BNST CRF and maintenance of weight loss

Maintenance of diet-induced weight loss is a major problem in the treatment of type II diabetes. Animal model studies have suggested an important role for corticotropin releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (BNST) in stress-reward interactions, and more recently in feeding behavior. In particular, CRF signaling within the BNST produces anorexia. Recent studies demonstrate that caloric restriction in mice produces a profound decrease in CRF levels in the BNST that persists even after a return to ad libitum feeding.
This may represent the removal of an important brake on stress-induced feeding behavior that contributes to diet relapse. Currently, however, very little is understood regarding the CRF system in the BNST. We have recently successfully utilized a genetic reporter strategy to isolate CRF neurons within the BNST for morphological and electrophysiological analysis. Here, we propose to use optogenetic and fluorescent-reporterbased animal models to determine inputs and outputs of CRF neurons in the BNST, to determine the specific inputs to the BNST that are opposingly regulated by CRF and orexin, and to examine the long-term impact of caloric restriction on the excitability of BNST CRF neurons and neuropeptide function in the region. The successful completion of these studies will delineate a microcircuit potentially involved in diet relapse and set the stage for 1) further ex vivo studies testing for means of controlling this circuit and 2) in vivo analysis of the impact of activation and inhibition of this circuit on feeding behavior.