognitive deficits become
clinically relevant.
On a cellular level, hippocampal demyelination and
inflammation are robust findings in post-mortem
specimens (Geurts et al., 2007). Most demyelination
lesions are chronic with subpial or subependymal loca-
tion. Whereas Papadopoulos et al. reported neuronal cell
loss in the CA1 and CA3-2 regions of approximately 30%
(Papadopoulos et al., 2009), Dutta et al., reported only
minor neuronal cell loss (Dutta et al., 2011). However,
the latter study showed a significant decrease in synaptic
density in the demyelinated hippocampus (Dutta et al.,
2011). Synaptophysin-positive pre-synaptic terminals in
CA1 and DG were reduced possibly due to
demyelination-associated synaptic pruning. In compar-
ison to motor cortex, levels of proteins involved in axonal
transport, synaptic plasticity, neuronal survival and
glutamatergic neurotransmission were altered in the
hippocampus. This suggests that the molecular machin-
ery associated with neuroplasticity (such as LTP) may
be impaired in MS (Dutta et al., 2011; Novkovic et al.,
2015). Experimentally, inflammatory changes in MS can
be modeled using experimental autoimmune
encephalomyelitis (EAE), an established animal model
of MS that shows acute or chronically relapsing inflamma-
tory and demyelinating autoimmune processes (Novkovic
et al., 2015). EAE leads to microglia-mediated neuroin-
flammation, demyelination, loss of hippocampal CA1
neurons and behavioral deficits in a spatial learning task
(Peruga et al., 2011).
The inflammatory changes in EAE also aect synaptic
plasticity in the hippocampus as LTP in CA1 is
compromised possibly due to enhanced IL-1b release
from infiltrating lymphocytes or activated microglia
(Nistico et al., 2014; Novkovic et al., 2015). Also, a
certain role of the complement system has been attribu-
ted to the synaptic changes in demyelinated hippocampi
(Michailidou et al., 2015). Notably, remyelination of the
hippocampal neurons reversed these alterations (Dutta
et al., 2013).
IMMUNE-MEDIATED NEUROINFLAMMATORY
LIMBIC ENCEPHALITIS AND HIPPOCAMPAL
FUNCTION
In the last decade, a new entity of inflammatory diseases
was recognized that typically aects the limbic system
including the medial temporal lobe system and the
hippocampus (Varley et al., 2015). The limbic encephalitis
is considered an autoimmune encephalitis as antibodies
10 T. Bartsch, P. Wul / Neuroscience xxx (2015) xxxxxx
targeting cell-surface or intracellular antigens can be
detected. In paraneoplastic limbic encephalitis, onconeu-
ral (paraneoplastic) antibodies, such as anti-Hu, anti-Ma2
(anti-Ta), CRMP5/CV2 and ANNA-3 target intracellular
antigens (Irani et al., 2014). On the other side, antibodies
against neuronal surface antigens attack voltage-gated
potassium channels, glutamic acid decarboxylase (GAD)
and NMDA, AMPA and GABA(B) receptors and thus
directly interfere with synaptic transmission and neuronal
plasticity (Irani et al., 2014). Antibodies are not directly
pathogenic and neuronal damage rather seems to be
mediated by cytotoxic T cells (Irani et al., 2014). Patients
with autoimmune limbic encephalitis present with suba-
cute memory disturbances that are accompanied by vari-
ous neuropsychiatric symptoms, such as disorientation,
confusion, temporal lobe seizures and behavioral abnor-
malities, that are suggestive of impaired limbic and hip-
pocampal structures. Memory impairment is particularly
pronounced in the episodic domain (Bartsch et al.,
2010, 2011; Bettcher et al., 2014). For example, antibod-
ies against NMDARs result in impaired hippocampal
synaptic function and leads to memory disturbances, psy-
chiatric symptoms and seizures (Hughes et al., 2010;
Moscato et al., 2010; Bettcher et al., 2014). In patients
with NMDA encephalitis, neuroinflammatory processes
lead to an impairment of hippocampal functional connec-
tivity and white matter integrity that correlated with individ-
ual memory impairment (Finke et al., 2013b). In mice, the
human NMDAR antibodies cause a decrease in the den-
sity of total and synaptic NMDAR clusters and total
NMDAR protein concentration in the hippocampus
(Planaguma et al., 2015). This suggests that these cell-
surface antibodies impair hippocampal NMDAR functions
and synaptic plasticity thus providing a rationale for func-
tional and neurodegenerative changes leading to cogni-
tive deficits.
