The hippocampus in aging and disease: From plasticity to vulnerability

doi:10.1016/j.neuroscience.2015.07.084

Neuroscience

Volume 309, 19 November 2015, Pages 1-16

https://doi.org/10.1016/j.neuroscience.2015.07.084 Get rights and content

Abstract

The 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 synaptic plasticity such as long-term potentiation and -depression have been identified and demonstrated in hippocampal circuits. 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 architecture as well as in intrinsic properties of hippocampal neurons and circuits. The high degree of hippocampal neuroplasticity might, however, be also negatively reflected in the pronounced vulnerability of the hippocampus to deleterious 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 findings regarding the functional organization of the hippocampus in light of the regional vulnerability in Alzheimer’s disease, ischemia, epilepsy, neuroinflammation and aging.

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 different subregions of the hippocampus subserves differential mnemonic operations (Kesner and Rolls, 2015). Indeed, in recent years, a differential and complex modular organization 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, 2008).

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 formation of new neurons (Leuner and Gould, 2010). Cellular neuroplasticity is not confined to physiology but also present in the context of progressive pathology, such as neurodegeneration in Alzheimer’s 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 modifications 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 vulnerability’ (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).

Section snippets

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

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 systems 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

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 intrahippocampal connectivity and electrophysiological findings suggest a dichotomic organization of hippocampal networks into

Acute damage to the hippocampus

For over 100 years it has been known that acute pathological conditions, such as ischemia, hypoglycemia, 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 reflection 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

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,

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

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 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

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

Multiple Sclerosis

MS is an inflammatory and demyelinating disease that affects 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

Immune-mediated neuroinflammatory limbic encephalitis and hippocampal function

In the last decade, a new entity of inflammatory diseases was recognized that typically affects 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 targeting cell-surface or intracellular antigens can be detected. In paraneoplastic limbic encephalitis, onconeural (paraneoplastic) antibodies, such as anti-Hu, anti-Ma2 (anti-Ta), CRMP5/CV2 and ANNA-3 target

Chemotherapy, cognitive impairment and hippocampal toxicity

Modern therapeutic options targeting cancer cells can have also effects 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 effects act on neural function and plasticity (Monje and Dietrich,

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 obesity 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

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

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 hippocampus and adjacent cortical structures contribute to sleep-dependent memory consolidation through interactions with distributed brain areas. According to a major hypothesis of

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

Acknowledgments

T.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 Wulff was supported by the Medical Research Council grant G1100546, the German Research Foundation FOR 2143 and the Faculty of Medicine, University of Kiel, Germany.

References (191)

A. Aksoy-Aksel et al.
Synaptic strength at the temporoammonic input to the hippocampal CA1 region in vivo is regulated by NMDA receptors, metabotropic glutamate receptors and voltage-gated calcium channels
Neuroscience
(2015)
P.C. Baier et al.
Impaired hippocampus-dependent and -independent learning in IL-6 deficient mice
Behav Brain Res
(2009)
D.M. Bannerman et al.
Regional dissociations within the hippocampus–memory and anxiety
Neurosci Biobehav Rev
(2004)
R.M. Barrientos et al.
Aging-related changes in neuroimmune-endocrine function: implications for hippocampal-dependent cognition
Horm Behav
(2012)
R.M. Barrientos et al.
Neuroinflammation in the normal aging hippocampus
Neuroscience
(2015)
F.P. Battaglia et al.
The hippocampus: hub of brain network communication for memory
Trends Cognit Sci
(2011)
H. Braak et al.
Staging of Alzheimer’s disease-related neurofibrillary changes
Neurobiol Aging
(1995)
T. Bueters et al.
Degeneration of newly formed CA1 neurons following global ischemia in the rat
Exp Neurol
(2008)
S.N. Burke et al.
Senescent synapses and hippocampal circuit dynamics
Trends Neurosci
(2010)
T.R. Butler et al.
Selective vulnerability of hippocampal cornu ammonis 1 pyramidal cells to excitotoxic insult is associated with the expression of polyamine-sensitive N-methyl-d-asparate-type glutamate receptors
Neuroscience
(2010)

P.A. Carpentier et al.

