REVIEWS

THE STRESSED HIPPOCAMPUS, SYNAPTIC PLASTICITY AND LOST MEMORIES

Jeansok J. Kim* and David M. Diamond
Stress is a biologically significant factor that, by altering brain cell properties, can disturb cognitive processes such as learning and memory, and consequently limit the quality of human life. Extensive rodent and human research has shown that the hippocampus is not only crucially involved in memory formation, but is also highly sensitive to stress. So, the study of stressinduced cognitive and neurobiological sequelae in animal models might provide valuable insight into the mnemonic mechanisms that are vulnerable to stress. Here, we provide an overview of the neurobiology of stressmemory interactions, and present a neuralendocrine model to explain how stress modifies hippocampal functioning.
Everybody knows what stress is and nobody knows what it is. Hans Selye1

*Department of Psychology and Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut 06520-8205, USA. Departments of Psychology, Pharmacology and Neuroscience Program, University of South Florida, Tampa, Florida 33620-8200, USA, and Veterans Hospital, Medical Research, 13000 Bruce B. Downs Blvd, Tampa, Florida 33612, USA. e-mails: jeansok.kim@yale. edu; ddiamond@chuma1. cas.usf.edu
doi:10.1038/nrn849

The term stress originally used in the field of engineering to describe a force that exerts physical strain on a structure is generally defined in biological systems as any condition that seriously perturbs the physiological/psychological homeostasis of an organism (BOX 1). The profound physiological consequences of stress were first shown empirically in Hans Selyes seminal paper of 1936: A syndrome produced by diverse nocuous agents2. Subsequent research showed the broad range of adverse physiological effects of stress in animals and humans, including adrenal-gland enlargement, atrophy of the thymus and lymph nodes, increased cardiovascular tone, immune-system suppression and ulcerations3. In recent decades, an important line of neuroscience research has shown that stressful experiences can have a negative impact on certain aspects of brain function. The field also developed an appreciation of the fact that the acute response to stress (for example, heightened cognition) is an adaptive mechanism, enabling an organism to respond effectively to a real or potential threat to its survival. However, the insidious

side of this survival strategy is that uncontrollable stress can have severe adverse repercussions, including deterioration in learning-and-memory capacity, an exacerbation of the ageing-related decline in cognition, and an enhanced susceptibility of hippocampal neurons to atrophy or necrosis in response to metabolic challenges47. Recent reviews have presented a thorough discussion of the neurobiological basis of the enhancement of memory by emotional arousal8,9. However, although stressful, and especially traumatic, experiences are known to produce intense, long-lasting memories of the events themselves811, it is also evident that stress impairs subsequent attention and memory1214, and can even induce profound amnesia1517. So, to complete our understanding of stressmemory interactions, it is important to address how stress corrupts the memory-storage process. This review is focused, in general, on the adverse effects of stress on memory, with specific reference to how stress affects hippocampus-dependent cognition and synaptic plasticity. Our focus on the mechanisms that underlie interactions between stress and the hippocampus should advance our understanding of how stress interferes with our ability to accurately encode information.
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Box 1 | What is stress? The term stress is routinely used as if it were a well-defined psychophysiological measure, such as blood pressure or galvanic skin response. On the contrary, stress is a nebulous description of diverse behavioural and physiological responses. Some investigators have addressed the complexity of this issue102,103, but we are unaware of a universal definition of stress with operationally defined terms that can be applied equally to rodents and people. A definition must address the following two issues. First, whether stress occurs is determined not by the physical parameters of environmental stimulation, but by how an organism perceives and reacts to the stimulus. For example, most people feel mild anxiety to outright panic on being asked to speak in public, whereas others enjoy speaking in an open forum. So, a definition must acknowledge that the same stimulus can be stressful to one person, but can give great pleasure to another. Second, there is no unique physiological state that is stress specific. It is tacitly accepted that an elevation of glucocorticoid levels is an indicator of a stress state, as rats that are exposed to a predator and people reporting high levels of stress tend to have elevated levels of glucocorticoids61,104. However, glucocorticoid levels are also elevated by pleasurable activities, such as feeding, exercise and sex105108. Moreover, stressor controllability has a profound influence on the impact of an aversive experience on physiology and behaviour56,109, yet glucocorticoid levels are relatively insensitive to controllability57,110,111. So, although glucocorticoid elevation can be useful in stress research, the level of this hormone is not a definitive measure of the presence or magnitude of stress. Levels of other neuromodulators such as 5-hydroxytryptamine, noradrenaline, dopamine and enkephalins can also increase under conditions that are considered to be stressful109,112, but we suggest that the search for a neuromodulator that is sensitive only to a stress state will fail. Given the problems in understanding what stress is, it is tempting to abandon the use of the term stress, and instead focus on direct causeeffect relationships. For example, rats that were exposed to a cat showed impaired memory62 and a suppression of synaptic plasticity61. The quagmire that surrounds the stress definition is eliminated by assuming that it was the cat, not stress, that affected memory and plasticity. However, it was still the rats perception and reaction to the cat that produced a psychophysiological state that we interpret as stress, which then influenced hippocampal processing. So, ignoring the issue of how to define stress does not make it go away. With these caveats in mind, we offer a three-component definition of stress that can be applied broadly across species and paradigms. First, stress requires heightened excitability or arousal, which can be operationally measured using electroencephalography, behavioural (motor) activity or neurochemical (adrenaline, glucocorticoid) levels.Arousal, however, can increase under either pleasurable or aversive conditions. So, second, the experience must also be perceived as aversive.Aversiveness can be defined as an indication that the subject would avoid or attenuate the intensity of the stressor if given the opportunity. Shock-avoidance conditioning in animals is stressful because it is arousing and the animals attempt to avoid, or at least minimize, their exposure to the shock. For people who find public speaking unpleasant, the experience satisfies the first two criteria of the stress definition, because they would find the experience arousing, and they would avoid making the presentation if possible. Those who enjoy public speaking might find the experience arousing, but because they dont want to avoid making the presentation, their experience would not be stressful. The third component of the definition of stress is controllability. Two animals that are exposed to the same level of electric shock can show arousal and attempt to make an avoidance response, but the experience can have very different behavioural and physiological effects if one animal has control over the termination of the shock56,109111. Corresponding work in people has shown that having control over an aversive experience has a profound mitigating influence on how stressful the experience feels113. The element of control (and the related concept of predictability) in the stress definition is the variable that ultimately determines the magnitude of the stress experience and the susceptibility of the individual to develop stress-induced behavioural and physiological sequelae. In summary, we define stress as a condition in which an individual is aroused by an aversive situation for example, a hostile employer, unpaid bills, a predator or a pawshock. The magnitude of the stress and its physiological consequences are influenced greatly by the individuals perception of its ability to control the presence or intensity of the stimulation.