Potassium channel complex antibodyassociated
encephalitis is the most common form of non-
paraneoplastic limbic encephalitis. MR imaging shows a
preferential aection of the hippocampus with an
extension to the parahippocampal or fusiform gyrus and,
in some patients, to remote areas such as the thalamus.
In many patients, the hippocampus is selectively
aected. The hippocampi show prominent swelling in the
T2-weighted imaging typically seen within the first three
months of disease onset. Typically, atrophic temporal-
mesial or hippocampal structures can be observed in the
later stages (Urbach et al., 2006; Bien et al., 2007).
CHEMOTHERAPY, COGNITIVE IMPAIRMENT
AND HIPPOCAMPAL TOXICITY
Modern therapeutic options targeting cancer cells can
have also eects on the cognitive domain including
learning and memory, attention, executive, processing
speed as well as mood that are clinically relevant and
add to the morbidity of patients (Seigers et al., 2013). In
recent years, putative key elements of this CNS toxicity
of chemotherapy have been identified on a cellular level
and it has been suggested that neurotoxic eects act on
neural function and plasticity (Monje and Dietrich, 2012).
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
Key elements include a direct cellular toxicity, alterations
in cellular metabolism, facilitation of oxidative stress and
induction of pro-inflammatory processes leading to myelin
toxicity, disruption of neurogenesis (Kaiser et al., 2014).
Thus, modern chemotherapeutic substances exert their
neurotoxic eect via several modes of action. Considering
the role of the hippocampus in learning and memory, its
ability for plasticity and its vulnerability, an impairment of
neurogenesis has been suggested to be a key element
in the deleterious eects of chemotherapy on hippocam-
pal function (Kaiser et al., 2014; Dietrich et al., 2015).
Experimentally, damage to neural progenitor cell
populations within germinal zones of the adult CNS has
been identified as one of the key concepts in
chemotherapy-associated impairments of neuroplasticity
and learning and memory (Seigers et al., 2013). Some
chemotherapies show a neurotoxic eect on glial progen-
itor cells and post-mitotic oligodendrocytes, the myelin
forming cells of the CNS that constitute white matter
integrity (Dietrich et al., 2015). Experimentally, it could
be shown that chemotherapy leads to an impairment of
hippocampus-dependent learning and frontal-temporal
networks. In chemotherapy-treated patients, several
human imaging studies suggest a reduction of hippocam-
pal volume accompanied by memory deficits, albeit there
are also studies that did not find volume loss and memory
deficits (Inagaki et al., 2007).
HIPPOCAMPAL DYSFUNCTION IN METABOLIC
DISEASES
In the last years, it has been shown that metabolic
influences on the cellular and systems level can
enhance or impair hippocampal plasticity (Fotuhi et al.,
2012). It became clear that metabolic alterations in obe-
sity and diabetes increase the likelihood of cognitive
decline and accelerate the conversion of cognitive
impairment to dementia (Stranahan, 2015). A model of
neurocognitive impairment in obesity and diabetes has
been suggested emphasizing a bidirectional influence of
the metabolic condition on cellular mechanisms involved
in synaptic plasticity (Stranahan and Mattson, 2011).
