Identification of chronic stress‐activated regions reveals a potential recruited circuit in rat brain
Open accessAbstract
Chronic stress induces presynaptic and postsynaptic modifications in the paraventricular nucleus of the hypothalamus that are consistent with enhanced excitatory hypothalamo‐pituitary‐adrenocortical (HPA) axis drive. The brain regions mediating these molecular modifications are not known. We hypothesized that chronic variable stress (CVS) tonically activates stress‐excitatory regions that interact with the paraventricular nucleus of the hypothalamus, culminating in stress facilitation. In order to identify chronically activated brain regions, ΔFosB, a documented marker of tonic neuronal activation, was assessed in known stress regulatory limbic and brainstem sites. Four experimental groups were included: CVS, repeated restraint (RR) (control for HPA habituation), animals weight‐matched (WM) to CVS animals (control for changes in circulating metabolic factors due to reduced weight gain), and non‐handled controls. CVS, (but not RR or WM) induced adrenal hypertrophy, indicating that sustained HPA axis drive only occurred in the CVS group. CVS (but not RR or WM) selectively increased the number of FosB/ΔFosB nuclei in the nucleus of the solitary tract, posterior hypothalamic nucleus, and both the infralimbic and prelimbic divisions of the medial prefrontal cortex, indicating an involvement of these regions in chronic drive of the HPA axis. Increases in FosB/ΔFosB‐immunoreactive cells were observed following both RR and CVS in the other regions (e.g. the dorsomedial hypothalamus), suggesting activation by both habituating and non‐habituating stress conditions. The data suggest that unpredictable stress uniquely activates interconnected cortical, hypothalamic, and brainstem nuclei, potentially revealing the existence of a recruited circuitry mediating chronic drive of brain stress effector systems.
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The infralimbic cortex is involved in coping with chronic stress, eventually leading to structural changes and prefrontal dysfunction.
“The most ventral subdomain of the mPFC is the infralimbic cortex (IL) and is involved in coping with chronic stress eventually leading to structural changes and prefrontal dysfunction [5–11].”
From Development of prefrontal cortex (2022) · cites this paper as [5]
The Results (Upstream Limbic Structures) report increased FosB/ΔFosB expression in the infralimbic cortex after chronic variable stress. The Discussion suggests that prefrontal activation may produce lasting changes in gene transcription and contribute to dysfunction, but does not establish that infralimbic involvement in coping leads to structural changes or prefrontal dysfunction. (LLM, conf=0.85)
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- Authors
- Flak, J. N., Solomon, M. B., Jankord, R., Krause, E. G., & Herman, J. P.
- Affiliations
- University of Cincinnati (US)
- Corresponding author
- Herman, James P.
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2012-07-12
- Volume
- 36
- Issue
- 4
- Pages
- 2547-2555
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- PMC
- PMC4538599
- OpenAlex
- W2102295712
- Cited by
- 87
- References
- 80
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 3 · 2019: 9 · 2018: 10 · 2017: 5 · 2016: 20 · 2015: 8 · 2014: 5 · 2013: 8
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (R01MH049698, MH069860, R01MH069860, MH049698)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Keywords
- chronic variable stress, chronic stress, ΔFosB, FosB, paraventricular nucleus, hypothalamic-pituitary-adrenal axis, nucleus tractus solitarius, posterior hypothalamic nucleus, infralimbic cortex, prelimbic cortex, medial prefrontal cortex, adrenal hypertrophy
- MeSH terms
- Animals, Brain Stem, Limbic System, Male, Stress, Psychological, Proto-Oncogene Proteins c-fos, Rats, Sprague-Dawley, Rats
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