Stress and hippocampal memory

CORTICOSTEROIDS

The principle glucocorticoids that are synthesized by the adrenal cortex and secreted in response to stress (cortisol in humans, corticosterone in rats).

Although the stress response is a complex biochemical cascade involving the release of diverse chemicals that can affect various aspects of memory, brain structures and physiological processes (FIG. 1), studies on isolated elements can provide valuable insights into the mnemonic mechanisms that are especially vulnerable to stress5. One brain structure that is crucially involved in both memory and the neuroendocrine regulation of stress hormones is the hippocampus. The hippocampus is a medial temporal lobe structure that is necessary for the formation of stable declarative (or explicit) memory in humans1821, and spatial (or relational/contextual) memory in rodents2125. This sea-horse-shaped structure is also a target of stress hormones, having one of the highest concentrations of receptors for CORTICOSTEROIDS

in the mammalian brain. One well-described neuroendocrine function of the hippocampus is to participate in terminating the stress response through glucocorticoid-mediated negative feedback that inhibits the hypothalamuspituitaryadrenal (HPA) axis3,4. The hippocampus is enriched with the two classes of corticosteroid receptors26: type I, mineralocorticoid receptors (MRs); and type II, glucocorticoid receptors (GRs). The adverse effects of stress on the hippocampus seem to be mediated largely by the lower-affinity GRs, which become heavily occupied with corticosteroids in response to stress2729. In the rat hippocampus, corticosterone binding to GRs has been shown to adversely affect neuronal metabolism, cell survival, physiological functions and neuronal morphology37. Consequently, certain hippocampal functions such as learning

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hippocampus-dependent recall tasks33. Moreover, the administration of stress levels of cortisol to normal human subjects selectively impairs verbal declarative memory without affecting non-verbal (procedural) memory34. In addition, people who are diagnosed with both depression and hypercortisolaemia show hippocampus-dependent memory impairments; similarly, patients with Cushings disease in which tumours in the adrenal gland cause excess secretion of glucocorticoids have deficits in declarative memory35 and hippocampal atrophy36, which can be reversed after treatment that reduces their cortisol levels37. Consistent with the findings in humans, rats that are exposed to stress or administered corticosterone (at doses comparable to those observed in response to stress) have deficits in spatial memory3841. Impairments of spatial memory have also been observed in transgenic mice with elevated corticosterone levels (due to the central overexpression of CORTICOTROPIN-releasing factor, CRF)42. Recently, stress has also been found to impair hippocampus-dependent object-recognition memory43,44. Interestingly, uncontrollable stress has also been shown to facilitate both delay 45 and trace46 EYEBLINK CONDITIONING in rats.Although both tasks require an intact cerebellum47, the hippocampus is also necessary for trace (but not for delay) eyeblink conditioning48. In contrast to eyeblink conditioning, however, stress and corticosterone seem to selectively affect hippocampus-dependent contextual (but not hippocampus-independent tone) fear conditioning in rats49,50. It seems, then, that stress exerts complex effects on hippocampal memory processing rather than uniform effects across different

CORTICOTROPIN

A polypeptide hormone, also known as adrenocorticotropic hormone (ACTH), which is secreted by the adenohypophysis of the pituitary. It stimulates the synthesis and secretion of corticosteroids, and the growth of the adrenal cortex.
EYEBLINK CONDITIONING