For example, a sedentary lifestyle, diabetes and obesity
may reduce adaptive cellular stress responses with
oxidative stress, and inflammatory pathways leading to
impaired synaptic plasticity, decreased neurogenesis
and increased neurodegeneration (Fontan-Lozano et al.,
2007; Stranahan, 2015). These mechanisms may lead
to enhanced vulnerability toward neurocognitive impair-
ment and AD. On the other hand, exercise and caloric
restriction enhance neuroprotection, neurogenesis, and
synaptic plasticity via induction of adaptive cellular stress
responses, e.g. via BDNF (Stranahan and Mattson,
2011). Some of the underlying mechanisms have been
identified. Diabetic states and high-caloric intake seem
to, at least partly, exert their eects via increased
glucocorticoid receptor activation and impaired insulin
and leptin signaling (Stranahan et al., 2008; Stranahan
and Mattson, 2011). A link between diabetes and neu-
rodegenerative diseases such as Alzheimers has been
suggested as the insulin-degrading enzyme (IDE) is also
 T. Bartsch, P. Wul / Neuroscience xxx (2015) xxxxxx
involved in the removal of beta-amyloid from the brain. It
is thus conceivable that both conditions, diabetes and
amyloid burden enhance each other by competing for
the same rescue pathway (Yang and Song, 2013). In
addition, obesity-induced neuroinflammation has been
linked to impaired hippocampal function (Yang and
Song, 2013; Erion et al., 2014). In sum, metabolic factors
do show an important influence on various cellular and
systems mechanisms involved in the regulation of hip-
pocampal plasticity which may lead to an increased vul-
nerability in disease states. Along these lines the
relevance of modifiable environmental factors including
cognitive activation, learning, life style factors, physical
activity and metabolic factors on hippocampal function
has been emphasized (Fotuhi et al., 2012).
THE HIPPOCAMPUS IN EPILEPSY
Epilepsy is a neurological disorder that is characterized by
recurrent seizures. Seizures are correlates of abnormal,
excessive or synchronous neuronal activity within the
CNS. The human hippocampus in particular is capable
in generating epileptic seizures and to facilitate a
chronic increase of cellular excitability which in turn is
thought to be the correlate of temporal lobe epilepsy
(TLE). TLE is a focal epilepsy characterized by seizures
originating in or primarily involving temporal lobe
structures including the hippocampus (ODell et al.,
2012; Sloviter and Bumanglag, 2013). The disease
course of TLE typically correlates with pathomorphologi-
cal neuronal changes termed hippocampal sclerosis
(HS; syn. Ammons horn sclerosis) that manifest with seg-
mental neuronal cell loss in the pyramidal cell layer of the
cornu ammonis CA1 and CA4 associated with reactive
astrogliosis (Cendes et al., 2014; Blumcke and Coras,
2015). It is dicult, however, to disentangle causes and
consequences of epileptogenesis and seizures in hip-
pocampal circuits. The current concept of TLE favors
complex multifactorial influences and mechanisms on dif-
ferent temporal scales and suggests a structural and
functional re-organization of neural circuits in CA3 and
DG with aberrant maturation and ectopic migration within
the dentate circuitry. These alterations of synaptic cir-
cuitry include aberrant mossy fiber sprouting, alterations
in dendritic branching, spine density and may lead to a
formation of recurrent excitatory collaterals that transform
the CA3 principal cells into an epileptogenic population
promoting seizure initiation and/or propagation by
increasing the net excitatory drive of dentate granule neu-
rons (Kienzler et al., 2009; ODell et al., 2012). Other
potential components of hippocampal epileptogenesis
include, among others, molecular rearrangement/plastic-
ity of ion channel and neurotransmitter receptor expres-
sion, neural injury, viral infections, as well as genetic
variations, epigenetic modifications, neuroinflammation,
blood brain-barrier leakage, angiogenesis and endocrine
influences. However, the precise role of these influences
in the generation of epileptogenic networks remains
unclear (Pitkanen and Sutula, 2002; ODell et al., 2012).
Hippocampal neurons are in particular vulnerable to
metabolic stress conditions and excitotoxicity in the wake
Please cite this article in press as: Bartsch T, Wulff P. The hippocampus in aging and disease: From plasticity to vulnerability. Neuroscience (2015),
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11
of epileptic seizures leading to cell loss (Forster et al.,
2012; Bartsch et al., 2015; Sierra et al., 2015). This itself
may stimulate mechanisms of neural plasticity and further
contribute to epileptogenesis. For example, it has been
shown that during epileptogenesis, aberrant neuronal cir-
cuits are formed by adult-generated granule cells in the
DG that itself are capable of inducing seizure activity
(Pun et al., 2012). These results suggest that seizure
induced neurogenesis may play critical role in epileptoge-
nesis in the hippocampus. In human patients, aspects of
microstructural damage and plasticity in the hippocampus
in epileptogenesis have begun to be studied using
MR-imaging aiming at identifying biomarkers of the
epileptogenic process, which are critical for the prognosis
of epilepsy as well as for the assessment of possible
treatment strategies (Sierra et al., 2015).
