Top Down Regulation of Feeding-related Behavior

PROJECT SUMMARY Obesity is one of the greatest public health concerns facing our country. The condition is linked to deficits in specific domains of cognitive function, namely working memory and behavior inhibition, which can affect food seeking and food intake behavior. Melanocortin peptides in the hypothalamus and their central nervous system-based receptors, such as the melanocortin 4 receptor (MC4R) play a role in obesity pathophysiology, as well as hyperphagia. Our preliminary data suggest a novel circuit linking arcuate hypothalamic neurons to MC4R-expressing neurons in the medial prefrontal cortex (mPFC). The mPFC is a region of the brain involved in goal-oriented and habit-based behavior, as well as the integration of external and internal cues. It is made up of discrete subregions that work together to coordinate behavior. Inputs to this region from the hypothalamic metabolism neurons that provide food or body-state-related information would likely be critical for effective feeding decisions, such as stopping eating when full, that could directly influence long term body weight gain. We propose that this melanocortin-based circuit relays food-related information that influences neuronal dynamics in the subregions of the mPFC and also regulates food intake to effect body weight. We hypothesize that this circuit specifically affects cognitive behavior associated with hyperphagia, impairing feeding and energy expenditure, which we will test using a number of complementary cutting-edge approaches in mice. First, we will define the connectivity between the two subpopulations of hypothalamus melanocortin peptide expressing neurons and the MC4R-expressing neurons in the subregions of the mPFC (Aim 1). Next, we determine the necessity of the melanocortin 4 receptor (MC4R) in each of the subregions of the mPFC in obesity-related physiology, food intake, and cognitive behavior (Aim 2). Finally, we will demonstrate the functional effects of the putative circuit in feeding, metabolism, and cognitive behavior (Aim 3). All studies will be done in male and female mice due to known sexually dimorphic properties within the mPFC subregions and MC4R. The proposed studies seek to demonstrate a functional circuit between the melanocortinergic hypothalamic neurons and the mPFC subregion MC4R-expressing neurons that is at least partly responsible for pathogenesis and hyperphagia in obesity. Results from these studies will identify critical targets linking feeding behavior, cognitive function, and obesity, and provide new avenues for novel treatment.