Necrosis, ageing and neurogenesis

Morphological changes Stress Synaptic plasticity Learning and memory

A Pavlovian conditioning task in which the subject learns to respond with eyelid closure to a conditioned stimulus (CS; tone or light) that has been contingently paired with an unconditioned stimulus (US; airpuff or shock to the eye). In the delay paradigm, the CS precedes and overlaps with the US. In the trace paradigm, there is an empty interval (or gap) between the CS and the US.
PURSUIT ROTOR

Neurochemical systems

A motor-skill learning task that is used to assess the subjects tracking errors and time on a moving target.
DELAYED NONMATCHING-TOSAMPLE TASKS

Figure 1 | Various effects on learning and memory as a function of the magnitude of stress. At a mild level of stress, certain neurochemical systems (for example, catecholamines, opiates, glucocorticoids) might affect learning. As the level of stress increases (in duration and/or intensity), several transient and permanent changes are observed in the hippocampus, including modifications in synaptic plasticity, morphological changes, suppression of adult neurogenesis and neuronal endangerment. These stress-associated changes in the brain can potentially influence learning-and-memory processes.

In such recognition memory tasks, presentation of a stimulus is followed by a delay, after which a choice is offered. In matching tasks, the originally presented stimulus must be chosen; in nonmatching tasks, a new stimulus must be selected. With small stimulus sets, the stimuli are frequently repeated, thus becoming highly familiar. So, typically, such tasks are more readily solved by short-term or working memory rather than by long-term memory mechanisms.

and memory are susceptible to disruption by stress, mediated in part by GR activation. Studies carried out largely over the past two decades have supported the idea that stress and stress hormones impair hippocampus-dependent forms of memory in both humans and animals3,6,7,17,30,31. For example, patients with post-traumatic stress disorder (PTSD) have hippocampal atrophy32 and marked deficits in

Box 2 | Hippocampus-dependent and -independent memory systems The hippocampus, which is one of the medial temporal lobe (MTL) structures, is thought to be crucial for declarative (or explicit) memory, but not non-declarative (or implicit) memory, in humans1821. Declarative types of memory are generally defined as those that involve consciously accessible records of facts and events; for example, recalling when, where and from whom one learned to drive a car. Non-declarative types of memory are usually defined as those that involve non-consciously expressed perceptualmotor skills; for example, the automatic act of driving a car. This concept of memory dichotomy originated with Milner and colleagues initial discovery of preserved non-declarative memory (mirror drawing, jigsaw-puzzle assembly, PURSUIT ROTOR and so on) in the profoundly amnesic patient H.M.18,114, which was supported by subsequent neuropsychological studies19. Tulving115 and others116 further showed dual qualitatively separable memory systems in normal subjects. Results from functional imaging studies20 are also consistent with the view that the hippocampus is crucially involved in declarative memory. A similar (hippocampal/MTL-dependent and -independent) memory dichotomy seems to exist in animals. In 1978, Mishkin117 found that lesioning the hippocampus and the amygdala produced memory deficits in the DELAYED NONMATCHING-TO-SAMPLE (DNMS) task (but not in the object-discrimination task) in non-human primates. Subsequent studies found that lesions that were confined largely to the hippocampus impaired a trial-unique DNMS task (with long delay intervals) in monkeys19. However, recently, there has been disagreement on whether the DNMS memory deficit is due to damage to the hippocampus per se, or damage to its connected MTL cortical areas118,119. In rodents, the hippocampus is generally considered to be involved in spatial (or relational) types of memory. OKeefe and Dostrovsky120 discovered place cells in the hippocampus, which fire preferentially when a rat is in a specific spatial location in an environment. Subsequent studies showed that various hippocampal manipulations (lesions, drugs, stimulations and gene mutations) alter performances on spatial-memory tasks, as assessed using the water maze, radialarm maze, circular maze and contextual conditioning in rats and mice2125,121126. In rabbits, the hippocampus is also necessary for trace eyeblink conditioning (in which the conditioned stimulus and the unconditioned stimulus are separated by a trace interval)48, but not for delay conditioning (in which the conditioned stimulus and the unconditioned stimulus overlap)47. The selective involvement of the hippocampus in trace (but not delay) conditioning has also been shown using fear conditioning in rats and mice127,128. As the hippocampus is involved in DNMS, trace conditioning, and transitive inference and other memory tasks, which seem to have a non-spatial quality, there is a continuing debate as to whether fundamental information processing in the hippocampus is spatial or relational in nature129,130.

