Project Summary Obesity is a major public health problem. Modulating energy expenditure through behavioral or pharmacological intervention is a key strategy to alter energy balance and battle obesity and metabolic diseases. Targeting molecular pathways underlying the cold-induced non-shivering thermogenesis has been an important and promising strategy to elevate energy expenditure in animals and humans. However, it is well- known that mammals compensatorily increase food intake due to higher expenditure, such as in the cold. While it is generally agreed that the brain centrally controls this feedback, the neural mechanism underlying this coupling is largely unknown. Here, we propose to systematically investigate the behavioral, metabolic, and circuit basis of cold-induced feeding. By combining calorimetry and behavioral modeling, our preliminary study demonstrated that cold-induced increase of food intake involves dynamic bi-directional behavioral switches and is mediated by non-canonical feeding circuits. Using whole-brain clearing, lightsheet imaging, and c-fos activity screening, we identified a group of nuclei at the ventral midline thalamus (vMT) associated with cold- induced feeding. The central hypothesis is that the vMT nuclei are activated by the elevated energy expenditure and recruit downstream targets to mediate cold-induced feeding. The first aim is to use in vivo calcium imaging to measure the endogenous activity of vMT in relationship to cold and feeding behaviors. The second aim is to use optogenetic and chemogenetic approaches to determine the causal significance of vMT neural activity in driving cold-induced feeding. The third aim combines anatomical mapping and functional manipulation to study how vMT integrates into the well-established feeding circuits in hypothalamic and limbic systems. The completion of these studies will provide a new understanding of the coupling between energy expenditure and intake in the brain, bringing many opportunities to leverage these mechanisms to maximize and maintain the metabolic benefits from targeting energy expenditure.