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Stress and Plasticity in the Limbic System

Authors:

Abstract

The adult nervous system is not static, but instead can change, can be reshaped by experience. Such plasticity has been demonstrated from the most reductive to the most integrated levels, and understanding the bases of this plasticity is a major challenge. It is apparent that stress can alter plasticity in the nervous system, particularly in the limbic system. This paper reviews that subject, concentrating on: a) the ability of severe and/or prolonged stress to impair hippocampal-dependent explicit learning and the plasticity that underlies it; b) the ability of mild and transient stress to facilitate such plasticity; c) the ability of a range of stressors to enhance implicit fear conditioning, and to enhance the amygdaloid plasticity that underlies it.
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0364-3190/03/1100–1735/0 © 2003 Plenum Publishing Corporation
Neurochemical Research, Vol. 28, No. 11, November 2003 (© 2003), pp. 1735–1742
Stress and Plasticity in the Limbic System*
Robert M. Sapolsky
1
(Accepted March 4, 2003)
The adult nervous system is not static, but instead can change, can be reshaped by experience.
Such plasticity has been demonstrated from the most reductive to the most integrated levels, and
understanding the bases of this plasticity is a major challenge. It is apparent that stress can alter
plasticity in the nervous system, particularly in the limbic system. This paper reviews that sub-
ject, concentrating on: a) the ability of severe and/or prolonged stress to impair hippocampal-
dependent explicit learning and the plasticity that underlies it; b) the ability of mild and transient
stress to facilitate such plasticity; c) the ability of a range of stressors to enhance implicit fear
conditioning, and to enhance the amygdaloid plasticity that underlies it.
KEY WORDS: Stress; hippocampus; glucocorticoids; amygdala; LTP; LTD.
INTRODUCTION
In 1967’s The Graduate, Dustin Hoffman, embark-
ing on life postcollege, was given some unwanted career
advice—plastics. And the field of neural plasticity has
yet to recover fully from this setback.
We all responded to that bit of advice with a snicker,
based on the pejorative view of “plastic” as artificial, un-
natural, cold, unyielding. And the problem is that neural
plasticity traditionally implies anything but that. Instead,
it is a good thing. Specifically, it is a field built around
the fact that experience can alter the nervous system adap-
tively, enhancing function in self-perpetuating ways. At
the level of the synapse, this is the world of long-term
potentiation and related electrophysiological phenomena.
At the cytoarchitectural level, it is the demonstration that
neurons can respond to the proper stimuli by forming new
synapses, by elaborating dendritic processes. At the cellular
level, it is the truly revolutionary finding that learning,
environmental enrichment, even exercise can stimulate
neurogenesis. As perhaps the most important cornerstone
of such plasticity, these instances of experience-dependent
modification of the nervous system can occur throughout
the lifetime.
Carl Cotman has made seminal contributions to this
topic, helping to make it one of the most exciting branches
of neuroscience. But neural plasticity has a dark side. It
is not the banality of “plastics,” but instead, the undesir-
able realm where “neural plasticity” means that experi-
ence is causing involution, impairment, and damage to the
nervous system. This can include impairment of LTP,
retraction of dendritic processes, inhibition of neurogene-
sis, and even the death of neurons.
In principle, this need not be particularly interesting,
the fact that there can be “good” and “bad” aspects to
neural plasticity. For example, there can be “good” and
“bad” aspects to, say, the neurobiological consequences
of things that we humans can ingest. Thus, ingest a well-
balanced diet and you promote proper neural develop-
ment; ingest a diet with vast excesses of alcohol and you
promote neuron death. This is a fairly unsubtle contrast.
What is fascinating in the realm of the adaptive and
0364-3190/03/1100–1735/0 © 2003 Plenum Publishing Corporation
* Special issue dedicated to Dr. Carl Cotman.
