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The stressed hippocampus, synaptic plasticity and lost memories

Key Points

  • Stress can disturb cognitive processes such as learning and memory, and consequently limit the quality of human life. This review provides an overview of the neurobiology of stress–memory interactions, and presents a neural–endocrine model to explain how stress modifies hippocampal functioning.

  • Stress can be defined as a condition in which an individual is aroused by an aversive situation, and its consequences are influenced greatly by the individual's perception of his or her ability to control the presence or intensity of the stimulus.

  • The hippocampus is involved in both memory and the neuroendocrine regulation of stress hormones. Hippocampal functions, such as learning and memory, are susceptible to disruption by stress, mediated in part by the activation of type II corticosteroid (glucocorticoid) receptors.

  • The primary physiological model of memory is long-term potentiation (LTP), and in vitro and in vivo electrophysiological studies have shown that stress interferes with the induction of hippocampal LTP.

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

  • The full expression of stress effects on the hippocampus seems to require co-activation of the amygdala and hippocampus, in concert with the direct actions on the hippocampus of neuromodulators, such as corticosterone, 5-hydroxytryptamine, opiates and corticotropin-releasing factor.

  • The key assumption of the neuroendocrine model is that alterations in hippocampal functioning after stress are due to an excessive activity exerted by the amygdala on the hippocampus.


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 stress-induced 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 stress–memory interactions, and present a neural–endocrine model to explain how stress modifies hippocampal functioning.

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Figure 1: Various effects on learning and memory as a function of the magnitude of stress.
Figure 2: Uncontrollable restraint–tailshock stress impairs LTP in the hippocampus in vitro.
Figure 3: Exposing a rat to a natural predator (a cat) impairs cognitive and electrophysiological measures of hippocampal functioning.
Figure 4: A hypothetical model of how neuromodulator–amygdala interactions mediate stress effects on hippocampal plasticity.


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glucocorticoid receptor

mineralocorticoid receptor


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long-term depression and depotentiation

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


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.


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.


A motor-skill learning task that is used to assess the subject's tracking errors and time on a moving target.


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.


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.


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


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.

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Kim, J., Diamond, D. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 3, 453–462 (2002).

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