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

AGUSTINA CABRAL; JEFFREY M. ZIGMAN; ENRIQUE PORSTIANSKY; MARIO PERELLO; EDITH SÁNCHEZ-JARAMILLO

San Diego

Congreso; Society for Neuroscience Annual Meeting; 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 a consequence, the hypothalamic-pituitary-adrenal (HPA) neuroendocrine axis; however, the neuronal circuits by which ghrelin engages this neuroendocrine response are unknown. Here, we show 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 the PVN. We also show that ghrelin receptor seems to be mainly located in GABAergic terminals within the PVN and that ghrelin is able to inhibit GABA release from the PVN explants. In addition, we found that peripherally-administered fluorescein-labeled ghrelin is able to gain access to the PVN, and that peripherally-administered ghrelin induces full activation of the PVN CRF neurons in ARC-ablated mice, which otherwise fail to increase food intake in response to the hormone. In contrast, ghrelin fails to activate the PVN CRF neurons of mice with ghrelin receptor expression limited to ARC AgRP neurons, which partially respond to its orexigenic actions. Thus, ghrelin seems to activate PVN CRF neurons via inhibition of a local GABAergic tone, in an ARC-Independent manner. These data suggest that the neuronal circuits mediatingghrelin?s role as an orexigenic vs. a stress