1
Departments of Biological Sciences, and of Neurology and Neuro-
logical Sciences, Stanford University, Gilbert Laboratory, MC 5020,
Stanford, California 94305-5020. Tel: 650-723-2649; E-mail: sapol-
sky@stanford.edu
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1736 Sapolsky
maladaptive features of experience-dependent neural plas-
ticity is how similar the experiences can be in bringing
about quite contrasting outcomes. Depending on changes
in the magnitude or duration of the stimulus, the indi-
vidual who is experiencing the stimulus, or the part of
the brain being considered, the outcome can be neural
plasticity of the “good” kind or of the “bad.”
In this review I will first consider the basic find-
ings regarding how one aspect of experience—the expe-
rience of stress—can have adverse effects on neural
plasticity. I will then consider some parameters in which
stress does not always have such adverse effects and
can even promote versions of the classically “good”
forms of neural plasticity.
DISCUSSION
Glucocorticoids and Their Adverse Effects on
Hippocampal-Dependent Cognition
Glucocorticoids (GCs) are the adrenal steroid hor-
mones secreted in response to stress. The hormones are
central to successfully coping with a major physical stres-
sor (such as fleeing a predator), as they mobilize stored
energy, increase cardiovascular tone, and suppress costly
anabolism (such as growth, tissue repair, reproduction,
digestion and immunity) for more auspicious times. How-
ever, if the exposure to GCs is prolonged, there are a
variety of pathological outcomes that become more likely,
including insulin-resistant diabetes, hypertension,
immunosuppression, and reproductive impairments (1).
These deleterious consequences include adverse
effects in the nervous system. The most dramatic ones
occur in the hippocampus, a primary GC target, with
ample quantities of corticosteroid receptors.
At the most integrated level, sustained stress or
exposure to GCs can impair aspects of hippocampal-
dependent cognition. Memory is not a monolithic
phenomenon; instead, there are a number of types of
memory, with the medial temporal lobe, and particularly
the hippocampus within it, playing a critical role in
explicit memory (concerned with facts and events) (2).
Thus stressors as different as a number of weeks of daily
restraint stress, brief exposure to the smell of a preda-
tor (a cat), or months of rotating group membership
disrupt spatial memory performance in rats (a classic
hippocampal-dependent explicit memory task in a
rodent) (3–5). The stress-induced GC secretion in these
instances appears to mediate the disruptive effects. As
evidence, similar time courses of administration of
exogenous GCs producing circulating levels typical of
the stress range also disrupt spatial memory perform-
ance (6–8). Such impaired performance could reflect
impairment of the initial consolidation of the spatial
information and/or the retrieval of it. Recent work sug-
gests that it is the retrieval component that is most sen-
sitive to the disruptive effects of GCs (9,10).
An emerging literature demonstrates that GCs can
disrupt hippocampal-dependent declarative memory per-
formance in humans as well. Some of these studies exam-
ine humans treated chronically with exogenous GCs to
control an autoimmune, or inflammatory disorder, or an
immune cancer (11,12). Moreover, declarative memory
performance in Cushing’s syndrome patients (in which
GCs are hypersecreted secondary to any of a number of
types of tumors) is impaired (13). A fascinating literature
of aged humans demonstrate that those whose basal GC
levels increase most dramatically with age over time, or
increase most dramatically in response to an acute stres-
sor, have the poorest declarative memory performance
(14–21). Finally, treatment of healthy volunteers with
exogenous GCs in the range used in clinical medicine
impairs declarative memory performance as well (22–29).
As with the rodent studies, the impaired performance in
the hippocampal-dependent tasks could represent impair-
ment of consolidation and/or retrieval; as with rodents, it
appears as if the retrieval component is most sensitive
(30). As important controls, a number of these studies
demonstrating impairment of hippocampal-dependent cog-
nition also demonstrated that hippocampal-independent
cognition remained intact (11,29).
Thus stress and/or exposure to elevated GC concen-
trations disrupt hippocampal-dependent cognition while
sparing hippocampal-independent cognition, in both
rodents and humans.
Mechanisms Underlying These Adverse GC Effects
There is considerable information regarding the
mechanisms contributing to these disruptive GC actions.
