Chronic Stress Remodels Synapses in an Amygdala Circuit–Specific Manner

doi:10.1016/j.biopsych.2018.06.019

Biological Psychiatry

Volume 85, Issue 3, 1 February 2019, Pages 189-201

https://doi.org/10.1016/j.biopsych.2018.06.019 Get rights and content

Abstract

Background

Chronic stress exposure increases the risk of developing various neuropsychiatric illnesses. The behavioral sequelae of stress correlate with dendritic hypertrophy and glutamate-related synaptic remodeling at basolateral amygdala projection neurons (BLA PNs). Yet, though BLA PNs are functionally heterogeneous with diverse corticolimbic targets, it remains unclear whether stress differentially impacts specific output circuits.

Methods

Confocal imaging was used to reconstruct the morphology of mouse BLA PNs with the aid of retrograde tracing and biocytin staining. The synaptic activity in these neurons was measured with in vitro electrophysiology, and anxiety-like behavior of the mice was assessed with the elevated plus maze and open field test.

Results

Chronic restraint stress (CRS) produced dendritic hypertrophy across mouse BLA PNs, regardless of whether they did (BLA→dorsomedial prefrontal cortex [dmPFC]) or did not (BLA↛dmPFC) target dmPFC. However, CRS increased the size of dendritic spine heads and the number of mature, mushroom-shaped spines only in BLA↛dmPFC PNs, sparing neighboring BLA→dmPFC PNs. Moreover, the excitatory glutamatergic transmission was also selectively increased in BLA↛dmPFC PNs, and this effect correlated with CRS-induced increases in anxiety-like behavior. Segregating BLA↛dmPFC PNs based on their targeting of ventral hippocampus (BLA→ventral hippocampus) or nucleus accumbens (BLA→nucleus accumbens) revealed that CRS increased spine density and glutamatergic signaling in BLA→ventral hippocampus PNs in a manner that correlated with anxiety-like behavior.

Conclusions

Chronic stress caused BLA PN neuronal remodeling with a previously unrecognized degree of circuit specificity, offering new insight into the pathophysiological basis of depression, anxiety disorders, and other stress-related conditions.

Section snippets

Animals

Male C57BL/6 mice were used and housed in groups (3–5 per cage) in a temperature- and humidity-controlled animal facility with ad libitum access to food and water under a 12-hour light/dark cycle. Mice were raised under the care of the Division of Laboratory Animals, Nanchang University. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Nanchang University.

Chronic Restraint Stress

At 50 to 53 days of age, mice were subjected to CRS by placing them in a restraint cylinder

CRS Causes Generalized Dendritic Hypertrophy in BLA PNs

We first assessed the impact of CRS on dendritic morphology in BLA PNs, regardless of their projection targets. Consistent with previous studies showing that CRS causes dendritic hypertrophy in amygdala PNs of rats (14), we found that C57BL/6J mice subjected to CRS exhibited significantly increased dendritic length and branch number compared with nonstressed control mice (Supplemental Figure S1A–C). Sholl analysis showed that increased dendritic length was particularly prominent in dendrites

Discussion

The major finding of the current study was that chronic stress significantly altered the morphology and synaptic physiology of amygdala projection neurons in a manner that was selective to certain output pathways. Specifically, mice subjected to repeated restraint stress showed dendritic hypertrophy, spine enlargement, and increased synaptic glutamatergic transmission, but only in BLA PNs not projecting to the dmPFC. Subsequent experiments revealed that this same set of stress-related changes

Acknowledgments and Disclosures

This work was supported by the National Basic Research Program of China (Grant No. 2014CB846100 [to B-XP]), National Natural Science Foundation of China (Grant Nos. 91332123 [to B-XP], 81601179 [to B-XP], 81503079 [to J-YZ], 81741759 [to B-XP], and 31700916 [principal investigator, Zhi-Peng Liu]), Natural Science Foundation of Jiangxi Province (Grant Nos. 20143ACB21002 [to B-XP], 20172BCB22005 [to B-XP], KJLD14013 [to B-XP], and 20161BAB215204 [to J-YZ]), and National Institute on Alcohol Abuse

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¹: J-YZ and T-HL contributed equally to this work.

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Archival ReportChronic Stress Remodels Synapses in an Amygdala Circuit–Specific Manner

Abstract

Background

Methods

Results

Conclusions

Section snippets

Animals

Chronic Restraint Stress

CRS Causes Generalized Dendritic Hypertrophy in BLA PNs

Discussion

Acknowledgments and Disclosures

Neuron

Biol Psychiatry

Neurosci Biobehav Rev

Curr Biol

Neuron

Curr Opin Neurobiol

Neuron

Neuron

Behav Brain Res

Neuron

Neuron

Behav Brain Res

Neuroscience

Neuropharmacology

Trends Neurosci

Biol Psychiatry

Prog Neurobiol

Neuron

Front Neuroendocrinol

Neuron

Mechanisms of stress in the brain

Nat Neurosci

Chronic stress causes frontostriatal reorganization and affects decision-making

Science

Stress and the brain: From adaptation to disease

Nat Rev Neurosci

Pathological circuit function underlying addiction and anxiety disorders

Nat Neurosci

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

Nat Neurosci

Phasic vs sustained fear in rats and humans: Role of the extended amygdala in fear vs anxiety

Neuropsychopharmacology

Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia

Am J Psychiatry

Stress, memory and the amygdala

Nat Rev Neurosci

Fear extinction deficits following acute stress associate with increased spine density and dendritic retraction in basolateral amygdala neurons

Eur J Neurosci

Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability

J Neurosci

Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons

J Neurosci

Archival Report
Chronic Stress Remodels Synapses in an Amygdala Circuit–Specific Manner