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The restrainttailshock stress procedure that was used in these studies was adapted from the learnedhelplessness paradigm56, in which animals cannot perform any adaptive response to escape an aversive experience. One consequence of learned helplessness is an impairment of learning and memory. Interestingly, rats that were given control over the termination of the shock showed more robust hippocampal LTP than yoked control animals57. So, the electrophysiological studies parallel the behavioural findings56, indicating that it is the uncontrollable psychological aspect of the shock, rather than the pain associated with the shock, that exerted the primary inhibitory effect on hippocampal LTP. Likewise, other forms of psychological stress produced, for example, by forced exposure to brightly lit, unfamiliar chambers impaired both LTP and primedburst potentiation (PBP, a low-threshold form of LTP) in behaving rats31,5860. Recent work has shown that stress produced by exposing rats to threatening environments including unavoidable exposure to a predator (cat) impaired both hippocampal PBP61 and hippocampusdependent spatial memory62 (FIG. 3). It is important to note, however, that cat exposure blocked PBP, but did not block LTP 61. This finding is consistent with other studies showing that PBP has a greater sensitivity than LTP to modulation by ageing, drugs, hormones and neuromodulators, which indicates that PBP is a more sensitive diagnostic of how behaviourally relevant variables affect hippocampal processing17. However, stress effects on hippocampal plasticity are not limited to LTP and PBP. Recent studies have found that stress and corticosterone enhance the induction of homosynaptic long-term depression (LTD) in area CA1. Specifically, restrainttailshock and exposure to a brightly lit, novel chamber enhanced LTD, but impaired LTP, both in vitro 63 and in vivo 58, and the application of corticosterone agonists to hippocampal slices enhanced LTD and impaired LTP64. The fact that stress impairs LTP, but enhances LTD, indicates that stress might alter the physiological range of plasticity (or induce metaplasticity a plasticity that affects ensuing synaptic plasticity), such that subsequent synaptic plasticity favours the development of depression over potentiation5. Although the expression of synaptic plasticity can be affected for days after a single stressful experience53,54, the effects are not permanent. This conclusion is based on work that showed that there is repeated impairment and recovery of hippocampal PBP and spatial memory in rats that are exposed to alternating stress-provoking (unfamiliar) and stress-neutral (familiar) environments17,59. So, the modulation of hippocampal functioning by stress involves a dynamic process that is under the continuous influence of an animals perception of its environment.
Other effects of stress on the hippocampus

Box 3 | Hippocampal synaptic plasticity and memory Long-lasting, activity-dependent changes in the strength of synaptic transmission, for which long-term potentiation (LTP) is the leading candidate synaptic model, have long been postulated to be fundamental for memory storage (Hebbs postulate51). LTP was first discovered in the rabbit hippocampus by Bliss and Lomo131 in 1973. Since then, LTP has been shown in various brain structures and neural tissues from rats, mice and, recently, aplysia68,69,132. In addition to its longevity, LTP is rapidly induced, strengthened by repetition, shows specificity and associativity68,69, and occurs prominently in the hippocampus a structure that is implicated in learning and memory1821. In theory, LTP alone provides an incomplete synaptic model of learning, because the continued potentiation of synapses will eventually lead to a saturation of all excitatory plasticity133. Decreases in synaptic efficacy are also needed to reset the synapses, and are accounted for by long-term depression (LTD) (or depotentiation, a reversal of LTP), which has also been shown in the hippocampus after the low-frequency stimulation of afferent fibres134. Both LTP and LTD at the SCHAFFER COLLATERAL/commissuralCA1 synapses seem to be mediated by mechanisms that are triggered by Ca2+ influx following the activation of NMDA (N-methyl-D-aspartate) receptors68,134. Several lines of evidence are consistent with the LTP (or synaptic-plasticity) hypothesis of learning. For example, pharmacological studies have shown that NMDA receptor antagonists, which block LTP induction in the hippocampus, also interfere with hippocampus-dependent spatial learning and the learning of odour-discrimination tasks24,69. Neurophysiological studies have shown learning-related increases in hippocampal cell excitability135, indicating that LTP or LTP-like changes are operative during learning. Recent studies from gene knockout/transgenic mice that show deficits in hippocampal LTP and spatial memory, and alterations in the properties of hippocampal place cells121123,136, provide further support. However, despite extensive correlational evidence, some questions remain137, so the LTP/synaptic-plasticity hypothesis lacks universal acceptance.

hippocampus-based memories. It might be relevant to consider the generalization that stress enhances hippocampus-dependent fear-related learning and memory, and impairs the processing of spatial information that is acquired outside the fear-conditioning context6,17 (BOX 2).
Stress and hippocampal plasticity

TETANIC STIMULATION

A train of stimuli in which afferent axons are briefly activated at high frequency. In LTP experiments, a 1-s train of pulses delivered at a frequency of 100 Hz is commonly used to potentiate transmission.
SCHAFFER COLLATERALS

Axons of the CA3 pyramidal cells of the hippocampus that form synapses with the apical dendrites of CA1 neurons.

