{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T20:39:55Z","timestamp":1788381595624,"version":"build-2803163510"},"posted":{"date-parts":[[2023,3,10]]},"group-title":"Physiology","reference-count":57,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,3,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Hirschsprung\u2019s disease (HSCR) is a congenital defect in which the enteric nervous system (ENS) does not develop in the distal bowel, requiring surgical removal of the portions of bowel without ENS ganglia (\u2018aganglionic\u2019) and reattachment of the \u2018normal\u2019 proximal bowel with ENS ganglia. Unfortunately, many HSCR patients have persistent dysmotility (e.g., constipation, incontinence) and enterocolitis after surgery, suggesting that the remaining bowel is not normal despite having ENS ganglia. Anatomical and neurochemical alterations have been observed in the ENS-innervated proximal bowel from HSCR patients and mice, but no studies have recorded ENS activity to define the circuit mechanisms underlying post-surgical HSCR dysfunction. Here, we generated a HSCR mouse model with a genetically-encoded calcium indicator to map the ENS connectome in the proximal colon. We identified abnormal spontaneous and synaptic ENS activity in proximal colons from GCaMP-Ednrb\n                  <jats:sup>-\/-<\/jats:sup>\n                  mice with HSCR that corresponded to motor dysfunction. Many HSCR-associated defects were also observed in GCaMP-Ednrb\n                  <jats:sup>+\/-<\/jats:sup>\n                  mice, despite complete ENS innervation. Results suggest that functional abnormalities in the ENS-innervated bowel contribute to post-surgical bowel complications in HSCR patients, and HSCR-related mutations that do not cause aganglionosis may cause chronic colon dysfunction in patients without a HSCR diagnosis.\n                <\/jats:p>","DOI":"10.1101\/2023.03.08.531750","type":"posted-content","created":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T20:35:36Z","timestamp":1678480536000},"source":"Crossref","is-referenced-by-count":2,"title":["Abnormal enteric nervous system and motor activity in the ganglionic proximal bowel of Hirschsprung\u2019s disease"],"prefix":"10.64898","author":[{"given":"Brian S.","family":"Edwards","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma S.","family":"Stiglitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian M.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9330-4454","authenticated-orcid":false,"given":"Kristen M.","family":"Smith-Edwards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023031404000679000_2023.03.08.531750v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2017.149"},{"key":"2023031404000679000_2023.03.08.531750v1.2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1900.sp000825"},{"key":"2023031404000679000_2023.03.08.531750v1.3","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1899.sp000752"},{"key":"2023031404000679000_2023.03.08.531750v1.4","doi-asserted-by":"publisher","DOI":"10.1097\/MOP.0000000000000210"},{"issue":"5","key":"2023031404000679000_2023.03.08.531750v1.5","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/s00383-004-1188-5","article-title":"Diagnosis and outcome of Hirschsprung\u2019s disease: does age really matter?","volume":"20","year":"2004","journal-title":"Pediatr Surg Int"},{"key":"2023031404000679000_2023.03.08.531750v1.6","doi-asserted-by":"publisher","DOI":"10.1007\/s00383-006-1783-8"},{"key":"2023031404000679000_2023.03.08.531750v1.7","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.1992.01420080068011"},{"key":"2023031404000679000_2023.03.08.531750v1.8","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-200009000-00009"},{"issue":"2","key":"2023031404000679000_2023.03.08.531750v1.9","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.jpedsurg.2016.11.023","article-title":"Functional outcomes in Hirschsprung disease: A single institution\u2019s 12-year experience","volume":"52","year":"2017","journal-title":"J Pediatr Surg"},{"issue":"8","key":"2023031404000679000_2023.03.08.531750v1.10","doi-asserted-by":"crossref","first-page":"822","DOI":"10.4240\/wjgs.v13.i8.822","article-title":"Persistent bowel dysfunction after surgery for Hirschsprung\u2019s disease: A neuropathological perspective","volume":"13","year":"2021","journal-title":"World J Gastrointest