The corticotropin-releasing factor (CRF) family of signaling molecules comprises four ligands (CRF, and urocortins (Ucns) 1-3), two receptors (CRFR1 and -R2) and a binding protein (CRFBP). This family is thought to play critical and interactive roles in the integration of endocrine, autonomic and behavioral responses to stress. An interconnected network of brain structures, termed the central autonomic system (CAS), harbors sensitive sites of stress-related CRF/Ucn action, but its components are generally lacking or impoverished in relevant ligand and/or receptor expression. Our goal is to clarify the functional anatomical organization that provides for generalized stress-induced CAS activation, by ascertaining the disposition and role of specific signaling molecules in specific locations that provide for recruitment of this circuitry in a range of challenge paradigms. Immunolocalization methods will be used at the light and electron microscopic levels to determine how CRFRs are distributed in CAS components, and their relation to ligand-containing terminal fields. We will work with other components of the program to pursue evidence of a novel CRFR enriched in CAS, and if successful, determine its distribution and role in CAS circuitry. Histochemical and anatomical methods will be used to identify molecular targets and sites within the CAS at which CRFR1 and R2 mechanisms interact to sculpt stress responses, and to identify the underlying circuitry. Pharmacologic manipulations in genetically manipulated mouse models will be used to pursue indications of an unexpected role for the CRFBP in signaling in the CAS. Anatomical and functional studies will seek to provide a context for a newly discovered soluble CRFR2 variant. Finally, we will explore a range of possible explanations for the failure of recently discovered CRFR2-selective ligands, Ucn 2 and 3, to activate sites of cognate receptor expression. We will compare the extent to which Ucn 1, 2 and 3-expressing cell groups may be differentially responsive to a range of challenge paradigms, and employ null mutant lines to probe the roles of each peptide system in CAS responses to stress. The CMS systems under scrutiny here play essential physiologic roles in stress adaptation, dysfunction of which has been linked to such diverse pathologies as autoimmune disease, hypertension and age-related deficits in learning and memory, and have been implicated in the etiology of a range of affective disorders, including anorexia nervosa and major depression.
Showing the most recent 10 out of 382 publications