For the past three decades, the primary physiological model of memory has been long-term potentiation (LTP) a sustained enhancement of synaptic efficacy that is produced by a brief (less than one second) TETANIC STIMULATION of excitatory afferent fibres (BOX 3). If the idea that changes in synaptic efficacy underlie information storage (Hebbs postulate51) is valid, then the finding that stress impairs hippocampus-dependent memory would predict that stress should also interfere with the induction of hippocampal LTP (or LTPlike processes). Extensive observations from in vitro and in vivo electrophysiological studies are consistent with this prediction, in that stress and stress hormones do indeed impair LTP. The first demonstration of a stress-induced suppression of LTP induction was reported in 1987 by Thompson, Levine and colleagues52. These investigators found that hippocampal slices prepared from adult rats that had experienced unpredictable and inescapable restrainttailshock stress showed marked impairments of LTP in the CA1 pyramidal cell region (FIG. 2). Subsequent studies showed that stress-induced LTP impairment lasts for at least 48 hours in rats53 and 24 hours in mice54, and that stress also reduces LTP in the dentate gyrus of the hippocampus55.

In addition to affecting synaptic plasticity and memory, stress and corticosterone have been shown to alter hippocampal dendritic morphology and to inhibit neurogenesis in the adult brain, which can potentially have an impact on memory-related functioning. These

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topics have been reviewed extensively elsewhere7,65, and will be addressed here only briefly. Stress and dendritic morphology. McEwen and colleagues7 have carried out an extensive analysis of the effects of chronic stress or corticosterone administration on dendritic morphology, and have shown that daily restraint stress, or corticosterone injections for three weeks, produced atrophy of the apical dendrites of CA3 pyramidal neurons. Others have shown that the effects of chronic stress on cellular morphology can also occur outside area CA3 for example, in the dentate gyrus and area CA166. Stress- and corticosteroneinduced atrophy can be blocked by drugs that reduce excitatory-amino-acid neurotransmission (phenytoin), reduce extracellular 5-hydroxytryptamine (5-HT) levels (tianeptine), or reduce general excitability through an enhancement of GABA (-aminobutyric acid) tone by a benzodiazepine (adinazolam)67, indicating that multiple neurotransmitter and hormone systems are involved in producing stress-induced dendritic atrophy in the hippocampus. One element that is common to many studies that show stress effects on the hippocampus is the involvement of NMDA (N-methyl-D-aspartate) receptors. The crucial role of NMDA-receptor-mediated Ca2+ ion influx (and the triggering of particular intracellular messenger cascades) in synaptic plasticity and memory is well described68,69. However, NMDA receptor activation also seems to be a central component of the manifestation of the adverse short- and long-term effects of stress on hippocampal morphology. For example, elevated levels of Ca2+ have been shown to accompany corticosterone-enhanced cell death, which can be alleviated by NMDA receptor antagonists7. It is perhaps ironic that hippocampal pyramidal cells deploy NMDA receptors to store information, although the same mechanism, if chronically overstimulated, can bring about their demise. Stress and adult neurogenesis. The production of granule cells in the adult dentate gyrus has been documented in a range of species, including the rat, marmoset, rhesus monkey, tree shrew and human70. The functional significance of the continued production of these cells throughout life is not fully understood, but it seems that this process is related to the demands of learning and memory71. For example, under conditions in which hippocampus-dependent learning occurs, there is an increase in the number of adult-generated granule cells and in the duration for which newly formed granule cells survive70,72. The production of new granule cells seems to be inhibited by stress or by experimentally produced elevations of corticosterone. Acute stress has been shown to decrease the proliferation of granule cells in adult rats, tree shrews and marmosets65. It has also been shown that chronic (daily) stress can result in a persistent elevation of cortisol levels and a decrease in the production of granule cells in adult tree shrews. Conversely, removal of endogenous corticosteroids stimulated the production
Stimulating electrode

Recording electrode

CA1

Sc

300

Percentage of pre-tetanus value

250

Control
200

150

Stress
100

50 0 5 10 15 20 25 30

Minutes after tetanus

Figure 2 | Uncontrollable restrainttailshock stress impairs LTP in the hippocampus in vitro. a | Schematic diagram of a transverse hippocampal slice, showing the arrangement of recording and stimulating electrodes. b | Post-tetanus population field potentials recorded from the cell-body layer of the CA1 field in response to test stimulation of the Schaffer collateral/commissural fibres (Sch). Tetanizing stimulation longterm potentiation induced in hippocampal slices prepared from unstressed control rats but not from stressed rats. Data replotted from REF. 52.

of new granule cells in young and old rats65. However, it is important to note that there is an ongoing disagreement about the standard for verifying adult neurogenesis after various experimental manipulations73. The mechanisms that underlie stress effects on granule cell proliferation are not fully understood, but the absence of MRs and GRs on granule cell precursors implies that glucocorticoids influence this process indirectly, perhaps through an increase in glutamatemediated neurotransmission. Just as stress affects hippocampus-dependent learning and LTP through glutamate release and activation of the NMDA receptor 63, stress also seems to inhibit granule cell proliferation through NMDA receptor activation65. Once again, the NMDA receptor serves as a common site of action in both the constructive (learning and memory) and destructive (inhibiting cell proliferation) effects of glucocorticoids in the hippocampus.
Neurochemical mediators of stress effects

