Journal
BIOLOGICAL PSYCHIATRY
Volume 74, Issue 9, Pages 672-679Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2013.03.024
Keywords
Depression-like behavior; glucocorticoid receptor; HPA axis; prefrontal cortex; rat; stress
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Funding
- National Institutes of Health [MH049698, MH069860, NS007453, MH097430]
- Udall Parkinson's Disease Center of Excellence Grant [NS058830]
- Gardner Family Center for Parkinson's Disease and Movement Disorders grant
- University Research Council Fellowship grant
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Background: Stress-related disorders (e.g., depression) are associated with hypothalamic-pituitary-adrenocortical axis dysregulation and prefrontal cortex (PFC) dysfunction, suggesting a functional link between aberrant prefrontal corticosteroid signaling and mood regulation. Methods: We used a virally mediated knockdown strategy (short hairpin RNA targeting the glucocorticoid receptor [GR]) to attenuate PFC GR signaling in the rat PFC. Adult male rats received bilateral microinjections of vector control or short hairpin RNA targeting the GR into the prelimbic (n = 44) or infralimbic (n = 52) cortices. Half of the animals from each injection group underwent chronic variable stress, and all were subjected to novel restraint. The first 2 days of chronic variable stress were used to assess depression- and anxiety-like behavior in the forced swim test and open field. Results: The GR knockdown confined to the infralimbic PFC caused acute stress hyper-responsiveness, sensitization of stress responses after chronic variable stress, and induced depression-like behavior (increased immobility in the forced swim test). Knockdown of GR in the neighboring prelimbic PFC increased hypothalamic-pituitary-adrenocortical axis responses to acute stress and caused hyper-locomotion in the open field, but did not affect stress sensitization or helplessness behavior. Conclusions: The data indicate a marked functional heterogeneity of glucocorticoid action in the PFC and highlight a prominent role for the infralimbic GR in appropriate stress adaptation, emotional control, and mood regulation.
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