Chronic Stress Induces Maladaptive Behaviors by Activating Corticotropin-Releasing Hormone Signaling in the Mouse Oval Bed Nucleus of the Stria Terminalis
Open accessAbstract
The bed nucleus of the stria terminalis (BNST) is a forebrain region highly responsive to stress that expresses corticotropin-releasing hormone (CRH) and is implicated in mood disorders, such as anxiety. However, the exact mechanism by which chronic stress induces CRH-mediated dysfunction in BNST and maladaptive behaviors remains unclear. Here, we first confirmed that selective acute optogenetic activation of the oval nucleus BNST (ovBNST) increases maladaptive avoidance behaviors in male mice. Next, we found that a 6 week chronic variable mild stress (CVMS) paradigm resulted in maladaptive behaviors and increased cellular excitability of ovBNST CRH neurons by potentiating mEPSC amplitude, altering the resting membrane potential, and diminishing M-currents (a voltage-gated K + current that stabilizes membrane potential) in ex vivo slices. CVMS also increased c-fos + cells in ovBNST following handling. We next investigated potential molecular mechanism underlying the electrophysiological effects and observed that CVMS increased CRH + and pituitary adenylate cyclase-activating polypeptide + (PACAP; a CRH upstream regulator) cells but decreased striatal-enriched protein tyrosine phosphatase + (a STEP CRH inhibitor) cells in ovBNST. Interestingly, the electrophysiological effects of CVMS were reversed by CRHR1-selective antagonist R121919 application. CVMS also activated protein kinase A (PKA) in BNST, and chronic infusion of the PKA-selective antagonist H89 into ovBNST reversed the effects of CVMS. Coadministration of the PKA agonist forskolin prevented the beneficial effects of R121919. Finally, CVMS induced an increase in surface expression of phosphorylated GluR1 (S845) in BNST. Collectively, these findings highlight a novel and indispensable stress-induced role for PKA-dependent CRHR1 signaling in activating BNST CRH neurons and mediating maladaptive behaviors. SIGNIFICANCE STATEMENT Chronic stress and acute activation of oval bed nucleus of the stria terminalis (ovBNST) induces maladaptive behaviors in rodents. However, the precise molecular and electrophysiological mechanisms underlying these effects remain unclear. Here, we demonstrate that chronic variable mild stress activates corticotropin-releasing hormone (CRH)-associated stress signaling and CRH neurons in ovBNST by potentiating mEPSC amplitude and decreasing M-current in male mice. These electrophysiological alterations and maladaptive behaviors were mediated by BNST protein kinase A-dependent CRHR1 signaling. Our results thus highlight the importance of BNST CRH dysfunction in chronic stress-induced disorders.
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The BNST has emerged as a key player in stress-related disorders.
“Another candidate downstream target of AgRP neurons is the bed nucleus of the stria terminalis (BNST) [20, 62], which has emerged as a key player in stress-related disorders [90, 91].”
From Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity (2021) · cites this paper as [90]
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- Authors
- Hu, P., Liu, J., Maita, I., Kwok, C., Gu, E., Gergues, M. M., Kelada, F., Phan, M., Zhou, J.-N., Swaab, D. F., Pang, Z. P., Lucassen, P. J., Roepke, T. A., & Samuels, B. A.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- University of Science and Technology of China (CN)
- Netherlands Institute for Neuroscience (NL)
- University of Amsterdam (NL)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2020-02-13
- Volume
- 40
- Issue
- 12
- Pages
- 2519-2537
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC7083537
- OpenAlex
- W3006526212
- Cited by
- 71
- References
- 107
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 15 · 2023: 9 · 2022: 6 · 2021: 15 · 2020: 4 · 2019: 1
- FWCI
- 5.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- Rutgers University Community Repository (Rutgers University) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- UvA-DARE (University of Amsterdam) (submittedVersion, cc-by)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion, other-oa)
- Funders
- Universiteit van Amsterdam
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Alzheimer Nederland
- National Institute on Alcohol Abuse and Alcoholism (R01AA023797)
- National Institute of Mental Health (R01MH112861)
- National Institute of Environmental Health Sciences (R21ES027119, P30ES005022)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- chronic stress, bed nucleus of the stria terminalis, corticotropin-releasing factor, protein kinase A, anxiety, neuronal excitability, M-current, GluR1 phosphorylation, PACAP, STEP, c-fos, optogenetic stimulation, H89
- MeSH terms
- Adaptation, Psychological, Animals, Chronic Disease, Corticotropin-Releasing Hormone, Male, Membrane Potentials, Mice, Inbred C57BL, Septal Nuclei, Stress, Psychological, Potassium Channels, Signal Transduction, Genes, fos, Protein Tyrosine Phosphatases, Cyclic AMP-Dependent Protein Kinases, Receptors, Corticotropin-Releasing Hormone, Excitatory Postsynaptic Potentials, Pituitary Adenylate Cyclase-Activating Polypeptide, Mice, Electrophysiological Phenomena
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