Stress activates an ensemble of neurochemical responses including secretions of glucocorticoids (such as corticosterone), catecholamines (such as adrenaline) and opiates from the HPA axis and in the autonomic nervous system37. So, the impairment of LTP after an uncontrollable stress experience can be influenced by

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corticosterone and LTP. Activation of MRs (which would occur at low-to-intermediate levels of corticosterone) has been shown to increase the magnitude of LTP, whereas activation of GRs (which would occur at stress levels of corticosterone) attenuated LTP but enhanced LTD64. The GR-specific effects on LTP have been confirmed in studies showing that administration of the GR antagonist RU38486 prevented the stressinduced impairments of LTP76. These findings indicate that low-to-intermediate levels of corticosterone enhance hippocampal synaptic plasticity by stimulating the highaffinity MR (perhaps with a small degree of activation of GRs)28. During intense stress, however, the high levels of corticosterone produce a greater activation of the GR, which results in a profound inhibitory effect on hippocampal plasticity. The relatively greater importance of GRs (compared with MRs) in mediating the adverse effects of corticosterone on the hippocampus is also indicated by findings that GR agonists and MR antagonists can impair spatial memory 6, and that a point mutation in the mouse GR gene blocks the exogenous effects of corticosterone on spatial memory29. Corticosterone can also alter the intrinsic properties of neurons in the hippocampus. Bath application of corticosterone has been shown to prolong the afterhyperpolarization (AHP) of CA1 pyramidal neurons by increasing the level of internal Ca2+ and thereby activating Ca2+-gated K+ channels77,78. Correspondingly, corticosterone also promotes the expression of genes that encode channels that enhance Ca2+ influx79. Recent work has shown that stress levels of corticosterone initially enhance MR-mediated hippocampal cellular excitability, which is then overtaken by a GR-mediated suppression of cellular activity78, which could impede the development of LTP. However, an increase in the corticosterone concentration per se does not seem to be sufficient to affect hippocampal LTP. This conclusion is based on findings that LTP can still be inhibited by stress in rats that have been depleted of corticosterone as a result of adrenalectomy80. Moreover, in normal animals that were administered dexamethasone (a synthetic glucocorticoid that blocks the release of corticosterone), stress-induced impairments of LTP still occurred81. More recent work has provided three different conditions in which there was an elevation of serum corticosterone levels in the absence of an inhibitory effect on hippocampal processing: first, rats with lesions of the amygdala did not develop a stress-induced suppression of LTP, despite the fact that the lesioned animals had elevated corticosterone levels82; second, the exogenous administration of stress levels of corticosterone, under otherwise nonstress conditions, did not produce a spatial-memory impairment in rats83; and third, male rats that were given access to a sexually receptive female had elevations of serum corticosterone, but no spatial-memory deficit83. So, elevated corticosterone, in the absence of fear and/or an intact amygdala is not sufficient to produce deficits in hippocampal processing. Other work has implicated non-glucocorticoid neuromodulators in the manifestation of stress effects

a
Percentage change

90 75 60 45 30 15 0 Home Chamber Cat

* *

3.5 3.0

Memory errors

2.5 2.0 1.5 1.0 0.5 0 WM-Home RM-Cat WM-Cat

Figure 3 | Exposing a rat to a natural predator (a cat) impairs cognitive and electrophysiological measures of hippocampal functioning. A rat with no previous exposure to a cat shows an innate freezing (fear) response in the presence of a cat. a | After 75 minutes of exposure to the cat, rats showed a complete suppression of synaptic plasticity (primed-burst potentiation, or PBP) in area CA1 of the hippocampus (bar labelled Cat). By contrast, rats placed in the chamber for 75 minutes without the cat (Chamber) showed as much PBP as rats that were undisturbed in their home environment (Home). b | Rats have excellent spatial working memory under non-stress conditions (WM-Home) when tested in the radial-arm water maze. However, rats that were exposed to a cat showed a selective impairment of hippocampusdependent working memory (WM-Cat), with no adverse effect of stress on hippocampus-independent reference memory (RM-Cat). Data replotted from REFS 61,62,83.

the interaction of different types of neuromodulator. There is strong support for the idea that one of the primary neuromodulators of LTP and memory is corticosterone. The effects of corticosterone on hippocampal plasticity are complex, in that there is a biphasic relationship between the level of corticosterone and the magnitude of LTP, such that both low (through adrenalectomy) and high (produced by stress or exogenous administration) levels of corticosterone are associated with LTP impairments, with maximal LTP occurring in animals with an intermediate level of corticosterone74,75. Subsequent studies substantiated the mechanistic basis of the inverted-U-shaped relationship between

