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"Role of the Perifornical Hypothalamus in Hypoglycemia Counterregulation"

by
Oleg Otlivanchik
MD/Ph.D. Program
B.S. 2008, Columbia University



Thesis Advisor: Barry Levin, M.D.
Professor
Department of Neurology and Neurosciences

Friday, May 23, 2014
2:00 P.M., Cancer Center G Level Conference Room


Abstract

The role of serotonin (5-hydroxytryptamine, 5-HT) in the perifornical hypothalamus (PFH), a previously unexplored member of the central nervous system glucoregulatory network, in modulating the counterregulatory response (CRR) to hypoglycemia was evaluated. Focal PFH glucopenia was sufficient to induce adrenal medullary epinephrine release and feeding while maintaining PFH euglycemia in the context of systemic insulin-induced hypoglycemia attenuated epinephrine (by 30%), but not norepinephrine or glucagon release. Feeding and adrenomedullary epinephrine release induced by focal PFH glucopenia were attenuated (by 47% and 65%, respectively) by systemic administration of the orexin receptor-1 antagonist SB334867A. Hypoglycemia-induced reversal of palatable food-reward conditioned place preference (CPP), a behavioral model of hypoglycemia awareness, was abolished by SB334867A when paired with hypoglycemia. Additionally, recurrent hypoglycemia attenuated hypoglycemia-induced reversal of food-reward CPP in conjunction with diminished prepro-orexin mRNA (by 50%) in the PFH, but not the adjacent lateral hypothalamus. PFH ablation of 5-HT signaling was sufficient to blunt the CRR (by 69%), but not feeding, induced by focal PFH glucopenia. On the other hand, increased PFH 5-HT availability amplified the epinephrine response (by 33%) to insulin-induced hypoglycemia. This work suggests a novel role for the PFH in glucoregulatory hormone release under conditions of systemic glucose deficit, mediated in part by local orexin neurons and 5-HT signaling.


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