Surg"},{"key":"2023031404000679000_2023.03.08.531750v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-1838(00)00127-2"},{"key":"2023031404000679000_2023.03.08.531750v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2003.12.004"},{"key":"2023031404000679000_2023.03.08.531750v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(97)00051-8"},{"key":"2023031404000679000_2023.03.08.531750v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2012.32"},{"key":"2023031404000679000_2023.03.08.531750v1.15","doi-asserted-by":"publisher","DOI":"10.1136\/gut.47.suppl_4.iv15"},{"key":"2023031404000679000_2023.03.08.531750v1.16","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00037.2013"},{"issue":"3","key":"2023031404000679000_2023.03.08.531750v1.17","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1113\/EP086077","article-title":"Network properties of interstitial cells of Cajal affect intestinal pacemaker activity and motor patterns, according to a mathematical model of weakly coupled oscillators","volume":"102","year":"2017","journal-title":"Exp Physiol"},{"key":"2023031404000679000_2023.03.08.531750v1.18","doi-asserted-by":"crossref","first-page":"328","DOI":"10.3389\/fphys.2018.00328","article-title":"Inhibitory Neural Regulation of the Ca (2+) Transients in Intramuscular Interstitial Cells of Cajal in the Small Intestine","volume":"9","year":"2018","journal-title":"Front Physiol"},{"key":"2023031404000679000_2023.03.08.531750v1.19","doi-asserted-by":"crossref","unstructured":"Baker SA , Drumm BT , Skowronek KE , Rembetski BE , Peri LE , Hennig GW , et al. Excitatory Neuronal Responses of Ca(2+) Transients in Interstitial Cells of Cajal in the Small Intestine. eNeuro. 2018;5(2).","DOI":"10.1523\/ENEURO.0080-18.2018"},{"key":"2023031404000679000_2023.03.08.531750v1.20","doi-asserted-by":"crossref","unstructured":"Baker SA , Leigh WA , Del Valle G , De Yturriaga IF , Ward SM , Cobine CA , et al. Ca(2+) signaling driving pacemaker activity in submucosal interstitial cells of Cajal in the murine colon. Elife. 2021;10.","DOI":"10.7554\/eLife.64099"},{"issue":"2","key":"2023031404000679000_2023.03.08.531750v1.21","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.jpedsurg.2020.04.002","article-title":"Pan-enteric neuropathy and dysmotility are present in a mouse model of short-segment Hirschsprung disease and may contribute to post-pullthrough morbidity","volume":"56","year":"2021","journal-title":"J Pediatr Surg"},{"issue":"5","key":"2023031404000679000_2023.03.08.531750v1.22","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.jpedsurg.2016.02.018","article-title":"Altered neurotransmitter expression profile in the ganglionic bowel in Hirschsprung\u2019s disease","volume":"51","year":"2016","journal-title":"J Pediatr Surg"},{"key":"2023031404000679000_2023.03.08.531750v1.23","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00420.2005"},{"key":"2023031404000679000_2023.03.08.531750v1.24","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00558.2007"},{"key":"2023031404000679000_2023.03.08.531750v1.25","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.12083"},{"key":"2023031404000679000_2023.03.08.531750v1.26","doi-asserted-by":"publisher","DOI":"10.1043\/0003-9985(2002)126&lt;0928:ADOICO&gt;2.0.CO;2."},{"issue":"1","key":"2023031404000679000_2023.03.08.531750v1.27","doi-asserted-by":"crossref","first-page":"e86100","DOI":"10.1371\/journal.pone.0086100","article-title":"Characterization of interstitial Cajal progenitors cells and their changes in Hirschsprung\u2019s disease","volume":"9","year":"2014","journal-title":"PLoS One"},{"issue":"12","key":"2023031404000679000_2023.03.08.531750v1.28","doi-asserted-by":"crossref","first-page":"6443","DOI":"10.1172\/JCI126584","article-title":"Intestinal proinflammatory macrophages induce a phenotypic switch in interstitial cells of Cajal","volume":"130","year":"2020","journal-title":"J Clin Invest"},{"issue":"1","key":"2023031404000679000_2023.03.08.531750v1.29","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.jcmgh.2021.08.016","article-title":"Unique Neural Circuit Connectivity of Mouse Proximal, Middle, and Distal Colon Defines Regional Colonic Motor Patterns","volume":"13","year":"2022","journal-title":"Cell Mol Gastroenterol Hepatol"},{"issue":"4","key":"2023031404000679000_2023.03.08.531750v1.30","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1053\/j.gastro.2020.09.030","article-title":"Sympathetic Input to Multiple Cell Types in Mouse and Human Colon Produces Region-Specific Responses","volume":"160","year":"2021","journal-title":"Gastroenterology"},{"issue":"2","key":"2023031404000679000_2023.03.08.531750v1.31","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1053\/j.gastro.2019.04.034","article-title":"Extrinsic Primary Afferent Neurons Link Visceral Pain to Colon Motility Through a Spinal Reflex in Mice","volume":"157","year":"2019","journal-title":"Gastroenterology"},{"key":"2023031404000679000_2023.03.08.531750v1.32","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/5.3.355"},{"key":"2023031404000679000_2023.03.08.531750v1.33","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/5.3.351"},{"issue":"3","key":"2023031404000679000_2023.03.08.531750v1.34","first-page":"303","article-title":"Endothelin