HYPOTHALAMIC HYPOCRETIN PATHWAYS MODULATING FEEDING

The lateral hypothalamus (LH) has a historical role as the "feeding center" of the brain. Although energy regulation is now known to be more complex, the role of the LH in food intake and body weight regulation remains strong. The recent discovery of the hypocretins (also known as orexins), Hcrt 1 and Hcrt 2, appears to provide a means to expand understanding of the LH and its role in the energy regulatory network. The Hcrts are newly identified orexigenic neuropeptides that elicit dose-dependent feeding following LH administration, and appear to interact with a variety of other important feeding-regulatory circuits. The Hcrt receptors are widely distributed throughout the brain, and are found in several key energy regulatory sites. Hcrt-containing neurons within the LH project to and activate several of these sites. The finding that LH Hcrt-containing neurons communicate with other key brain sites involved in appetite and body weight regulation, and the finding that Hcrt stimulation of LH activates those sites is, we think, of critical importance. The investigators have experience probing the nature of interactions between brain sites connected by specific neuromodulators. The existing data indicates that such an approach will be very useful in determining how the LH and the Hcrts fit into the energy regulatory network, and will aid in our understanding of energy homeostasis and metabolic disorders. Further, if the neural pathways influenced by the Hcrts are determined, then pharmacological alteration of these pathways can be explored. The overall hypothesis to be tested is as follows: hypocretin containing neural pathways originating in the LH communicate with other feeding regulatory brain sites and neuromodulators in an integrated fashion to modulate feeding. The specific aims of this project are to localize the specific site of Hcrt action within the LH, verify the significance of Hcrt in the LH by testing other regions for Hcrt feeding effects (mapping/feeding studies); measure behaviors and meal patterns elicited in response to LH Hcrt (feeding/behavioral studies); develop the neural map of feeding sensitivity to Hcrt 1 (cFos immunohistochemistry, lesion/feeding studies); determine amino acid involvement in Hcrt 1 induced feeding (GABA)/glutamate interaction feeding studies); and determine communication between LH Hcrt feeding signals and other feeding related neuromodulators (interaction feeding studies).