Site-Specific Genetic Manipulation of Amygdala Corticotropin-Releasing Factor Reveals Its Imperative Role in Mediating Behavioral Response to Challenge
Abstract
Background Faulty regulation of the central extrahypothalamic corticotropin-releasing factor (CRF) expression is associated with stress-related psychopathologies including anxiety disorders and depression. Extensive pharmacological literature describes the effects of CRF agonists or antagonists' administration on anxiety-like behavior. However, the relevance of the endogenous agonist, presumed to be CRF, has never been explicitly demonstrated. Several genetic models have been used to study the role of CRF in the physiological response to stress and in stress-related disorders. Nevertheless, developmental compensatory mechanisms and lack of spatial and temporal specificity limited the interpretations of these studies.Methods Two lentiviral-based systems were designed, generated, and used to knockdown (KD) or conditionally overexpress (OE) CRF in the central amygdala (CeA) of adult mice. Behavioral responses associated with the CeA, such as anxiety, depression and fear memory, and the plasma corticosterone levels were evaluated under both basal and stressful conditions.Results Changing the CeA-CRF levels mildly affected anxiety-like behaviors under basal conditions. However, following exposure to an acute stressor, CeA-CRF-KD strongly attenuated stress-induced anxiety-like behaviors, whereas a short-term CeA-CRF-overexpression enhanced the stress-induced effects on these behaviors. Interestingly, a significant increase in basal corticosterone levels in the CeA-CRF-KD mice was observed, demonstrating the importance of endogenous CeA-CRF levels for basal, but not stress-induced, corticosterone levels.Conclusions These results highlight the pivotal role of CeA CRF expression regulation in mediating adequate behavioral responses to stress and introduce these novel viral tools as a useful approach for dissecting the role of central CRF in mediating behavioral and neuroendocrine responses to stress.
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The central amygdala nucleus (CEA) has been implicated in learning and expression of fear responses, as well as the expression of stress-induced anxiety behaviors.
“Functionally, CEA has been implicated in learning and expression of fear responses,105, 106, 107 as well as the expression of stress-induced anxiety behaviors.108, 109, 110, 111, 112, 113”
From Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress (2014) · cites this paper as [112]
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- Authors
- Regev, L., Tsoory, M., Gil, S., & Chen, A.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- Chen, Alon
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 71
- Issue
- 4
- Pages
- 317-326
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2138655843
- Cited by
- 93
- References
- 50
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 6 · 2020: 3 · 2019: 8 · 2018: 12 · 2017: 8 · 2016: 9 · 2015: 6 · 2014: 9 · 2013: 11 · 2012: 7
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Research Council (260463)
- Israel Science Foundation
- Roberto and Renata Ruhman
- Legacy Heritage Biomedical Science Partnership
- Israel Ministry of Health
- Mr. and Mrs. Mike Kahn
- Mr. Jorge David Ashkenazi
- Mr. and Mrs. Barry Wolfe
- Nella and Leon Benoziyo Center for Neurosciences
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- corticotropin-releasing factor, central amygdala, stress response, anxiety-like behavior, depression, fear memory, corticosterone, lentiviral overexpression, stress-induced anxiety, anxiety disorders
- MeSH terms
- Amygdala, Animals, Anxiety, Behavior, Animal, Corticosterone, Corticotropin-Releasing Hormone, Depression, Gene Expression Regulation, Genetic Vectors, Mice, Transgenic, Stress, Physiological, Stress, Psychological, Lentivirus, Mice, Gene Knockdown Techniques
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