Immune influence on adult neural stem cell regulation and function

Neuron

(2009)

G. Chetelat et al.

Three-dimensional surface mapping of hippocampal atrophy progression from MCI to AD and over normal aging as assessed using voxel-based morphometry

Neuropsychologia

(2008)

S.J. Coultrap et al.

Differential expression of NMDA receptor subunits and splice variants among the CA1, CA3 and dentate gyrus of the adult rat

Brain Res Mol Brain Res

(2005)

S.R. Das et al.

Measuring longitudinal change in the hippocampal formation from in vivo high-resolution T2-weighted MRI

Neuroimage

(2012)

J. Dietrich et al.

Chemotherapy, cognitive impairment and hippocampal toxicity

Neuroscience

(2015)

A. Engvig et al.

Hippocampal subfield volumes correlate with memory training benefit in subjective memory impairment

Neuroimage

(2012)

M.S. Fanselow et al.

Are the dorsal and ventral hippocampus functionally distinct structures?

Neuron

(2010)

M. Fouquet et al.

Role of hippocampal CA1 atrophy in memory encoding deficits in amnestic mild cognitive impairment

Neuroimage

(2012)

S.M. Gold et al.

Smaller cornu ammonis 2–3/dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms

Biol Psychiatry

(2010)

J.F. Guzowski et al.

Ensemble dynamics of hippocampal regions CA3 and CA1

Neuron

(2004)

G.J. Harry et al.

Dentate gyrus: alterations that occur with hippocampal injury

Neurotoxicology

(2003)

R. Havekes et al.

The impact of sleep deprivation on neuronal and glial signaling pathways important for memory and synaptic plasticity

Cell Signal

(2012)

J. Heine et al.

Imaging of autoimmune encephalitis – relevance for clinical practice and hippocampal function

Neuroscience

(2015)

J.G. Howland et al.

Synaptic plasticity in learning and memory: stress effects in the hippocampus

Prog Brain Res

(2008)

S.R. Hulme et al.

Emerging roles of metaplasticity in behaviour and disease

Trends Neurosci

(2013)

M.R. Hunsaker et al.

The operation of pattern separation and pattern completion processes associated with different attributes or domains of memory

Neurosci Biobehav Rev

(2013)

J. Kaiser et al.

Neural correlates of chemotherapy-related cognitive impairment

Cortex

(2014)

R.P. Kesner et al.

A computational theory of hippocampal function, and tests of the theory: new developments

Neurosci Biobehav Rev

(2015)

B. Kolb et al.

Searching for the principles of brain plasticity and behavior

Cortex

(2014)

M. Kostic et al.

Deleterious versus protective autoimmunity in multiple sclerosis

Cell Immunol

(2015)

J.C. Kreutzmann et al.

Sleep deprivation and hippocampal vulnerability: changes in neuronal plasticity, neurogenesis and cognitive function

Neuroscience

(2015)

R. La Joie et al.

Differential effect of age on hippocampal subfields assessed using a new high-resolution 3T MR sequence

Neuroimage

(2010)

J.B. Aimone et al.

Regulation and function of adult neurogenesis: from genes to cognition

Physiol Rev

(2014)

D.G. Amaral et al.

The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies)

Prog Brain Res

(2007)

V.M. Anderson et al.

Hippocampal atrophy in relapsing-remitting and primary progressive MS: a comparative study

Mult Scler

(2010)

E. Avignone et al.

Differential responses to NMDA receptor activation in rat hippocampal interneurons and pyramidal cells may underlie enhanced pyramidal cell vulnerability

Eur J Neurosci

(2005)

A. Bakker et al.

Pattern separation in the human hippocampal CA3 and dentate gyrus

Science

(2008)

T. Bartsch

The Clinical Neurobiology of the Hippocampus

(2012)

T. Bartsch et al.

Selective affection of hippocampal CA-1 neurons in patients with transient global amnesia without long-term sequelae

Brain

(2006)

T. Bartsch et al.

Focal MR spectroscopy of hippocampal CA-1 lesions in transient global amnesia

Neurology

(2008)

T. Bartsch et al.

CA1 neurons in the human hippocampus are critical for autobiographical memory, mental time travel, and autonoetic consciousness

Proc Natl Acad Sci U S A

(2011)

