Focus on stress

Neighborhood matters: divergent patterns of stress-induced plasticity across the brain

Journal name:
Nature Neuroscience
Volume:
18,
Pages:
1364–1375
Year published:
DOI:
doi:10.1038/nn.4115
Received
Accepted
Published online

Abstract

The fact that exposure to severe stress leads to the development of psychiatric disorders serves as the basic rationale for animal models of stress disorders. Clinical and neuroimaging studies have shown that three brain areas involved in learning and memory—the hippocampus, amygdala and prefrontal cortex—undergo distinct structural and functional changes in individuals with stress disorders. These findings from patient studies pose several challenges for animal models of stress disorders. For instance, why does stress impair cognitive function, yet enhance fear and anxiety? Can the same stressful experience elicit contrasting patterns of plasticity in the hippocampus, amygdala and prefrontal cortex? How does even a brief exposure to traumatic stress lead to long-lasting behavioral abnormalities? Thus, animal models of stress disorders must not only capture the unique spatio-temporal features of structural and functional alterations in these brain areas, but must also provide insights into the underlying neuronal plasticity mechanisms. This Review will address some of these key questions by describing findings from animal models on how stress-induced plasticity varies across different brain regions and thereby gives rise to the debilitating emotional and cognitive symptoms of stress-related psychiatric disorders.

At a glance

Figures

  1. Brain areas implicated in stress-related psychiatric disorders.
    Figure 1: Brain areas implicated in stress-related psychiatric disorders.

    The amygdala, PFC and hippocampus undergo contrasting structural and functional changes in stress disorders and in turn differentially regulate the stress response through HPA activity (both positively and negatively).

  2. Commonly used rodent models of stress.
    Figure 2: Commonly used rodent models of stress.

    Several stress procedures (acute stressors, blue; chronic stressors, red) have been used to study the effects of stress on neural plasticity in rodents. Widely used physical stressors include repeated exposure to immobilization and restraint stress29, 72, 147. In contrast, a range of naturalistic or ethologically relevant stressors have also been used to trigger innate fear. These commonly used models of psychosocial stress include predator odor and exposure to bright elevated platform42, 80, 148, as well as maternal separation and social defeat136, 149, 150.

  3. Behavioral stress triggers distinct spatiotemporal patterns of plasticity at multiple levels of neural organization.
    Figure 3: Behavioral stress triggers distinct spatiotemporal patterns of plasticity at multiple levels of neural organization.

    (a) Contrasting patterns of plasticity across brain areas induced by chronic stress. At the behavioral level, chronic stress enhances fear and anxiety while impairing spatial and working memory and fear extinction. At the network level, stress causes an increase in neural activity in the amygdala, whereas it has the opposite effect in the hippocampus. At the levels of neurons and synapses, repeated stress leads to growth of dendrites and spines in the amygdala, but loss of dendritic arbors and spines in the hippocampus and mPFC. These morphological changes are accompanied by enhanced LTP in the amygdala, as well as by impaired and/or reduced LTP in the hippocampus and mPFC. At the molecular level, BDNF protein is increased in the amygdala, but decreased in the hippocampus. In the mPFC, certain forms of stress increase BDNF mRNA expression, whereas others do not. The effect of chronic stress on BDNF protein levels in the mPFC is not known (Fig. 5). (b) Short-term (immediate to 24 h after) and delayed (10 d later) effects of a single episode of acute stress. Both the short and delayed effects of stress are different between the hippocampus and amygdala. In terms of the short-term effects, although some measures of plasticity are impaired in the hippocampus, others are enhanced in the amygdala. In both areas some parameters remain unaffected. All of the parameters exhibit a delayed increase in the amygdala.

  4. Stress enhances fear by forming new synapses with greater capacity for LTP in the lateral amygdala.
    Figure 4: Stress enhances fear by forming new synapses with greater capacity for LTP in the lateral amygdala.

