Ghrelin and neuropeptide Y: Actions and interactions within the neuroanatomically distributed system for the control of feeding behavior

Ghrelin, a recently discovered peptide-hormone, has been portrayed as a hunger signal. It is produced in the gut and acts centrally to cause increases in food intake in humans and animals. It is widely believed that ghrelin\u27s orexigenic effect is mediated by the central Neuropeptide (NPY) system, although there are many locations within the brain at which the ghrelin-NPY interactions may take place. Most attention has been focused on the hypothalamus, to the neglect of potentially important contributions of the caudal brainstem (CBS), within which GHS-R (ghrelin\u27s receptor), and NPY neurons and receptors (R) are strongly represented. The studies presented in this dissertation broadly address the interactions between ghrelin and the NPY system, segregating pathways and integrative processes seated in different levels of the neuraxis. In addition to a forebrain site of action for the hyperphagic response to ghrelin, we identify a sensitive site within the CBS; we observed hyperphagic responses to ghrelin administration to both the 4th (hindbrain) ventricle and, with doses that were sub-threshold for the ventricle, to the brainstem parenchyma. We showed that activity of NPY Y1 R and Y5 R subtypes are both essential for responses to forebrain and CBS ghrelin delivery. In both cases the Y1 R contribution stems from receptor sub-populations within the CBS. Interestingly, the Y5 R contribution depended on injection site, with forebrain Y5 R activity required for the forebrain-elicited response, and a hindbrain receptor complement required for the 4th ventricle response. In separate studies we explored the site and Y R subtype selectivity requirements for the hyperphagic response to NPY itself. As for ghrelin, Y R subtype requirements varied with site of drug delivery. The profile obtained, however, was different from that described for ghrelin with respect to (1) the location of the relevant Y R subpopulations, and (2) the different combinatory principles by which Y1- and Y5 R-related signals are integrated (summation and OR gate for NPY; AND gate for ghrelin). We can firmly reject the hypothalamocentric perspective. Taken together, our results capture some of the richness of the neuroanatomically distributed system for the control of feeding behavior