Chronic stress dysregulates amygdalar output to the prefrontal cortex
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Chronic stress contributes to the neuropathology of mental health disorders, including those associated with anxiety. The basolateral amygdala (BLA) coordinates emotional behavioral responses through glutamatergic outputs to downstream regions such as the prefrontal cortex (PFC), nucleus accumbens core (NAcc) and bed nucleus of the stria terminalis (BNST). We explored the effects of chronic stress on BLA outputs to the PFC, NAcc and BNST using slice electrophysiology combined with optogenetics in two inbred mouse strains with distinct stress-induced anxiety responses. We found that ten consecutive days of chronic restraint stress enhanced pre-synaptic glutamate release at BLA-to-PFC synapses in C57BL/6J mice, but reduced pre-synaptic glutamate release at these synapses in DBA/2J mice. To assess the behavioral relevance of enhanced glutamate output at BLA-to-PFC synapses, we approximated the effects of chronic stress on the BLA-PFC circuit using optogenetics. We found that photostimulation of the BLA-PFC circuit in unstressed C57BL/6J mice produced persistent (i.e., post-stimulation) increased anxiety-like behavior and hyperactivity in the elevated plus-maze - a profile consistent with prototypical behavioral responses of stressed C57BL/6J mice. These data demonstrate that chronic stress dysregulates the BLA-PFC circuit by altering pre-synaptic glutamate release from BLA outputs, and provide a mechanism by which chronic stress can lead to increased anxiety.
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The BLA is generally hyperactive following chronic stress.
“The stress-induced attenuation of BLA→DMS activity was surprising because the BLA is, generally, hyperactive following chronic stress54–61 (c.f.62).”
From A dual-pathway architecture for stress to disrupt agency and promote habit (2025) · cites this paper as [61]
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- Authors
- Lowery-Gionta, E. G., Crowley, N. A., Bukalo, O., Silverstein, S., Holmes, A., & Kash, T. L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- National Institute on Alcohol Abuse and Alcoholism (US)
- Corresponding author
- Kash, Thomas Louis
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 139
- Pages
- 68-75
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC6067970
- OpenAlex
- W2810802618
- Cited by
- 84
- References
- 50
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 6 · 2023: 9 · 2022: 9 · 2021: 14 · 2020: 13 · 2019: 11 · 2018: 2
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 308 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuropharmacology (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U. S. Department of Defense (W81XWH-10-1-0999)
- National Institute on Alcohol Abuse and Alcoholism's Intramural Research Program
- Bowles Center for Alcohol Studies
- National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism (F32-022549, F31-022280)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- chronic stress, basolateral amygdala, prefrontal cortex, glutamate release, anxiety, restraint stress, inbred mouse strains, C57BL/6J mice, DBA/2J, optogenetic stimulation, elevated plus maze, hyperactivity, stress-induced anxiety, synapses
- MeSH terms
- Animals, Anxiety, Chronic Disease, Male, Membrane Potentials, Mice, Inbred C57BL, Mice, Inbred DBA, Motor Activity, Neural Pathways, Neurons, Restraint, Physical, Species Specificity, Stress, Psychological, Prefrontal Cortex, Glutamic Acid, Tissue Culture Techniques, Optogenetics, Basolateral Nuclear Complex
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