The role of sympathetic signaling in inflammation-induced colon dysfunction and recovery

PROJECT SUMMARY Inflammatory bowel disease is characterized by remitting and relapsing bouts of intestinal inflammation and symptoms of abdominal pain, dysmotility, and autonomic dysfunction persist beyond the periods of active inflammation. Evidence suggests that neural pathways of the Gut-Brain Axis, particularly the sympathetic nervous system, are involved in pathophysiology, but until recently technical restrictions have limited the ability to fully understand the underlying neural circuit mechanisms. Therefore, the proposed training and research plans are focused on developing the Applicant’s expertise in sympathetic regulation of gastrointestinal function in health and disease. The training plan focuses on development of innovative technical skills and comprehensive career mentorship with the goal of providing the Applicant a complete set of skills necessary to develop into an independent scientist investigating the Gut-Brain Axis. The research plan complements this training by investigating how sensory-sympathetic neural pathways regulate the outcomes of colitis and recovery, specifically delineating the mechanisms used by two distinct circuits innervating the colon: (1) extrinsic primary afferent neuron (ExPAN)-spinal-sympathetic pathways and (2) intestinofugal afferent neuron (IFAN)-sympathetic pathways. This will be achieved through two Specific Aims utilizing innovative ex vivo imaging techniques with optogenetic reporters in intact sensory-sympathetic colon circuits, advanced in vivo chemogenetic approaches, and cutting-edge in vitro systems with patient-derived organoids and microfluidic devices. Aim 1 will define the changes in ExPAN- and IFAN-mediated activation of sympathetic neurons in the prevertebral ganglia (PVG) during active colon inflammation and after recovery. Aim 2 will determine the role of PVG sympathetic neurons for dysmotility and mucosal healing in colitis. The proposed research and training will significantly advance the applicant's expertise in cutting-edge techniques and technologies related to gut-brain signaling, while uncovering novel mechanisms that address a critical gap in our understanding of sympathetic regulation in colitis.