Animals have a remarkable ability to restore metabolic homeostasis after a challenge to their internal state. In order to maintain energy balance after a meal, the composition and quantity of ingested food needs to be closely monitored to coordinate the physiological responses of visceral organs. Dysregulation of this process leads to metabolic disease like obesity and diabetes. However, how sensory signals of nutritional state are detected and processed to generate metabolic commands is poorly understood. Vagal sensory neurons innervate the gut and are poised to detect diverse interoceptive cues. My postdoctoral work in Dr. Zachary Knight's lab has generated a cellular map of vagal sensory neurons that links their molecular identity to their target organ innervations and putative gut signals. This work provided a roadmap for the use of genetic tools to manipulate vagal subtypes with high specificity. In the mentored phase of this grant, I will build upon my postdoctoral discoveries by investigating how vagal sensory neurons regulate autonomic responses to achieve metabolic homeostasis (Aim 1). These mentored experiments will allow me to gain deep understanding of metabolic regulation and autonomic physiology, as well as to acquire additional surgical skills to manipulate the GI tract. The target of vagal neurons is the nucleus tractus solitarius (NTS), a key metabolic center that integrates neural and circulating humoral signals and generates complex physiological and behavioral commands to maintain energy balance. In the independent phase of this grant, I will build upon my graduate and postdoctoral training to further investigate how the downstream neuronal circuits in the NTS integrate and process interoceptive signals, and how they generate output commands to drive metabolic responses (Aim 2 and Aim 3). This grant will allow me to expand my current experimental and intellectual skills and develop additional expertise in metabolic regulation as well as electrophysiology guided circuit mapping, under the guidance of my advisory committee who are expertise in those fields. This will further link my sensory neurobiology skillset to the study of physiologic function and advance my career goal of being an independent researcher.
This project focuses on addressing a fundamental question about how nutritional signals are detected and processed by the brain to maintain metabolic homeostasis. Building on recent technical advances in the genetic identification of cell types and the in vivo recording of their activity, this project aims to answer how the diverse vagal sensory and downstream NTS neurons encode gut-derived signals and drive physiological responses to maintain energy homeostasis.
