CORTICOTROPIN RELEASING FACTOR RECEPTOR FUNCTION IN CNS

DESCRIPTION (provided by applicant): Corticotropin releasing factor (CRF) receptors are involved in the stress response; CRF produces generalized arousal and anxiety-like behaviors in rodents. Two related genes encode the CRF1 and CRF2 receptor subtypes, which exhibit distinct expression patterns in the brain. Paradoxically, the brain areas involved in stress-related autonomic responses express low or undetectable levels of CRF receptors. In addition, the role of CRF in brain regions that express the highest levels of CRF receptors (e.g. cortex and cerebellum) remains unexplored. CRF1 and CRF2 are G-protein coupled receptors but the functional consequences of receptor activation are poorly understood. Electrophysiological experiments are needed to elucidate how CRF affects neuronal function. A major obstacle to conducting these experiments is identifying the neurons that express CRF receptors in brain slices. We propose to non-destructively label neurons that express CRF receptors by the targeted expression of fluorescent proteins in transgenic mice. We will generate two transgenic mouse lines labeling neurons that express CRF1 and CRF2, respectively in order to unequivocally identify them for electrophysiological recording. These animals will be used to expand our understanding of CRF receptor function as well as to develop secondary assays for the development CRF receptor subtype selective antagonists as therapeutic agents. PROPOSED COMMERCIAL APPLICATION: Small molecule antagonists to CRF receptors are proposed to be therapeutic for treating anxiety and depression. Yet the mechanism by which the CRF system affects brain function is unknown. This research will produce and important tool for studying the function of CRF receptors in situ. It will enable development of functional (electrophysiological) assay(s) for CRF receptors in a native system and lead to the development of optimal small molecule drugs that target the CRF system.