Regulation of enteric motor neurocircuits by enteric glia in health and disease

Michigan State University, East Lansing MI

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Abstract

PROJECT SUMMARY Experiencing gut inflammation imparts long-lasting effects on the neural control of gut motility that contribute to persistent gut motility issues in irritable bowel syndrome and inflammatory bowel disease. Intestinal motility is governed by neural circuits in the enteric nervous system (ENS) and changes in how enteric motility neurocircuits function play a central role in post-inflammatory gut dysfunction. The underlying mechanisms remain poorly understood. Enteric glia surround enteric neurons and regulate gut motility through effects on neuronal excitability and neuroinflammation. The overall goal of this proposal is to define how specialized interactions between enteric glia and neurons regulate motility and how alterations in those mechanisms contribute to post-inflammatory gut dysfunction. This proposal tests the central hypothesis that enteric gliotransmission regulates gut motor function through subtype-specific effects on enteric neurons and that inflammation provokes a switch in gliotransmission that disrupts neural control of gut motor functions. This dual hypothesis will be tested in two specific aims that utilize neuron subtype-targeted genetically encoded calcium indicators and glial chemogenetic actuators to study how glia modulate specific types of enteric neurons, and a post-inflammatory model of enteric neuroplasticity to study how glia contribute to ENS hyperexcitability following inflammation. Aim 1 will study the cell- and synapse-specificity of gliotransmission in propulsive motility neurocircuits by testing the hypothesis that enteric gliotransmission regulates propulsive motility through subtype-specific effects on enteric neurons. Aim 1.1 will involve cellular imaging experiments that combine neuron subtype-targeted GCaMP expression with glial cell activation using chemogenetics to test the hypothesis that enteric gliotransmission preferentially influences interneurons in propulsive motility reflexes. Aim 1.2 will use the DNBS colitis model to understand how changes to the nature and specificity of gliotransmission promote ENS hyperactivity following inflammation. Aim 2 will study how glia regulate colonic motor complex behavior by coordinating excitatory neurons. Aim 2.1 will use calcium imaging experiments in mice that express GCaMP in cholinergic neurons and chemogenetic actuators in glia to test the hypothesis that enteric gliotransmission mediated by S100B regulates rhythmic cholinergic neuron activity underlying colonic motor complexes. Aim 2.2 will test the hypothesis that a failure of this glial regulatory system contributes to uncoordinated colonic motor complex function following inflammation through effects on neuron and glial excitability. The results of this study will provide novel insight into glial mechanisms that regulate ENS circuits. A better understanding of the glial mechanisms that regulate motility will facilitate developing new therapeutics that modify ENS command of gut motility.