Efferent vagal modulation of neuropod cells in the small intestine

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ABSTRACT Functional gastrointestinal (GI) diseases are the most common diagnoses in gastroenterology. Such disorders, like irritable bowel syndrome or functional dyspepsia, are recognized by altered GI sensitivity and motility. Though the pathophysiology is complex, a conserved feature is the bidirectional alteration in brain- gut signaling. Thus, these are classified as disorders of brain-gut interaction. While the vagus nerve is the main brain-gut link, how the brain relays neural signals that modulate GI epithelial sensory function is unknown. My long-term career goal is to document how neural circuits originating from the brain alter the gut’s ability to sense nutrients. With the support of the NIH Mentored Research Scientist Development Award — K01, the objective of this proposal is to delineate a brain-to-gut neural circuit that could be used to alter sensory transduction at the gut epithelium. This will be accomplished in three aims: Aim 1. Determine the neurotransmitters and hormones released by intestinal sensory cells in response to excitatory neurotransmitter stimulation. An in vitro organoid and sorted single cell assay will be used to measure release in culture. This aim will demonstrate that an excitatory neurotransmitter can stimulate vesicular release in enteroendocrine cells. Aim 2. Pair vagal stimulation with sensory epithelial cell calcium imaging and electrophysiology to evaluate the functional connectivity of vagal neurons synapsing onto intestinal sensory cells. This aim will demonstrate a functional connection where neurons increase the excitability of sensory cells in the proximal small intestine. Aim 3. Utilize both retrograde (post- to pre-synapse) rabies virus and anterograde (pre- to post- synapse) herpes simplex virus to trace a mono-synaptic connection between the brainstem and intestinal sensory epithelial cells. This aim will establish an anatomical map for how the brainstem is connected to neuropod cells. Identifying functional neural circuits connecting the brain and the gut will enable the understanding of the mechanisms behind visceral hypersensitivity. Together with my mentoring team, we have designed this project to provide me with the necessary research and professional training for me to excel as an independent investigator in the field of sensory neurogastroenterology.