T. Bartsch et al.

Selective neuronal vulnerability of human hippocampal CA1 neurons: lesion evolution, temporal course, and pattern of hippocampal damage in diffusion-weighted MR imaging

J Cereb Blood Flow Metab

(2015)

T. Bartsch et al.

Focal lesions of human hippocampal CA1 neurons in transient global amnesia impair place memory

Science

(2010)

O. Bendel et al.

Reappearance of hippocampal CA1 neurons after ischemia is associated with recovery of learning and memory

J Cereb Blood Flow Metab

(2005)

O. Bergmann et al.

Neuroscience. Why adults need new brain cells

Science

(2013)

B.M. Bettcher et al.

More than memory impairment in voltage-gated potassium channel complex encephalopathy

Eur J Neurol

(2014)

C.G. Bien et al.

Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy

Neurology

(2007)

T. Bliss et al.

Neuroscience. Controlling the ups and downs of synaptic strength

Science

(2004)

Blümcke I, Coras R (2015) Clinico-pathological subtypes of hippocampal sclerosis in temporal lobe epilepsy and their...

H.M. Bonnici et al.

Multi-voxel pattern analysis in human hippocampal subfields

Front Hum Neurosci

(2012)

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EditorialThe hippocampus in aging and disease: From plasticity to vulnerability

Abstract

Introduction

Section snippets

Hippocampal anatomy

Neuroplasticity and the hippocampus

Hippocampal organization along the longitudinal axis

Acute damage to the hippocampus

Chronic influences on the hippocampus and during aging

Hippocampal neuroplasticity and adult neurogenesis

The hippocampus and the regulation of stress

Neuroinflammation in the hippocampus

Multiple Sclerosis

Immune-mediated neuroinflammatory limbic encephalitis and hippocampal function

Chemotherapy, cognitive impairment and hippocampal toxicity

Hippocampal dysfunction in metabolic diseases

The hippocampus in epilepsy

Sleep and hippocampal vulnerability

Concluding remarks

Acknowledgments

Neuroscience

Behav Brain Res

Neurosci Biobehav Rev

Horm Behav

Neuroscience

Trends Cognit Sci

Neurobiol Aging

Exp Neurol

Trends Neurosci

Neuroscience

Neuron

Neuropsychologia

Brain Res Mol Brain Res

Neuroimage

Neuroscience

Neuroimage

Neuron

Neuroimage

Biol Psychiatry

Neuron

Neurotoxicology

Cell Signal

Neuroscience

Prog Brain Res

Trends Neurosci

Neurosci Biobehav Rev

Cortex

Neurosci Biobehav Rev

Cortex

Cell Immunol

Neuroscience

Neuroimage

Regulation and function of adult neurogenesis: from genes to cognition

Physiol Rev

The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies)

Prog Brain Res

Hippocampal atrophy in relapsing-remitting and primary progressive MS: a comparative study

Mult Scler

Differential responses to NMDA receptor activation in rat hippocampal interneurons and pyramidal cells may underlie enhanced pyramidal cell vulnerability

Eur J Neurosci

Pattern separation in the human hippocampal CA3 and dentate gyrus

Science

The Clinical Neurobiology of the Hippocampus

Selective affection of hippocampal CA-1 neurons in patients with transient global amnesia without long-term sequelae

Brain

Focal MR spectroscopy of hippocampal CA-1 lesions in transient global amnesia

Neurology

CA1 neurons in the human hippocampus are critical for autobiographical memory, mental time travel, and autonoetic consciousness

Proc Natl Acad Sci U S A

Selective neuronal vulnerability of human hippocampal CA1 neurons: lesion evolution, temporal course, and pattern of hippocampal damage in diffusion-weighted MR imaging

J Cereb Blood Flow Metab

Focal lesions of human hippocampal CA1 neurons in transient global amnesia impair place memory

Science

Reappearance of hippocampal CA1 neurons after ischemia is associated with recovery of learning and memory

J Cereb Blood Flow Metab

Neuroscience. Why adults need new brain cells

Science

More than memory impairment in voltage-gated potassium channel complex encephalopathy

Eur J Neurol

Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy

Editorial
The hippocampus in aging and disease: From plasticity to vulnerability