receptor-mediated signaling in hirschsprung disease","volume":"5","year":"1996","journal-title":"Hum Mol Genet"},{"key":"2023031404000679000_2023.03.08.531750v1.35","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/5.3.347"},{"key":"2023031404000679000_2023.03.08.531750v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90016-7"},{"key":"2023031404000679000_2023.03.08.531750v1.37","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/3.8.1217"},{"key":"2023031404000679000_2023.03.08.531750v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90017-5"},{"issue":"3","key":"2023031404000679000_2023.03.08.531750v1.39","first-page":"568","article-title":"A genetic study of Hirschsprung disease","volume":"46","year":"1990","journal-title":"Am J Hum Genet"},{"key":"2023031404000679000_2023.03.08.531750v1.40","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420320204"},{"key":"2023031404000679000_2023.03.08.531750v1.41","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-27592-5_13"},{"key":"2023031404000679000_2023.03.08.531750v1.42","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2011.225938"},{"key":"2023031404000679000_2023.03.08.531750v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2012.12.006"},{"key":"2023031404000679000_2023.03.08.531750v1.44","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1097\/01.mpg.0000441925.75189.01","article-title":"Developmental and Postnatal Changes in the Enteric Nervous System","volume":"57","year":"2013","journal-title":"Journal of Pediatric Gastroenterology and Nutrition"},{"key":"2023031404000679000_2023.03.08.531750v1.45","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00092.2010"},{"key":"2023031404000679000_2023.03.08.531750v1.46","doi-asserted-by":"publisher","DOI":"10.1136\/gut.44.5.666"},{"issue":"4","key":"2023031404000679000_2023.03.08.531750v1.47","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.jpedsurg.2008.06.006","article-title":"A novel corrective pullthrough surgery in a mouse model of Hirschsprung\u2019s disease","volume":"44","year":"2009","journal-title":"J Pediatr Surg"},{"issue":"4","key":"2023031404000679000_2023.03.08.531750v1.48","first-page":"1339","article-title":"Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions","volume":"4","year":"2014","journal-title":"Compr Physiol"},{"key":"2023031404000679000_2023.03.08.531750v1.49","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1113\/jphysiol.1978.sp012248","article-title":"The sacral parasympathetic reflex pathway regulating colonic motility and defaecation in the cat","volume":"276","year":"1978","journal-title":"J Physiol"},{"key":"2023031404000679000_2023.03.08.531750v1.50","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0603-10.2010"},{"key":"2023031404000679000_2023.03.08.531750v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/0950-3528(88)90020-6"},{"issue":"Suppl 4","key":"2023031404000679000_2023.03.08.531750v1.52","first-page":"iv33","article-title":"Sympathetic input into the enteric nervous system","volume":"47 Suppl 4","year":"2000","journal-title":"Gut"},{"key":"2023031404000679000_2023.03.08.531750v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.12.002"},{"key":"2023031404000679000_2023.03.08.531750v1.54","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1999.0539m.x"},{"key":"2023031404000679000_2023.03.08.531750v1.55","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15937"},{"key":"2023031404000679000_2023.03.08.531750v1.56","doi-asserted-by":"crossref","unstructured":"Pan W , Rahman AA , Stavely R , Bhave S , Guyer R , Omer M , et al. Schwann Cells in the Aganglionic Colon of Hirschsprung Disease Can Generate Neurons for Regenerative Therapy. Stem Cells Transl Med. 2022.","DOI":"10.1093\/stcltm\/szac076"},{"issue":"6","key":"2023031404000679000_2023.03.08.531750v1.57","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1053\/j.gastro.2017.01.005","article-title":"Optogenetic Demonstration of Functional Innervation of Mouse Colon by Neurons Derived From Transplanted Neural Cells","volume":"152","year":"2017","journal-title":"Gastroenterology"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.03.08.531750","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:22:41Z","timestamp":1768450961000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.03.08.531750"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,10]]},"references-count":57,"URL":"https:\/\/doi.org\/10.1101\/2023.03.08.531750","relation":{},"subject":[],"published":{"date-parts":[[2023,3,10]]},"subtype":"preprint"}}