The corticotropin-releasing factor (CRF) family of signaling molecules plays important and interactive roles in effecting integrated endocrine, autonomic and affective/behavioral responses to stress. It includes four ligands (CRF and urocortin (Ucn) 1-3) that signal though either or both of two G protein-coupled receptors (CRFRl and CRFR2). An interconnected network of CNS cell groups, termed the central autonomic system (CAS), comprises sensitive sites of stress-related CRF/Ucn action, but neither the bases for CRF ligandreceptor signaling within them, nor the circuitry that provides for documented interactions between CRFR1 - and R2-dependent mechanisms in sculpting individual modes of stress adaptation, are well understood. We will work with other components of the Program to validate immunologic and molecular genetic tools with which to determine how CRFRs are distributed in CAS components, and their relation to ligand-containing terminal fields. Evidence that functional manifestations of the ligand-receptor 'mismatch' may be accommodated by presynaptic CRFR expression, novel endogenous Ucn forms and/or systemic effects of centrally administered peptides will be pursued. A second major goal is to define the extended circuitries that provide for CRFR interplay in regulating stress-induced activation of (1) hypothalamic neurons that govern activation of the pituitary-adrenal axis, and (2) cell groups in the amygdala that mediate affective behaviors related to anxiety. Transgenic CRFR reporter mice will be employed to identify stress-sensitive, receptor-bearing intrinsic and extrinsic cell groups potentially involved in these functions. Combined histochemical and axonal transport methods will then be used to progressively unravel candidate circuitries by which CRFR1 and -R2 mechanisms may interact to shape the endpoints of interest and the disposition of CRFR ligands within them. Finally, site-specific, conditional gene targeting methods will be used to test the functional involvement of key nodes of the implicated circuits in stress-induced pituitary-adrenal hormone secretion and behavioral measures of anxiety. The results are expected to provide a systems level perspective on the role of the central CRF system in critical facets of the stress response, and a stringent test of the integrative capacities attributed to this system in stress adaptation.
Aspects of the central CRF system have been implicated as potential targets for therapeutic intervention in obesity, autoimmune disease, a range of affective disorders and age-related neurodegenerative disease. Small molecule CRFR1 antagonists are in advanced clinical trials for the treatment of depression and other anxiety-related disorders. In providing a functional neuroanatomical context for CRF signaling in key sites of stress-related peptide action, our results are expected to inform these and other potential applications.
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