Interrogating Ventral Pallidal Circuits as a Therapeutic Target for Obesity

PROJECT SUMMARY Over two-thirds of Americans are overweight or obese, with the recent rise in obesity prevalence strongly correlated with widespread access to palatable, energy-dense foods. These foods, typically highly processed and rich in calories, salt, sugar, and fat, exhibit extraordinary appetitive properties, leading to pathological overeating. For instance, palatable foods can override the body's satiety signals, while regular consumption can cause taste desensitization, making healthier options taste bland in comparison. Furthermore, it is hypothesized that the reinforcing properties of such foods activate reward circuitry, leading to a dissociation between caloric need (the number of calories required to maintain stable weight) and food intake (the number of calories consumed), which ultimately results in obesity. While numerous brain areas are involved in appetite control, this research focuses on the ventral pallidum (VP), a major relay structure in the reward system which plays a key role in processing the pleasure and motivation associated with ingestive behavior. However, the potential to manipulate VP activity to suppress or reverse excessive body weight remains unexplored. In this proposal, I plan to use a multifaceted approach to investigate VP neuronal responses during palatable food consumption and how this activity contributes to pathological consumption behavior. Since foods high in dietary fat disproportionately affect satiety and induce hyperphagia in humans and other animals, I hypothesize that VP neurons are more strongly activated by fat consumption than carbohydrate consumption. To test this, I will record population calcium signals from VP neurons in head-fixed mice consuming mixtures with varying proportions of fats and carbohydrates. With the long-term goal of evaluating whether ventral pallidal manipulations can serve as a viable therapeutic strategy for obesity treatment, I will employ a chronic inactivation strategy on VP neurons and assess its effectiveness in producing weight loss in obese animals. Understanding the neural basis of obesity pathology, and specifically why fat-enriched foods induce hyperphagia, will inform the development of future therapeutics aimed at achieving substantial weight loss in individuals with obesity.