This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.An increase in corticotropin releasing hormone (CRH) is a putative factor in the pathophysiology of stress-related disorders. Because CRH expression in the central nucleus of the amygdala (CeA) is important in adaptation to chronic stress, we hypothesized that unrestrained synthesis of CRH in the CeA would mimic the consequences of chronic stress exposure and cause dysregulation of the hypothalamic pituitary adrenal (HPA) axis, increase emotionality, and disrupt reproduction. To test this hypothesis, we used a lentiviral vector to increase CRH expression site-specifically in the CeA of female rats. Increased synthesis of CRH in the CeA amplified CRH and arginine vasopressin (AVP) peptide concentration in the paraventricular nucleus of the hypothalamus (PVN) and decreased glucocorticoid negative feedback, both markers associated with the pathophysiology of depression. In addition, continuous expression of CRH in the CeA also increased the acoustic startle response and depressive-like behavior in the forced swim test. Protein levels of gonadotropin releasing hormone (GnRH) in the medial preoptic area (MPOA) were significantly reduced by continuous expression of CRH in the CeA and this was associated with a lengthening of estrous cycles. Finally, sexual motivation but not sexual receptivity was significantly attenuated by continuous CRH synthesis in ovariectomized estradiol - progesterone primed females. These data indicate that unrestrained CRH synthesis in the CeA produces a dysregulation of the HPA axis, as well as many of the behavioral, physiological, and reproductive consequences associated with stress-related disorders.
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