EditorialThe hippocampus in aging and disease: From plasticity to vulnerability
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.
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