GABAPVp-originated neural circuits mediate metabolic benefits during cold exposure

PROJECT SUMMARY Despite the tremendous efforts in obesity research, pharmacological interventions that solely suppress appetite alone have proven largely ineffective in addressing this global health issue. Therefore, increasing energy expenditure has emerged as an alternative means to combat the obesity epidemic. Emerging evidence suggests that cold exposure is a promising approach to alleviate obesity and related metabolic disorders, but the neurobiological mechanisms mediating cold response remain poorly understood. In my pilot studies, I demonstrated that cold exposure evokes a profound activation of neurons in the posterior periventricular hypothalamic nucleus (PVp), most of which are GABAergic. I further showed that activation of GABAergic neurons in the PVp (GABAPVp neurons) increases both food intake and energy expenditure. Strikingly, repeated activations of these GABAPVp neurons resulted in improved glucose tolerance and insulin sensitivity, despite the fact that mice constantly ate more. Together, I developed a hypothesis that GABAPVp-originated neural circuits mediate metabolic benefits during cold exposure. The K99 phase will focus on unravelling the physiological relevance of cold-sensitive PVp neurons in energy and thermal homeostasis. I will use intersectional genetics to dissect the functional relevance of different PVp subsets on energy and thermal regulations during cold exposure. In addition, I will employ the GRIN lens calcium imaging system to monitor the response to cold exposure and feeding in individual GABAPVp neurons. During the R00 phase, I will utilize the techniques and the problem-solving experience I acquire from the K99 phase to identify the downstream targets that mediate the effects of GABAPVp neurons and the cold-sensor. I will combine the Cre-loxP, Flpo-Frt strategies and retrograde viral vectors to determine the contributions of the lateral periaqueductal gray (LPAG) and lateral parabrachial nucleus (LPBN) to energy and thermal homeostasis during cold exposure. I will also assess the effects of Kcnk2 in GABAPVp neurons on cold-sensing as well as energy and thermal balance. The K99 phase will provide an ideal training opportunity to equip me with essential techniques, knowledge, and problem-solving skills, which will prepare me for the R00 phase of research and growing into an independent researcher focusing on neural mechanisms of obesity and energy balance.