    Chronic stress strengthens the structural basis of synaptic connectivity causing dendritic growth and spinogenesis. These newly formed dendritic spines have larger NMDAR-mediated synaptic currents as a result of the formation of NMDAR-only or silent synapses. Stress also lowers synaptic inhibition. This creates conditions that facilitate the induction of greater LTP in the amygdala. This, in turn, gives rise to stronger auditory-evoked potentials (AEPs) in awake, behaving animals. Together, these cellular and network level changes give rise to stronger fear memories.

  5. Temporal features of stress-induced plasticity in the amygdala and hippocampus.
    Figure 5: Temporal features of stress-induced plasticity in the amygdala and hippocampus.

    Effect of 10-d chronic immobilization stress on in vivo neuronal activity in the hippocampus and the amygdala in awake, behaving rodents. (a) Chronic stress impairs spatial discrimination at the network level in the hippocampus. On day 11, 24 h after the end of 10-d chronic stress, mice were challenged to discriminate between two linear tracks (track 1 and track 2) that were similar in shape and dimensions with only some differences in color and texture. Examples show firing rate maps of different place cells on these tracks for control (left) and stressed (right) mice. Analysis of the ensemble representation, but not at the single neuron level, suggested that stress limits the ability of the CA1 pyramidal population to properly distinguish the two similar tracks, although context discrimination was not affected in control mice (adapted from ref. 119). (bd) During chronic stress, AEPs were simultaneously monitored in areas CA1 (b), CA3 (c) and LA (d). On day 1, 1 h (indicated by black inverted triangle) after a single exposure to acute stress, AEP amplitudes were enhanced in all three areas. This increase was evident even 1 d later in the LA, but not in the CA1 and CA3 areas. 1 d after the tenth day of chronic stress, AEP amplitudes were back to baseline in the CA1 and CA3 areas, whereas a significant increase was still visible in the LA. This enhancement returns to baseline after a 10-d stress free recovery. (e) Chronic stress causes a gradual impairment of directional coupling from hippocampal areas CA1 to CA3 and a gradual enhancement from the LA to CA1. 1 h after the first episode of acute stress (day 1), functional coupling was strengthened between CA3–CA1, CA1–LA and LA–CA1. 24 h after the tenth day of stress, only LA–CA1 connectivity continued to be strong. This persisted even after a 10-d stress-free recovery. The strength of Granger spectral causality values are coded by the thickness of lines between the three recording sites. The arrowheads indicate the direction of Granger causal influence. Solid and dotted lines indicate presence and absence of dominant directional influence, respectively (adapted from ref. 137).

  6. Interactions and interdependence of stress-induced plasticity between brain areas.
    Figure 6: Interactions and interdependence of stress-induced plasticity between brain areas.

    (a) Stress impairs in vivo LTP in the BLA–mPFC and hippocampus–mPFC pathways. Stress also suppresses the modulation of hippocampal LTP by the BLA. Origin of the arrow indicates the location of stimulation and arrowhead indicates site of recording of changes in plasticity. Lesion or inactivation (×) of the BLA rescues behavioral deficits in spatial (hippocampus) and working memory (mPFC) caused by stress. These BLA manipulations also reverse stress-induced LTP deficits in the hippocampus. (b) Granger causality graphs depicting the modulation of directional influence. Chronic stress causes a persistent impairment of directional coupling from hippocampal area CA3 to CA1. In contrast, directional coupling from the LA to area CA1 is enhanced after chronic stress. The strength of Granger spectral causality values are coded by the thickness of lines between the three recording sites. The arrowheads indicate the direction of Granger causal influence. Solid and dotted lines indicate presence and absence of dominant directional influence, respectively (adapted from ref. 137).

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Affiliations

  1. Centre for Brain Development and Repair, Institute of Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences, Bangalore, India.

    • Sumantra Chattarji &
    • Mohammed Mostafizur Rahman
  2. Laboratory for Circuit and Behavioral Physiology, RIKEN Brain Science Institute, Wakoshi, Saitama, Japan.

    • Anupratap Tomar
  3. Department of Neurobiology, Stanford University, Stanford, California, USA.

    • Aparna Suvrathan
  4. Department of Neurobiology, University of Chicago, Chicago, Illinois, USA.

    • Supriya Ghosh

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