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in vivo LTP of the perforant path/dentate gyrus96. Abe and colleagues96 have found that infusions of NMDA receptor antagonists into the basolateral nucleus of the amygdala (BLA) impair dentate-gyrus LTP (without affecting hippocampal baseline activity), a finding that indicates that amygdalar NMDA receptors might be involved in regulating hippocampal LTP. Moreover, high-frequency stimulation of the BLA augments dentate-gyrus LTP 96. But more specifically, stimulation of the amygdala (and exposing rats to stress) has a timedependent, biphasic (an immediate excitatory and a longer-lasting inhibitory) effect on hippocampal LTP 97. Interestingly, lesions of the amygdala also prevent stressinduced increases in catecholamine turnover98, which is thought to impair the working-memory function of the prefrontal cortex99. Anatomically, the amygdala is connected both directly (amygdalo-hippocampal bundles arise from the magnocellular and parvicellular divisions of the basolateral amygdala and terminate in area CA1 and the subiculum) and indirectly (through the entorhinal cortex) to several hippocampal regions100, providing various routes by which it can influence hippocampal functioning. Collectively, there is a growing literature indicating that the full expression of stress effects on the hippocampus requires co-activation of the amygdala and hippocampus, in concert with the actions of neuromodulators (such as corticosterone, 5-HT, opiates and CRF) directly on the hippocampus.
Putting it all together: a system-level model

Amygdala g(s) Stress or

Stress hormones, opioids, others

m >0

m =0

HPA axis

Hippocampus or h(s) (m,h(s)); m > 0, h(s) > 0 (m,h(s)); m = 0, h(s) > 0

Figure 4 | A hypothetical model of how neuromodulatoramygdala interactions mediate stress effects on hippocampal plasticity. Stress activates the hypothalamuspituitaryadrenal (HPA) axis, resulting in elevated secretion of glucocorticoids, catecholamines, enkephalins and other neuromodulators, which affect the hippocampus and amygdala. The influence that stress neuromodulators (variable s) have on the hippocampus is a function of their direct effects on the hippocampus, denoted by h(s), and the effects of these neuromodulators on the amygdala, denoted by g(s). The output from the amygdala (variable m) is a crucial component of the stressinduced modulation of hippocampal plasticity. The interaction between m and h(s) is denoted by f(m,h(s)). The model shows that when there is an experimentally induced reduction in the amygdalar input to the hippocampus (as a result of damage or inactivation of the amygdala, m = 0), plasticity in the hippocampus is intact under stress conditions (upper right). However, with intact amygdalar input in response to stress (m > 0), plasticity in the hippocampus is disturbed (for example, impaired long-term potentiation (LTP) and enhanced long-term depression (LTD); lower right). The green circles on the matrices represent synapses with normal capacity to generate plasticity (for example, normal LTP), thereby accommodating normal hippocampusdependent memory. The pink circles represent synapses with altered properties of plasticity (for example, impaired LTP and enhanced LTD), which impair subsequent hippocampus-dependent memory. The conjunction of inputs m and h(s) is required for plasticity in the hippocampus to be disrupted. The model predicts that stress effects on the hippocampus can be prevented by reducing the amygdalar input (upper part of the figure) to the hippocampus. Conversely, the model predicts that these stress effects can be exacerbated by increasing the amygdalar input to the hippocampus.

on hippocampal functioning. First, the administration of naltrexone (an opioid antagonist) has been reported to block stress effects on both learning84 and LTP85, indicating that stress-induced opioid peptides might be involved in mediating stress effects on synaptic plasticity. Second, the 5-HT system seems to be involved in mediating stress effects on the hippocampus. Stress elevates 5-HT levels in the hippocampus 86, and exogenously applied 5-HT can inhibit CA1 LTP in vitro 87 and in vivo in freely moving rats88, indicating that endogenous 5-HT exerts a suppressant effect on synaptic plasticity that underlies memory formation. Third, NMDA receptor antagonists block the effects of stress on learning89, LTP 63 and the GR-mediated impairment of LTP90. So, it seems that, in addition to glucocorticoids, other neuromodulators are crucially involved in the effects of stress on hippocampal plasticity.
Amygdala, stress and hippocampal functioning

An accumulating body of evidence indicates that the amygdala is central to emotional learning8,9, and to manifesting stress-related behaviours and changes in hippocampal functioning. Lesions or pharmacological suppression of the amygdala prevent stress-induced gastric erosion91, analgesia92 and anxiety-like behaviour93, block the modulatory effects of drugs on hippocampus-dependent memory94,95, and impair

In this review, we have emphasized that local effects of neuromodulators on the hippocampus act in conjunction with influences from the amygdala to alter hippocampus-dependent memory and synaptic plasticity. A similar idea of a modulating or driving input has been proposed for the interactions between neocortical and subcortical pathways to explain alterations in receptivefield properties of neurons in the visual cortex101. On the basis of diverse observations of plasticity in different systems, we have developed a model that describes a subset of the neuralendocrine interactions that are necessary preconditions for producing stress effects on hippocampal functioning (FIG. 4). There are five specific premises to the model: First, stress hormones can directly affect the hippocampus (denoted in FIG. 4 as the h(s) input to the hippocampus: h(s) > 0, stress; h(s) = 0, no stress). Supporting evidence: the hippocampus is enriched with corticosteroid receptors4,6,26; there is a biphasic relationship between the level of corticosterone and LTP74,75; corticosterone affects the intrinsic properties of hippocampal neurons77,78, and reduces LTP and enhances LTD in vitro90. Second, stress hormones can directly or indirectly influence the amygdala (denoted as the g(s) input to the amygdala: g(s) > 0, stress; g(s) = 0, no stress). Supporting evidence: the amygdala (BLA) is also enriched with corticosteroid receptors26; the adrenal hormone adrenaline, which is released during stress, activates the vagus nerve to the nucleus solitary, which

