PROJECT SUMMARY Obesity is a common, serious, and costly chronic disease that continues to increase in the world. Understanding the causes and determinants of obesity is a critical step toward developing effective policies and treatments to prevent this pandemic. The fundamental cause of obesity and overweight is an imbalance of energy homeostasis between calorie consumption and expenditure. Energy homeostasis is strictly regulated by the central nervous system, and the hypothalamus is a brain region thought to play a critical role in the regulation of energy balance. The perifornical area of the anterior hypothalamus (PeFAH) was identified in 2015 and its function is unknown. The PeFAH has extensive extracellular structures, perineuronal nets (PNNs), to enmesh GABAergic neurons. I found that chronic disruption of PNNs in the PeFAH decreases the excitability of GABAergic neurons and prevents high-fat diet induced weight gain and fat mass accumulation. The first objective of this proposal is to use loss-of-function and gain-of-function model to determine the functional relevance of PeFAH PNNs in energy homeostasis in mice fed with high-fat diet. The second objective is to determine how PNNs regulate excitability/synaptic activity of GABAPeFAH neurons, and I will also use pharmacological, chemogenetic and genetic methods to further investigate the possible orexigenic role of GABAPeFAH neurons in energy homeostasis. The proposed studies are expected to substantially advance the understanding about the newly discovered brain region in regulation of feeding behavior and metabolic process in general. They could be novel therapeutic targets for the treatment or prevention of obesity or overeating.