As an initial critical observation, GCs and stress impair
the synaptic plasticity essential to hippocampal-dependent
cognition. Thus stress disrupts long-term potentiation
(LTP) and primed burst potentiation (PBP) in a variety
of hippocampal cell fields in vivo (31–37), with the sug-
gestion that PBP is more vulnerable to this effect than
is LTP (38). Moreover, administration of exogenous
GCs in a regimen producing circulating concentrations
typical of stress also disrupt LTP and PBP (36,39–42).
In addition, both premortem stress and in vitro GC expo-
sure disrupt LTP in hippocampal slices in vitro (38,43).
There are two receptors for GCs found in the brain
(with ample concentrations of both in the hippocampus),
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Stress and Plasticity in the Limbic System 1737
with the high-affinity mineralocorticoid receptor (MR)
occupied heavily under basal conditions, and the low
affinity glucocorticoid receptor (GR) occupied heavily
only during major stressors. Heavy occupancy of GR
mediates these disruptive effects of stress and GCs upon
LTP (39,42,44). Such GR occupancy leads to increased
calcium conductance in hippocampal neurons; this in
turn leads to prolonged opening of calcium-dependent
potassium channels, thereby prolonging afterhyperpo-
larizations. This results in decreased neuronal excitabil-
ity (45–48).
It has come to be recognized that LTP can be coun-
teracted by long-term depression (LTD). Not surprisingly,
stress and GCs enhance LTD under conditions where they
disrupt LTP (35,39,49).
These GC effects at the level of synaptic plasticity
could readily explain the ability of the hormone to
impair cognition. However, GCs have deleterious effects
on the cytoarchitectural level in the hippocampus as
well. Specifically, over the course of a few days to
weeks, stress and/or exposure to elevated GC concen-
trations will cause retraction of dendritic processes in
rats. Golgi staining reveals that the atrophy arises from
a loss of apical dendritic branch points and decreases in
the length of apical dendrities (6,50–53). Such regres-
sion occurs in CA1 and CA3 cell fields of the hip-
pocampus (50,51,54) and can be caused by an array of
stressors and, in those cases, the regression is GC
dependent (55). Importantly, with the cessation of stress
or GC exposure, the process is slowly reversible, with
neuron rebuilding processes (52).
The mechanisms underlying this phenomenon are
being revealed. GC-induced atrophy is NMDA-receptor
mediated, because it is blocked by receptor antagonists
(51), or by drugs that decrease the release of glutamate,
such as dilantin (56,57). There appears to be a seroton-
ergic involvement as well, because the atypical antide-
pressant tianeptine, which decreases serotonergic tone, is
also protective (52,58). As would be expected, stress- or
GC-induced atrophy of dendritic processes also leads to
the cognitive deficits described above and, importantly,
pharmacological interventions that block the former can
prevent the latter (59).
The effects of stress upon dendritic arborization have
also been demonstrated in the nonhuman primate (60) and
may extend to the human as well. Magnetic resonance
imaging of Cushing’s syndrome patients has revealed
selective decreases in hippocampal volume (13), where
more severe hypersecretion of GCs correlated with
smaller hippocampi and more impairments of hippocam-
pal-dependent cognition. Importantly, this shrinkage is
reversible with the correction of the GC excess (61), sug-
gesting the reversible atrophy of processes seen in the
animal studies.
Another somewhat controversial route by which
stress and GCs may impair cognition has emerged in
recent years. The acceptance by the neuroscience com-
munity that the early, heretical reports of adult neuroge-
nesis in the hippocampus are true represents a revolution
in the field. Environmental enrichment, exercise and
estrogen all promote such neurogenesis. Conversely,
stress inhibits hippocampal neurogenesis in rodents and
nonhuman primates (62). The mechanisms underlying
this fascinating phenomenon are poorly understood at
present, but may well be related to the effects of GCs
upon neurotrophins and cell cycle genes (62). At least
some newly born neurons in the adult hippocampus
appear to form functional connections with other neurons
(63). Far more controversial, however, is whether such
neurogenesis is necessary or sufficient to explain any
instances of learning and memory (64). Thus, it is not
clear whether inhibition of neurogenesis by stress has
cognitive consequences.
