Energy homeostasis is tightly regulated by the central nervous system which controls food intake and energy expenditure and the hypothalamus is the key neural circuit for energy homeostasis. Dysfunctions in hypothalamic circuitry result in obesity/anorexia and impairment of cognitive function. Information flow within neural circuitry relies on synaptic transmission, i.e. calcium-mediated synaptic vesicle release. The long-term goal of my laboratory is to understand the neural circuitry that controls feeding and obesity in the human brain. The hypothalamus is enriched with neuropeptides but has a complicated synaptic wiring pattern. To understand the cell type- and pathway-specific regulations of synaptic transmission by hormones controlling obesity and feeding such as leptin, synaptic outputs (axonal projections) from hypothalamus will be identified using neural tracers including fluorescent beads or viral-mediated expression of fluorescent proteins; synaptic inputs to hypothalamus will be identified using optogenetic manipulations. High-resolution electrophysiological and optical methods will be used for the readout of calcium triggered synaptic vesicle release. Molecular perturbations including mouse genetics will be utilized to manipulate specific proteins involved in synaptic functions, neuropeptide release and regulations. Research areas in my lab are to investigate several fundamental questions including: 1) how peptidergic hormones including leptin, ghrelin and insulin, and neuropeptides including neuropeptide Y and proopiomelanocortin regulate synaptic functions with defined synaptic connections within the hypothalamic region in control and obese states, and to evaluate the behavioral outcomes in animals; 2) to unravel the molecular mechanisms of peptidergic regulation of synaptic functions in the hypothalamus; 3) to elucidate the molecular mechanisms of neuropeptide release in hypothalamic neurons regulated by peptidergic hormones; and finally 4) to establish a cellular-based model using derived human neurons from pluripotent stem cells or fibroblasts for study of hormonal regulation on synaptic functions in human brain.
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