Corticotropin-releasing factor overexpression in the central amygdala: Gene expression, HPA axis function, and behavior

Mood and anxiety disorders including major depressive disorder and post-traumatic stress disorder have been associated with a disrupted hypothalamic-pituitary-adrenal (HPA) axis response to stress, attributed to corticotropin-releasing factor (CRF) overexpression in the paraventricular nucleus of the hypothalamus (PVN). However, PVN output is determined by summation of signals from limbic and brainstem sources; disruption in one of these regions may result in increased PVN CRF and thus HPA axis hyperactivity. Long-term gene expression changes which confer the chronic nature of these disorders may take place primarily in the PVN or may take place primarily in limbic structures, which then modulate the PVN. The utility of CRFergic circuits as pharmaceutical targets for the treatment of mood and anxiety disorders could be improved with greater knowledge of distinct, regionally-specific CRF expression patterns. The goal of this research is to develop tools to manipulate gene expression within CRF-producing cells. Here we describe a transgenic mouse in which 3.0Kb of the CRF promoter reliably targets transgene expression to CRF-producing neurons. The cell-type specificity of this promoter was also employed in a lentiviral vector to overexpress CRF from CRFergic cells. Because the CeA is known to influence the behavioral stress-response and hypothesized to play a role in HPA axis regulation, this virus was injected bilaterally into the CeA of adult male rats. Chronic CRF overexpression in the CeA increased expression of CRF and vasopressin in the PVN, leading to increased HPA axis activation, and decreased expression of MR in the hippocampus, resulting in HPA axis disinhibition. These gene-expression changes and HPA axis hyperactivity also resulted in an increase in anxiety-like behavior. These data suggest that HPA axis hyperactivity in human patients may be secondary to altered signals from CRF neurons within the CeA. This and future work elucidating the precise mechanisms through which overexpression of CRF precipitates psychopathology may provide useful preventative and therapeutic tools for mood and anxiety disorders.