The Hunger Hormone Ghrelin Dynamically Tunes Phasic Mesolimbic Signals Underlying Food-Directed Behaviors.

摘要

The neurobiology of feeding behavior has long been studied in the context of homeostasis. However, in today's obesogenic society, this framework is insufficient to explain the dramatic rise in the incidence of obesity. This is likely due to the prevalence of calorically dense, highly palatable foods and the preponderance of environmental cues that signal their availability. Food stimuli promote consumption by engaging neural circuits underlying reinforcement and motivated behavior. Recently, it has come to light that peptide hormones that signal energy status act in motivational circuits to alter food intake. Thus, feeding hormones may modulate how motivational circuitry encodes food and food cues, which could be a novel mechanism underlying the ability of feeding hormones to influence food-directed behavior.;My experiments focus on ghrelin, a hormone released by the stomach which is the only known peripheral peptide that promotes food intake. In the first study, I sampled sub-second fluctuations in dopamine concentration in the NAc using fast-scan cyclic voltammetry (FSCV) while rats retrieved sugar pellets (food reward). In a second study, I sampled sub-second fluctuations in NAc dopamine using FSCV and recorded the activity of NAc neurons using in vivo electrophysiology in rats that were trained to associate a cue with the delivery of food reward. During these recordings, I manipulated central ghrelin signaling with intracranial injections of ghrelin to determine whether ghrelin regulated phasic mesolimbic signaling.;I found that central ghrelin increased, while ghrelin receptor blockade decreased, dopamine release evoked by food. I went on to show that intra-LH, but not intra-VTA, administration of ghrelin recapitulated the results of central ghrelin infusions, implicating the LH as a potential site of action. Next, I demonstrated that intra-VTA orexin could be a plausible mechanism underlying the ability of central and LH ghrelin to regulate food-evoked dopamine release. Additionally, central ghrelin augmented both phasic dopamine release and phasic increases in NAc activity evoked by a food-predictive cue. My results highlight novel mechanisms for ghrelin and physiological state to influence how the brain responds to food reward and food-related stimuli, particularly in areas of the brain linked to reinforcement and goal-directed behavior.