SLEEP AND HIPPOCAMPAL VULNERABILITY
The hippocampus plays a key role in sleep-dependent
memory consolidation in animals and humans
(Diekelmann and Born, 2010). Consolidation of newly
formed memories refers to the process of stabilization of
a memory trace either by strengthening or reducing the
susceptibility to interference. In humans, the hippocam-
pus and adjacent cortical structures contribute to
sleep-dependent memory consolidation through interac-
tions with distributed brain areas. According to a major
hypothesis of sleep-dependent memory consolidation of
episodic memory, neuronal activity associated with the
encoding process during wakefulness becomes replayed
(reactivated) during ensuing sleep and thus mediates sys-
tem consolidation processes involving the redistribution of
memories from an intermediate hippocampus-dependent
to a long-term hippocampus-independent store (Wilson
and McNaughton, 1994; Diekelmann and Born, 2010).
This transfer is thought to be mediated by synchronous
network pattern in the hippocampus during slow-wave
sleep (ONeill et al., 2010). Sleep has also been
implicated in the regulation of plasticity as it has been
suggested that one of the critical functions of sleep is
the restoration of synaptic homeostasis in terms of renor-
malization of synaptic strength. This homeostatic regula-
tion of synaptic strength is thought to increase neuronal
signal-to-noise ratios and thus to facilitate the integration
and consolidation of new memories (Tononi and Cirelli,
2014). As described, many critical cognitive functions of
the hippocampus require specific brain states such as
slow-wave sleep for the processing of mnemonic informa-
tion. Thus, hippocampal function is very sensitive to a dis-
ruption of these processes by sleep deprivation and sleep
loss leading to impaired formation of hippocampus-
dependent memories (Kreutzmann et al., 2015). Sleep
deprivation not only interrupts sleep-dependent cognitive
processing leading to impaired cognitive functioning, but
has widespread eects on synaptic plasticity mechanisms
in the hippocampus (Prince and Abel, 2013). Short
periods of sleep deprivation impair hippocampal plasticity
by aecting LTP, second-messenger signaling (cAMP-
protein kinase A (PKA)), adenosine, cellular transcription
factors (CREB), neurotrophic signaling (BDNF), and
12 T. Bartsch, P. Wul / Neuroscience xxx (2015) xxxxxx
glutamate receptor expression (Havekes et al., 2012).
Long-term sleep loss may lead to reduced hippocampal
cell proliferation and impaired neurogenesis thus impair-
ing hippocampal plasticity and structural integrity on a
longer time scale (Kreutzmann et al., 2015). Sleep depri-
vation after learning in humans also alters the connectivity
between brain regions as a shift from the hippocampo-
neocortical network to an increased striatal navigation-
related activity was observed (Orban et al., 2006).
CONCLUDING REMARKS
The research of the last decades has highlighted
the multifaceted structure and function of the
hippocampus as a pivotal structure involved in cognitive
and behavioral regulation. These functions of the
hippocampus are a reflection of the high degree of
neuroplasticity and tightly linked to the instrinsic
properties of hippocampal neurons, circuits and neural
populations. This particular degree of neuroplasticity
may also be involved in the particular vulnerability and
susceptibility of the hippocampus to deleterious
conditions such as ischemia, epilepsy, chronic stress
and neurodegeneration. From a clinical viewpoint,
the unique level of neuroplastic mechanisms in the
hippocampus may be further explored with regard to
questions of resilience, regeneration and restoration
to metabolic and behavioral stress that could lead to
therapeutic interventions on a cellular and systems level
in neurological, neurodegenerative, and psychiatric
diseases.
AcknowledgmentsT.B. has been supported by the German
Research Foundation SFB 654, FOR 2093, the German Cluster
of Excellence Inflammation-at-Interfaces (ExC 306) and by the
Faculty of Medicine, University of Kiel, Germany. Peer Wul
was supported by the Medical Research Council grant
G1100546, the German Research Foundation FOR 2143 and
the Faculty of Medicine, University of Kiel, Germany.
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