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

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2022 · $344,842

## Abstract

PROJECT SUMMARY
Reflexive motor behaviors of the intestine including peristalsis are controlled by the enteric nervous system
(ENS); a complex neural network embedded in the gut wall. Perturbations within the ENS contribute to the
development of dysmotility in irritable bowel syndrome, inflammatory bowel disease, and severe motility
disorders such as chronic intestinal pseudo-obstruction, but the mechanisms responsible for persistent
changes in enteric neural circuitry are unknown. Recent data show that enteric glia, non-neuronal cells that
surround enteric neurons, regulate neuronal excitability and contribute to 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 disease. This proposal tests the central hypothesis that
enteric glia are specialized to potentiate the activity of ascending excitatory neural pathways involved in normal
contractile motility, and that disruption of this regulatory system by inflammation contributes to neuronal
hyperexcitability. This dual hypothesis will be tested in two specific aims that utilize genetically encoded
calcium indicators to study neuron-glia interactions, 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 neuronal hyperexcitability following inflammation. Aim 1 will test the hypothesis that enteric glia
are specialized to sense excitatory neurons and potentiate ascending neural pathways involved in the
contractile phase of motility. Aim 1.1 will use genetically encoded calcium indicators to study glial recruitment
by polarized neural pathways in motility reflexes. Aim 1.2 will combine the chemogenetic activation of enteric
glia with neuronal and glial imaging using genetically encoded calcium indicators to test the hypothesis that glia
differentially affect subsets of enteric neurons. Aim 2 will test the hypothesis that glia contribute to neuronal
hyperexcitability following colitis by increasing positive feedback to excitatory neurons and by reducing
inhibitory feedback from inhibitory neurons. Aim 2.1 will study how altered interactions between glia and
excitatory neurons contribute to neuronal hyperexcitability following colitis. Aim 2.2 will use mutant mice and
selective drugs to study how glia contribute to neuronal hyperexcitability through interactions with inhibitory
neurons. The results of this study will provide novel insight into glial mechanisms that regulate the excitability
of enteric neural circuits. A better understanding of the glial mechanisms that regulate motility will facilitate the
development of therapeutics for dysmotility by revealing novel targets to modify gastrointestinal reflexes.

## Key facts

- **NIH application ID:** 10436828
- **Project number:** 5R01DK103723-08
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** BRIAN D. GULBRANSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $344,842
- **Award type:** 5
- **Project period:** 2019-05-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436828

## Citation

> US National Institutes of Health, RePORTER application 10436828, Regulation of enteric motor neurocircuits by enteric glia in health and disease (5R01DK103723-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10436828. Licensed CC0.

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