Abstract
Stress affects gastrointestinal (GI) function causing dysmotility, especially in disorders of gut-brain interactions (DGBI) patients. GI motility is regulated by the enteric nervous system (ENS), suggesting that stress alters ENS biology to cause dysmotility. While stress increases glucocorticoid levels through the hypothalamus-pituitary-adrenal axis, how glucocorticoids affect GI motility is not known. Glucocorticoid signaling reduces expression of specific transcriptional isoforms of brain-derived neurotrophic factor (BDNF) in the central nervous system, altering signaling through its receptor Tropomyosin-related kinase B (TrkB) to cause behavioral defects. However, since the nature of ENS-specific Bdnf isoforms and their response to glucocorticoids remains unknown, we are limited in studying how stress impacts the ENS to cause dysmotility. Here, in male and female mice, we establish that stress-responsive Bdnf isoforms that are transcriptionally regulated at exons 4 and 6 represent >85% of all Bdnf isoforms in the post-natal ENS, and that Bdnf and Ntrk2 (TrkB) are expressed by enteric neurons. We further show using male mice dosed with a synthetic glucocorticoid receptor (GR) agonist dexamethasone (Dexa), that increased glucocorticoid signaling in ENS significantly reduces the expression of Bdnf transcripts and protein and that it significantly reduces GI motility. Finally, by using HIOC, a specific synthetic agonist of TrkB, we observe that HIOC treatment significantly improved GI motility of a cohort of Dexa-treated male mice, when compared to Dexa-treated and HIOC-untreated mice. Our results implicate BDNF- TrkB signaling in the etiology of stress-associated dysmotility and suggest that TrkB is a putative therapeutic target for dysmotility in DGBI patients.