Finally, an excess of stress and/or GCs can affect
the viability of hippocampal neurons. Specifically, both
compromise the ability of such neurons to survive a
variety of coincident neurological insults, such as
seizure, hypoxia-ischemia, and hypoglycemia (65).
Moreover, truly prolonged exposure to either can kill
hippocampal neurons outright (66–68); it has been sug-
gested that the atrophy of dendritic processes that would
precede any such neuron death can be viewed as an
involutional defense, a cellular hibernation, in effect,
decreasing the risks of neuron death (69). However, it
should be noted that the direct neurotoxic effects of
stress and GCs rarely occur, and require unphysiologi-
cal extremes of GC exposure.
Thus, excessive stress or GC exposure can impair
hippocampal-dependent cognition, and there are an array
of mechanisms that seemingly mediate this; these find-
ings clearly fall under the rubric of stress having “bad”
effects upon neural plasticity. I now consider two strik-
ing exceptions to this.
Stress, Stimulation and Inverse-U’s
Whether considering childhood, old age, or any
point in between, optimal function does not arise from
a life without challenge. Instead, it involves the opti-
mal amounts of challenge, what we typically refer to
as “stimulation.” Virtually by definition, what we view
to be stimulatory is transient exposure to a mild
stressor. A sufficiently severe challenge, no matter how
transient, is aversive. Moreover, a truly prolonged
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1738 Sapolsky
challenge, no matter how mild, is also aversive (in this
regard, it is not by chance that roller coaster rides are
3 minutes, rather than 3 weeks in duration). Stimula-
tion not only is not aversive, but is reinforcing, as
shown by the capacity of transient exposure to mildly
elevated GC levels to enhance dopaminergic transmis-
sion in the ventral tegmental/nucleus accumbens
“pleasure” pathways (70).
Given these effects of mild, transient stressors, it
is not surprising that such “stimulatory” stressors also
enhance hippocampal-dependent cognition. When com-
bined with the disruptive effects of more severe or pro-
longed stressors upon such cognition, this forms an
“inverse-U” pattern (71); the transition from subphysio-
logical or basal GC concentrations into the mild stress
range enhances cognition, and elevations beyond that
disrupt cognition. This inverse-U pattern has been
shown with enhancement with mild stressors and dis-
ruption with more severe ones (3,5,59,72–77). It has
also been demonstrated in rodents exposed to exogenous
GCs, rather than to stress regimens (78,79). Moreover,
a similar inverse-U pattern holds at the electrophysio-
logical level. Thus, whereas severe stressors or GC
exposure disrupt LTP and PBP, milder exposure
enhances it (41,47,74,80,81).
Some elegant studies have revealed the mecha-
nisms underlying such inverse-U patterns. As noted, the
hippocampus contains ample quantities of both MR and
GR, with the former heavily occupied basally, while the
latter, with its order of magnitude lower affinity, is only
heavily occupied in response to major stressors. This
suggests a relatively straightforward scenario: the tran-
sition from basal to mild stress levels of GCs, and the
resulting transition from heavy to saturating MR occu-
pancy, is responsible for the enhancing effects upon
synaptic plasticity and cognition. The transition to major
stress levels of GCs and the resulting heavy GR occu-
pancy then mediates the deleterious effects.
There is considerable evidence supporting this pic-
ture. Thus MR occupancy enhances LTP and PBP (39,
41,79,80,81), as well as hippocampal-dependent spatial
memory tasks (82). As an explanation for the enhanced
excitability, MR occupancy reduces 5HT-1a receptor-
mediated, calcium-independent potassium currents,
thereby shortening afterhyperpolarization duration (45).
And completing the two-receptor mediation of an
inverse-U pattern, heavy GR occupancy enhances LTD
(39) and disrupts spatial memory (83,84).
