Ghrelin activates corticotropin-releasing factor neurons of the hypothalamic paraventricular nucleus via regulation of GABA inputs

A. CABRAL; E. PORSTIANKY; E. SÁNCHEZ JARAMILLO; J. M. ZIGMAN; M. PERELLÓ

Congreso; Neuroscience 2016 Annual Meeting - Society for Neuroscience; 2016

Ghrelin is a stomach-derived hormone that activates the corticotropin-releasing factor(CRF)-producing neurons of the paraventricular nucleus of the hypothalamus (PVN) and, as aconsequence, the hypothalamic-pituitary-adrenal (HPA) neuroendocrine axis; however, theneuronal circuits by which ghrelin engages this neuroendocrine response are unknown. Here, weshow that ghrelin-induced activation of PVN CRF neurons does not require neuropeptide Y(NPY) signaling but requires a decrease of γ-aminobutyric acid (GABA) signaling within thePVN. We also show that ghrelin receptor seems to be mainly located in GABAergic terminalswithin the PVN and that ghrelin is able to inhibit GABA release from the PVN explants. Inaddition, we found that peripherally-administered fluorescein-labeled ghrelin is able to gainaccess to the PVN, and that peripherally-administered ghrelin induces full activation of the PVNCRF neurons in ARC-ablated mice, which otherwise fail to increase food intake in response tothe hormone. In contrast, ghrelin fails to activate the PVN CRF neurons of mice with ghrelinreceptor expression limited to ARC AgRP neurons, which partially respond to its orexigenicactions. Thus, ghrelin seems to activate PVN CRF neurons via inhibition of a local GABAergictone, in an ARC-independent manner. These data suggest that the neuronal circuits mediatingghrelin?s role as an orexigenic vs. a stress