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Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behavioral anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus.

ABSTRACT: Environmental stress has been demonstrated to increase susceptibility for mood and anxiety disorders, and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, the primary endocrine response to stress, is often observed in these patients. HPA axis activation is initiated by corticotropin-releasing factor (CRF) from the hypothalamus, leading to the hypothesis that hypothalamic CRF overexpression contributes to HPA axis hyperactivity in psychiatric patients. In addition, elevated CRF in cerebrospinal fluid is observed in mood and anxiety disorder patients, suggesting that CRF is also being overproduced from extrahypothalamic sources such as the central amygdala (CeA) and overactivity of the amygdala in neuroimaging studies is a consistent finding in anxiety and depression patients. Due to the importance of CRF and the amygdala in the etiology of stress-sensitive psychiatric disorders, the present study sought to further dissect the impact of CRF overexpression (OE) in the amygdala on downstream behavioral, endocrine, and gene-expression changes typically associated with chronic stress. To test the hypothesis that elevated CRF output from the amygdala would reproduce HPA axis hyperactivity and behavioral symptoms of chronic stress, we developed a lentiviral vector in which 3.0kb of the CRF promoter drives overexpression of CRF (LVCRFp3.0CRF). In adult male rats, Experiment-1 examined behavioral consequences of chronic CRF overexpression from the amygdala; the dexamethasone (Dex)/CRF test was used to measure HPA axis reactivity. Experiment-2 focused on HPA axis disruptions; the dexamethasone-suppression and CRF-stimulation tests as well as the Dex/CRF test were used. In both experiments, expression of HPA-axis related transcripts were assessed.

SUBMITTER: Flandreau EI

PROVIDER: S-EPMC3164918 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behavioral anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus.

Flandreau Elizabeth I EI Ressler Kerry J KJ Owens Michael J MJ Nemeroff Charles B CB

Psychoneuroendocrinology 20110526 1

Environmental stress has been demonstrated to increase susceptibility for mood and anxiety disorders, and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, the primary endocrine response to stress, is often observed in these patients. HPA axis activation is initiated by corticotropin-releasing factor (CRF) from the hypothalamus, leading to the hypothesis that hypothalamic CRF overexpression contributes to HPA axis hyperactivity in psychiatric patients. In addition, elevated CRF in ...[more]

PMID: 21616602

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Project description:Corticotropin-releasing factor (CRF) immunoreactive (ir) neurons of the paraventricular nucleus of the hypothalamus (PVN) play pivotal role in the coordination of stress response. CRF-producing cells in the central nucleus of amygdala (CeA) and oval division of the bed nucleus of stria terminalis (BNSTov) are also involved in stress adaptation and mood control. Immediate early gene products, subunits of the transcription factor activator protein 1 (AP1) are commonly used as acute (FOS) and/or chronic (FOSB/deltaFOSB) markers for the neuronal activity in stress research. It is well known that the course of aging affects stress adaptation, but little is known about the aging-related stress sensitivity of CRF neurons. To the best of our knowledge, the stress-induced neuronal activity of CRF neurons in the course of aging in acute and chronic stress models was not studied systematically yet. Therefore, the aim of the present study was to quantify the acute restraint stress (ARS) and chronic variable mild stress (CVMS) evoked neuronal activity in CRF cells of the PVN, CeA, and BNSTov using triple-label immunofluorescence throughout the whole lifespan in the rat. We hypothesized that the FOS and FOSB content of CRF cells upon ARS or CVMS decreases with age. Our results showed that the FOS and FOSB response to ARS declined with age in the PVN-CRF cells. BNSTov and CeA CRF cells did not show remarkable stress-induced elevation of these markers neither in ARS, nor in CVMS. Exposure to CVMS resulted in an age-independent significant increase of FOSB/delta FOSB immunosignal in PVN-CRF neurons. Unexpectedly, we detected a remarkable stress-independent FOSB/deltaFOSB signal in CeA- and BNSTov-CRF cells that declined with the course of aging. In summary, PVN-CRF cells show decreasing acute stress sensitivity (i.e., FOS and FOSB immunoreactivity) with the course of aging, while their (FOSB/deltaFOSB) responsivity to chronic challenge is maintained till senescence. Stress exposure does not affect the occurrence of the examined Fos gene products in CeA- and BNSTov-CRF cells remarkably suggesting that their contribution to stress adaptation response does not require AP1-controlled transcriptional changes.

Project description:We have previously demonstrated that viral-mediated overexpression of corticotropin-releasing factor (CRF) within the central nucleus of the amygdala (CeA) reproduces many of the behavioral and endocrine consequences of chronic stress. The present experiment sought to determine whether administration of the selective serotonin reuptake inhibitor (SSRI) escitalopram reverses the adverse effects of CeA CRF overexpression. In a 2×2 design, adult male rats received bilateral infusions of a control lentivirus or a lentivirus in which a portion of the CRF promoter is used to drive increased expression of CRF peptide. Four weeks later, rats were then implanted with an Alzet minipump to deliver vehicle or 10mg/kg/day escitalopram for a 4-week period of time. The defensive withdrawal (DW) test of anxiety and the sucrose-preference test (SPT) of anhedonia were performed both before and after pump implantation. Additional post-implant behavioral tests included the elevated plus maze (EPM) and social interaction (SI) test. Following completion of behavioral testing, the dexamethasone/CRF test was performed to assess HPA axis reactivity. Brains were collected and expression of HPA axis-relevant transcripts were measured using in situ hybridization. Amygdalar CRF overexpression increased anxiety-like behavior in the DW test at week eight, which was only partially prevented by escitalopram. In both CRF-overexpressing and control groups, escitalopram decreased hippocampal CRF expression while increasing hypothalamic and hippocampal expression of the glucocorticoid receptor (GR). These gene expression changes were associated with a significant decrease in HPA axis reactivity in rats treated with escitalopram. Interestingly, escitalopram increased the rate of weight gain only in rats overexpressing CRF. Overall these data support our hypothesis that amygdalar CRF is critical in anxiety-like behavior; because the antidepressant was unable to reverse behavioral manifestations of CeA CRF-OE. This may be a potential animal model to study treatment-resistant psychopathologies.

Dataset Information

Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behavioral anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus.

Publications

Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behavioral anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus.

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