7. Project Summary: The proposal describes a five-year plan for training Dr. Li Ye to achieve his goal to become an independent investigator in the central regulation of metabolism. The training and career development plan includes a compelling research project, training in laboratory techniques and didactic scientific and career development seminars and courses. The applicant has more than a decade of experiences working in both molecular metabolism and systems neurosciences. During his Ph.D., Dr. Ye was trained with Dr. Bruce Spiegelman, a well-recognized leader in the field of obesity and diabetes. His previous findings in metabolic research have been published in many high-impact journals and have been then cited near 4,000 times in the subsequent works of his peers. During the proposed training, Dr. Karl Deisseroth, a leading expert in neurosciences will mentor the applicant’s scientific and career development. Dr. Deisseroth has trained numerous prominent scientists who now hold faculty positions in academic institutions. In addition, an advisory committee with highly regarded expertise in hypothalamic and feeding research (Dr. Luis de Lecea and Dr. Brad Lowell) will provide the applicant scientific advice and career guidance. The overall goal of the project is to study neural mechanisms responsible for coordinating food intake and metabolic demands. The obesity epidemic is putting an enormous burden on the public health systems, by contributing to the increased prevalence of type 2 diabetes, cardiovascular and neurodegenerative diseases. Obesity is a result of energy imbalance, in which energy consumption chronically exceeds the expenditure. There are two types of feeding, one driven by metabolic need and the other by the hedonic aspect of palatable food. The former is mainly regulated by the hypothalamic and hindbrain structures that are responsive to peripheral hormonal signals such as leptin, insulin, and ghrelin. The latter is predominantly controlled by the reward systems including the mesolimbic pathway and dopamine signaling. Preliminary studies suggested these systems converge in the lateral hypothalamus area (LH). Dissecting the circuit, cellular and molecular bases separating these two systems in the LH is key to understanding the central control of energy balance and its dysfunction during obesity, however, differentiating intermingled neural ensembles within a brain region has been difficult. In his early postdoctoral work, the candidate has developed a series of CLARITY and optogenetics-based technologies with sufficient throughput to map brain-wide connectivity as well as with the ability to retain molecular information at the single cell level to distinguish intermingled neuronal populations. Using these tools, the candidate has successfully dissected two anatomically intermingled but functionally distinct ensembles representing opposite valences in the medial prefrontal cortex. These recent advances in systems neuroscience ...