More recent studies suggests that this dichotomy
between MR and GR actions is oversimplified. Specifi-
cally, the enhancing effects of mild, transient GC
elevations are not only mediated by MR (and the tran-
sition from heavy to saturating occupancy), but by GR
as well (with the transition from very low to moderate
occupancy) (83–88). Thus, the inverse-U that contrasts
stimulation with major stress is not merely due to a con-
trast between MR and GR, but rather between MR plus
moderate GR occupancy, on one hand, versus heavy GR
occupancy on the other.
Stress, Implicit Memory, and Flashbulb Memory
I now discuss a second realm in which stress can
facilitate, rather than disrupt, memory. As noted, there are
multiple types of memory, and whereas explicit memory
is concerned with facts and events, “implicit” memory cov-
ers an array of non-declarative processes. These include
classical Pavlovian conditioning of autonomic responses,
procedural memory concerned with nonconscious skills
and habits, and reflex pathways. This is the realm of con-
ditioned responses to fear. The learned, nonconscious, and
autonomic nature of such memory is shown when one’s
heart begins to race when in a setting similar to where
some trauma occurred, even before one is consciously
aware of the similarity of the setting.
Stress is particularly effective at enhancing aspects
of implicit memories related to autonomic conditioning,
implicit reflexes, and fear. For example, many (but not
all) stressors will enhance subsequent classical Pavlovian
eyeblink conditioning in a rat (89–91); specifically, the
enhancement takes the form of more and larger magni-
tude eyeblinks in response to the conditioned stimulus.
Similarly, stress enhances Pavlovian conditioning of
freezing responses in rats (84,92). While stress-induced
GC secretion is required for such cases of enhancement,
the GCs seem to be permissive, in that stressors that do
or do not enhance such conditioning do not differ in the
magnitude of GC secretion they provoke.
The amygdala, another limbic structure rich in cor-
ticosteroid receptors, plays a critical role in fear con-
ditioning and in its potentiation by stress (71,92,93).
Thus, under circumstances where prolonged stress dis-
rupts the cognition that is mediated by the hippocam-
pus, it facilitates amygdala-dependent cognition. A
fascinating literature is now documenting this polarity
on a more reductive level. Specifically, under circum-
stances in which stress impairs hippocampal LTP, it
facilitates amygdaloid LTP (93). Even more remark-
ably, a recent report demonstrates that under circum-
stances in which stress causes atrophy of dendritic
processes in the hippocampus, the same stressor causes
extension of processes by neurons in the amygdala (94)
and in the bed nucleus of the stria terminalis, an amyg-
daloid projection site central to anxiety (95). The mech-
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Stress and Plasticity in the Limbic System 1739
anisms underlying these opposing effects remain to be
uncovered.
Stress facilitates another aspect of the interactions
between fear and memory. Fear-evoked memory forma-
tion is not merely about autonomic reflexes. Our hearts
do not merely race when we consider planes piloted into
skyscrapers. Instead, in addition to these implicit, con-
ditioned memories, we have explicit memories as well
of where we were, for example, when hearing the news
on September, 11th, 2001. Such “flashbulb” memories
are characterized by their vividness and, amid the vivid-
ness, their relatively low level of accuracy. Flashbulb
memories related to stress and trauma reflect the fact that
we not only form implicit memories about such events,
but form explicit memories centered around contextual
cues about the event. As such, stress enhances condi-
tioning to contextual cues of a stressor (83,92,96,97).
In a classical and fascinating demonstration of this phe-
nomenon in humans, subjects were read one of two 12-
sentence stories. Both had identical beginning and last
four sentences; however, in one case, the middle four
sentences described a strongly emotional and disturbing
scene, whereas in the other case, those middle four sen-
tences were affectively neutral. It was then shown that
some weeks later, recall of the middle four sentences
was superior in individuals who had heard the disturb-
ing scene, compared with those who heard the neutral
one; recall of the first and last four sentences did not dif-
fer between the groups (98).
