Study of mechanisms mediating ghrelin-induced activation of hypophysiotropic CRF neurons

MARIO PERELLO; AGUSTINA CABRAL; SPRING VALDIVIA; MIRTA REYNALDO; ANABELA PATRONE; DANIEL CASTROGIOVANNI; EDUARDO JAVIER LÓPEZ SOTO; FRANCINA AGOSTI; SILVIA RODRÍGUEZ; JESICA RAINGO

Banff

Simposio; Keystone Symposium; 2013

Ghrelin is a stomach-derived hormone that regulates food intake and neuroendocrine function. Previous evidence indicates that ghrelin indirectly activates the corticotropin-releasing factor (CRF)-producing neurons of the hypothalamic paraventricular nucleus (PVN), which regulate the hypothalamic-pituitary-adrenal axis. Here, we characterized in vitro and in vivo the neuronal mechanism by which ghrelin activates the hypophysiotropic CRF neurons in mice. We found that ghrelin administration directly into the PVN activates c-fos --a marker of cellular activation-- in the CRF neurons of the PVN and the hypothalamic-pituitary-adrenal axis. It is known that ghrelin activates neuropeptide Y (NPY)-expressing neurons of the arcuate nucleus (ARC), which in turn activate CRF neurons. However, we found that mice with either pharmacological blockage of NPY signaling or with the ARC chemically-lesioned fully responded to ghrelin-induced activation of hypophysiotropic CRF neurons. In contrast, ghrelin-induced activation of the CRF neurons was blocked by pretreatment of mice with a GABA receptor agonist. Thus, it seems that ghrelin activates CRF neurons through a local GABAergic neuronal circuitry that is independent of NPY signaling. Then, we tested if ghrelin modifies presynaptic calcium channels activity as a mechanism to control neurotransmitter release in the PVN. In hypothalamic culture neurons, we found that ghrelin receptor is located at pre-synaptic level and that ghrelin inhibits calcium current levels in a concentration dependent manner. Thus, we postulate that ghrelin activate CRF neurons via inhibition of pre-synaptic calcium channels and the resulting inhibition of GABA release.