Deconstructing brainstem circuits for visceral senses

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PROJECT SUMMARY/ABSTRACT The ability to tightly control metabolic homeostasis is critical for animal survival. The internal sensory nervous system monitors the status of organs, providing feedback signals that enable the brain to maintain homeostasis by executing behavioral and physiological responses. For example, the system detects and encodes gastrointestinal cues signaling the quality and quantity of food ingested during a meal to control feeding behavior, digestive physiology, and whole-body metabolism. Dysregulation of internal sensory systems that monitor the digestive system can lead to various diseases, including obesity, diabetes, and anorexia. The internal sensory gateway in the brainstem, the nucleus of the solitary tract (NTS), receives inputs from the gastrointestinal, respiratory, and cardiovascular systems through the vagus nerve and other neural/humoral pathways. In turn, the NTS projects to diverse higher-order brain regions to generate our perceptions of satiety, hunger, nausea, and visceral pain. Despite the importance of internal sensory systems in health and disease, how neural circuits process visceral signals to regulate behavior and physiology is vastly understudied. Disentangling the highly interconnected brainstem neurons requires a comprehensive analysis of the anatomy, sensory coding, and function of the NTS network to understand the circuit components that mediate individual visceral senses. In Dr. Stephen Liberles’ lab, my initial postdoctoral work deciphered the sensory representations of bodily cues in the NTS. In this proposal, the goal is to determine how internal sensory information, after being processed in the NTS, is sorted into downstream brain regions to control specific aspects of behavior and physiology. First, the neuroanatomical logic by which NTS projections are organized will be investigated (Aim 1). Second, visceral cues transmitted by each projection will be determined using in vivo calcium imaging of NTS projection neurons (Aim 2). Last, the functional roles of NTS projections in controlling behavior and autonomic physiology will be established, with the focus on pathways that mediate physiological satiation (Aim 3). Research in this proposal will be conducted under the guidance of Dr. Stephen Liberles, who pioneered the study of viscerosensory neurons in the vagus nerve using genetic approaches, Dr. Clifford Saper, a leading scientist in the neuroanatomy of the viscerosensory system, and Drs. Bradford Lowell and Eleftheria Maratos-Flier, experts in neural control of appetite and energy metabolism. This proposal will establish a functional atlas of NTS projection neurons in visceral senses, providing insights into our understanding of the neuro-circuitry underlying metabolic homeostasis and strategies to develop targeted treatments for metabolic and viscerosensory disorders.