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in turn innervates and influences the amygdala95; the local application of noradrenaline or corticosterone can modulate the formation of emotional memory94,95. Third, amygdalar projections to the hippocampus can modify hippocampal functioning (denoted as the m inputs to the hippocampus: m > 0, stress with functioning amygdala; m = 0, stress with inactivated amygdala). Supporting evidence: the BLA projects both directly and indirectly (through the entorhinal cortex) to the hippocampus (including area CA1)100; pharmacological manipulations of the amygdala modulate hippocampus-dependent memory94,95; electrical stimulation of the amygdala can affect the development of hippocampal LTP96,97. Fourth, the CA1 area of the hippocampus can function normally without the amygdala under non-stress conditions. Supporting evidence: amygdala-lesioned rats are unimpaired on a hippocampus-dependent spatialmemory WATER-MAZE TASK82; hippocampal slices obtained from intact or amygdala-lesioned rats show LTP 82. Fifth, the hippocampus requires both m and h(s) inputs to undergo stress-induced alterations in synaptic plasticity (which can alter ensuing memory); and the m input modulates or drives the h(s) input, which determines the magnitude of stress effects in the hippocampus. Supporting evidence: the amygdala is necessary for intra-hippocampus-administered drugs to modulate (enhance or impair) memory and for mediating memory-modulatory effects of stress hormones95; lesions of the amygdala (no m input to the hippocampus) prevent stress effects on hippocampal LTP and spatial memory82; fear impairs hippocampal LTP and spatial memory, but increases in corticosterone without co-activation of the hippocampus and amygdala (produced by exogenous corticosterone or by copulation in male rats) do not impair hippocampus-dependent memory83. The key assumption of our model that alterations in hippocampal functioning after stress are due to excessive activity exerted by the amygdala on the hippocampus provides clear empirical predictions of direct relevance to examining the role of the amygdala in mediating stress effects on the functioning of the hippocampus. Specifically, experimental manipulations that block or reduce the output from the amygdala (which would reduce the m input to the hippocampus) during stress should prevent or reduce the effects of stress on the hippocampus. Conversely, manipulations of the amygdala that enhance its output (which would increase the m input to the hippocampus) during stress would exacerbate stress effects on hippocampal functioning. So, our model predicts that pharmacological manipulations of the amygdala, such as infusing -adrenoceptor agonists into the BLA (which would normally enhance hippocampal memory formation95) during stress, could actually exacerbate stress effects on subsequent hippocampal plasticity and memory. By contrast, infusing -adrenoceptor antagonists into the amygdala (which would normally impair hippocampal memory formation95) during stress would attenuate stress effects on ensuing hippocampal functions. These predictions should also apply to other drugs for example, GABA receptor and opioid receptor antagonists and agonists, which increase or decrease (respectively) noradrenaline release in the amygdala to enhance or impair hippocampal memory formation under normal conditions.
Concluding remarks

WATER-MAZE TASK

A learning task in which an animal is placed in a pool filled with opaque water and has to learn to escape to a hidden platform that is placed at a constant position. The animal must learn to use distal cues, and the spatial relationship between them and the platform.

Stress, a naturalistic factor that contributes to memory impairments, constitutes a significant problem in todays increasingly populous and long-living society. The hippocampus a structure that is involved in memory processing and regulating the HPA axis seems to be particularly susceptible to exposure to uncontrollable stress. Here, we have described the manifold effects that stress exerts on the hippocampus, and some neurochemical systems that might be involved in mediating stress effects. One aspect of the modulation of hippocampal functioning by stress is described by our model, which takes into account the effects of hormones, such as corticosterone, on the hippocampus, acting directly as well as through an obligatory pathway that includes amygdala activation. Stress effects on the hippocampus and on memory are undoubtedly more complex than the simple neural endocrine model that we have proposed, and are likely to involve other neural structures and neuromodulators. Despite its simplicity, this model helps to illustrate the importance of studying neural structures in isolation in vitro, in addition to the interacting components of neural systems, to gain an understanding of how stress affects the brain and cognition.

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DATABASES The following terms in this article are linked online to: LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/ glucocorticoid receptor | mineralocorticoid receptor OMIM: http://www.ncbi.nlm.nih.gov/Omim/ Cushings disease FURTHER INFORMATION Encyclopedia of Life Sciences: http://www.els.net/ hippocampus | learning and memory | long-term depression and depotentiation | long-term potentiation MIT Encyclopedia of Cognitive Sciences: http://cognet.mit.edu/MITECS/ hippocampus | long-term potentiation | memory | memory, animal studies | memory, human neuropsychology | neuroendocrinology | stress Access to this interactive links box is free online.

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