{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:59:18Z","timestamp":1785416358190,"version":"3.56.0"},"posted":{"date-parts":[[2024,12,17]]},"group-title":"Neuroscience","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T00:00:00Z","timestamp":1734393600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01AG066768"],"award-info":[{"award-number":["R01AG066768"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21AG072107"],"award-info":[{"award-number":["R21AG072107"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Diacomp Foundation Pilot Award"],"award-info":[{"award-number":["Diacomp Foundation Pilot Award"]}],"id":[{"id":"https:\/\/ror.org\/012mef835","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Maryland Genetics, Epidemiology, and Medicine training program"],"award-info":[{"award-number":["Maryland Genetics, Epidemiology, and Medicine training program"]}],"id":[{"id":"https:\/\/ror.org\/01d35cw23","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32GM148383"],"award-info":[{"award-number":["T32GM148383"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Harvard Digestive Disease Core","award":["Pilot Award"],"award-info":[{"award-number":["Pilot Award"]}]},{"name":"Walter Benjamin Fellowship","award":["528835020"],"award-info":[{"award-number":["528835020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Stress is a key contributor to gastrointestinal (GI) dysmotility, particularly in patients with disorders of gut-brain interactions (DGBI). Since GI motility is governed by the enteric nervous system (ENS), stress may act by altering ENS function. While stress activates glucocorticoid signaling via the hypothalamic-pituitary-adrenal axis, the impact of stress-mediated glucocorticoid signaling on ENS biology remains poorly understood. In the central nervous system, glucocorticoids reduce specific isoforms of brain-derived neurotrophic factor (BDNF), impairing signaling through its receptor, TrkB, and contributing to behavioral dysfunction. However, the identity of ENS-specific\n                  <jats:italic>Bdnf<\/jats:italic>\n                  isoforms, their glucocorticoid sensitivity, and the effect of enhanced TrkB signaling on GI motility in stressed animals has not been characterized. Here, using male and female mice, we show that &gt;85% of post-natal ENS\n                  <jats:italic>Bdnf<\/jats:italic>\n                  transcripts are glucocorticoid-responsive isoforms. We also demonstrate that both BDNF and its receptor TrkB (\n                  <jats:italic>Ntrk2<\/jats:italic>\n                  ) are expressed by enteric neurons. In male mice, stress and administration of dexamethasone\u2014a synthetic glucocorticoid receptor (GR) agonist\u2014cause GI dysmotility, which we demonstrate is associated with significantly reduced\n                  <jats:italic>Bdnf<\/jats:italic>\n                  transcripts in the longitudinal muscle \u2013 myenteric plexus (LM-MP) tissue\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Dexamethasone exposure also represses\n                  <jats:italic>Bdnf<\/jats:italic>\n                  transcript and mature protein levels in LM-MP tissue\n                  <jats:italic>in vitro<\/jats:italic>\n                  . Notably, treatment with HIOC, a selective TrkB agonist, rescues GI transit defects in dexamethasone-treated animals. These findings identify BDNF-TrkB signaling as a key modulator of stress-induced ENS dysfunction and highlight TrkB as a promising therapeutic target for GI dysmotility in DGBI.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance statement<\/jats:title>\n                  <jats:p>\n                    How stress causes gastrointestinal (GI) dysmotility is not well understood. GI motility is regulated by the enteric nervous system (ENS), which is responsive to brain-derived neurotrophic factor (BDNF), which signals through its receptor tropomyosin related kinase B (TrkB). By altering glucocorticoid signaling, stress modulates brain\u2019s BDNF levels to cause behavioral changes. However, if this pathway is similarly responsible for stress\u2019s effects on GI dysmotility is not well understood. Here, by identifying the nature of ENS-specific\n                    <jats:italic>Bdnf<\/jats:italic>\n                    isoforms, studying their response to stress and glucocorticoid signaling, and testing the effect of a TrkB agonist to improve gut motility in a model of glucocorticoid-driven dysmotility, we implicate altered BDNF-TrkB signaling as an important mechanism driving stress-associated dysmotility.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.12.13.628260","type":"posted-content","created":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T12:32:01Z","timestamp":1735734721000},"source":"Crossref","is-referenced-by-count":4,"title":["Reduced enteric BDNF-TrkB signaling drives stress-dependent glucocorticoid-mediated GI dysmotility"],"prefix":"10.64898","author":[{"given":"Jared","family":"Slosberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivas N.","family":"Puttapaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippa","family":"Seika","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Min","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alpana","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainsleigh","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2298-0623","authenticated-orcid":false,"given":"Subhash","family":"Kulkarni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025100617301885000_2024.12.13.628260v3.1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.21139"},{"key":"2025100617301885000_2024.12.13.628260v3.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.69.9.2668"},{"key":"2025100617301885000_2024.12.13.628260v3.3","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4886(91)90082-N"},{"key":"2025100617301885000_2024.12.13.628260v3.4","doi-asserted-by":"crossref","first-page":"e59452","DOI":"10.1371\/journal.pone.0059452","article-title":"Ex vivo neurogenesis within enteric ganglia occurs in a PTEN dependent manner","volume":"8","year":"2013","journal-title":"PLoS One"},{"key":"2025100617301885000_2024.12.13.628260v3.5","doi-asserted-by":"publisher","DOI":"10.1242\/dev.121.8.2461"},{"key":"2025100617301885000_2024.12.13.628260v3.6","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2007.131839"},{"key":"2025100617301885000_2024.12.13.628260v3.7","doi-asserted-by":"crossref","unstructured":"Bonfiglio F , Liu X , Smillie C , Pandit A , Kurilshikov A , Bacigalupe R , Zheng T , Nim H , Garcia-Etxebarria K , Bujanda L et al (2021) GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome. 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