Such explicit memories are the purview of the hip-
pocampus, and this is initially quite puzzling, given the
extensive literature reviewed above showing stress to
disrupt hippocampal-dependent cognition. This paradox
can be resolved with the view that during stress, the hip-
pocampus is less able to perform its traditional role of
the processing of objective, neutral declarative infor-
mation, and instead is recruited into a more amygdala-
like role. In effect, the highly affective, often inaccurate
process of forming a flashbulb memory seems like what
would be produced were the amygdala to “attempt”
to take on the task of forming a declarative memory,
rather than if the job were done by the more steady
hippocampus.
Remarkably, this nonscientific framing is actually
quite accurate, in that the hippocampus forms declara-
tive flashbulb memories during stress only when driven
by amygdaloid arousal. This is shown with an elegant
and detailed series of studies (reviewed in [96,99])
demonstrating that stress-induced enhancement of con-
textual memory consolidation by the hippocampus is
blocked by lesions of the amygdala, specifically of the
basolateral amygdala. Activation of the amygdala dur-
ing stress requires arousal by the sympathetic nervous
system. During stress, circulating catecholamines stimu-
late the afferent branch of the vagus nerve, which stimu-
lates the nucleus of the tractus solitarius (NTS). This in
turn causes the NTS to stimulate the amygdala via a
major noradrenergic input. Furthermore, the normal
recruitment by the amygdala of the hippocampus into
this cognitive role during stress requires GC action
within the hippocampus, amygdala, and NTS; as evi-
dence, microinfusion of GR antagonists into any of
those structures disrupts stress-induced enhancement of
contextual learning. Thus the phenomenon requires
cooperation between the adrenocortical branch of the
stress-response (i.e., the secretion of GCs) and the
adrenomedullary/sympathetic branch.
CONCLUSION
The classical work in the early 1960s showing that
environmental enrichment during infancy could cause
lasting and beneficial effects upon the brain helped usher
in a view of use-dependent plasticity in the nervous sys-
tem. This stance has formed a strong scientific rationale
behind a number of basically optimistic interventions in
humans, ranging from the Head Start program in children
to rehabilitation strategies poststroke in elderly individ-
uals. In this context, the adverse effects of stress upon
the nervous system—the capacity of stress to impair
synaptic plasticity in the hippocampus, to involute the
processes of hippocampal neurons, to hasten the death
of such neurons, and to impair neurogenesis—have
always been viewed as the dark side of plasticity.
Given that, the discovery that stress could do essen-
tially opposite things in the amygdala, namely enhancing
plasticity and arborization of dendritic processes, seems
initially like a welcome counter to the grim effects of
stress in the hippocampus. To a biologist purely con-
cerned with the function of synapses or neural networks,
perhaps it is. Nonetheless, it must be recalled that these
“good” effects of stress upon function of amygdaloid neu-
rons are ultimately highly deleterious. This is because of
the relevance of potentiated amygdaloid function to fear,
anxiety and posttraumatic stress disorder (PTSD). As but
one example of the relevance of this, two recent and very
nonsensationalist papers (99, 100) generate credible esti-
mates of up to 500,000 excess cases of PTSD emerging
in the New York City area as a result of the occurrences
on September, 11th, 2001. In that staggering context, the
ability of stress to enhance the function of synapses and
neurons is anything but salutary, and underlines the press-
ing need to understand these effects more fully.
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Chronic restraint stress causes significant dendritic atrophy of CA3 pyramidal neurons that reverts to baseline within a week. Therefore, the authors assessed the functional consequences of this atrophy quickly (within hours) using the Y maze. Experiments 1-3 demonstrated that rats relied on extrinsic, spatial cues located outside of the Y maze to determine arm location and that rats with hippocampal damage (through kainic acid, colchicine, or trimethyltin) had spatial memory impairments. After the Y maze was validated as a hippocampally relevant spatial task, Experiment 4 showed that chronic restraint stress impaired spatial memory performance on the Y maze when rats were tested the day after the last stress session and that tianeptine prevented the stress-induced spatial memory impairment. These data are consistent with the previously demonstrated ability of tianeptine to prevent chronic stress-induced atrophy of the CA3 dendrites.