The role of pituitary adenylate cyclase-activating polypeptide neurons in the hypothalamic ventromedial nucleus and the cognate PAC1 receptor in the regulation of hedonic feeding

Abstract

We explored the role of pituitary adenylate cyclase-activating polypeptide (PACAP) neurons in the hypothalamic ventromedial nucleus (VMN) in regulating hedonic feeding. We hypothesized that VMN PACAP neurons would inhibit reward-encoding mesolimbic (A10) dopamine neurons and thereby suppress impulsive consumption brought on by intermittent exposure to highly palatable food. Visualized whole-cell patch clamp recordings coupled with in vivo behavioral experiments were utilized in wildtype, PACAP- cre, TH- cre and TH- cre/PAC1 receptor-floxed mice. We found that optogenetic stimulation of VMN PACAP neurons inhibited postsynaptic targets in the ventral tegmental area (VTA), an effect replicated by bath application of exogenous PACAP during recordings from preidentified A10 dopamine neurons. These inhibitory actions were abrogated by the PAC1/VPAC2 receptor antagonist PACAP6-38, the KATP channel blocker tolbutamide, and by selective knockdown of the PAC1 receptor in A10 dopamine neurons. PACAP delivered directly into the VTA decreases binge feeding accompanied by reduced meal size and duration. These effects are negated by PACAP6-38, PAC1 receptor knockdown in A10 dopamine neurons, and apoptotic ablation of VMN PACAP neurons. These findings demonstrate that VMN PACAP neurons blunt impulsive, binge feeding behavior by activating PAC1 receptors and KATP channels to inhibit A10 dopamine neurons. As such, they impart impactful insight into potential treatment strategies for conditions such as obesity and food addiction. Work funded by PHS grant DA024314. Work funded by PHS grant DA024314. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.