This application is the second modified resubmission of the competitive renewal application of NIH MH- 42088, seeking five years of support which would represent years 19-23 of this project on the Psychobiology of Corticotropin-releasing Factor (CRF). In the past 18 years, research supported by this grant has contributed to a significant extent to establishing CRF as a neurotransmitter in extrahypothalamic and hypothalamic brain areas, to elucidating its role in the mammalian stress response, to characterizing its role in the pathogenesis of mood and anxiety disorders and most recently in demonstrating persistent alterations in response to early life trauma. There is also substantial evidence that CRF-containing neural circuits are the target of drugs of abuse such as cocaine, anxiolytics such as benzodiazepines and perhaps of particular clinical relevance that they are particularily responsive to withdrawal from a variety of CNS acting drugs. The current proposal builds upon our previous body of work, as well as proposing some more novel, higher risk research paths. We propose to extend our recent work identifying the Quantitative Trait Loci (QTL) that control hypothalamic CRF gene expression to limbic brain regions, as well as to study gender differences in CRF gene expression regulation. The results of the QTL experiment will impact on the directions taken in both of the other specific aims. In view of the increasing evidence that CRF1 receptor antagonists possess antidepressant properties, we shall determine whether these novel agents share with other antidepressants the now well documented effect of increasing hippocampal neurogenesis after chronic, but not acute, drug administration, as well as assessing effects on other measures of neuroplasticity. In addition we seek to finally characterize the molecular and electrophysiological properties of CRF neurons in hypothalamic and extrahypothalamic brain areas using novel techniques including transgenic mice with fluorescent reporters under control of the CRF expression locus. These studies, taken together, will provide novel information on the neurobiology of CRF systems, with a focus on their putative role in the pathophysiology of depression and related mood and anxiety disorders, in addictive disorders and the potential clinical utility of CRF1 receptor antagonists in the treatment of these devastating illnesses. ? ? ?
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