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Early Life Adversity in Rodent and Porcine Models Induces Enteric Cholinergic System Upregulation and Mast Cell Hyperplasia
Author(s) -
Pohl Calvin Seneca,
Fried David,
Gulbransen Brian,
Moeser Adam
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1047.2
Subject(s) - choline acetyltransferase , enteric nervous system , vesicular acetylcholine transporter , endocrinology , downregulation and upregulation , acetylcholinesterase , medicine , acetylcholine , cholinergic , mast cell , biology , cholinergic neuron , immunology , biochemistry , gene , enzyme
Early life adversity (ELA) is a major risk factor for development of functional gastrointestinal (GI) disorders (FGID's) later in life. Disturbances in enteric nervous system function play a central role in stress‐related GI disease associated with ELA, but the alterations in ENS function and phenotype are poorly understood. We addressed this issue by characterizing the changes in intestinal secretomotor neuron function and motility induced by ELA in the murine neonatal maternal separation (NMS) model and the porcine early weaning stress (EWS) model. Compared with normal‐handed (NH) control mice, adult, C57BL/6 mice previously exposed to NMS exhibited alterations in colonic motility characterize by increased strength (130%), duration (130%) and frequency (200%) of migrating motor complexes, ( p <0.001 ) . Using a combination of Ussing Chambers and electrical field stimulation, we found that NMS mice exhibited heightened ileal and colonic secretomotor neuron activity measured as delta short circuit current ( I sc ) (2 fold increase relative to NH controls, p <0.05). Quantitative PCR and Western blotting showed an upregulated (by 1.3 fold) expression of choline acetyltransferase (CHAT) and vesicular choline acetyltransferase (VACHT), both involved in acetylcholine synthesis and transport ( p< 0.05 ) . Choline transporter 1 (CHT1) and Acetylcholinesterase (ACHE) were unchanged in NMS mice. Mast cell tryptase was upregulated (by 1.6 fold) in colonic tissue of NMS mice compared to NH controls ( p <0.05). Similarly, juvenile and adult pigs that were previously subjected to EWS, exhibited 2–3 fold heightened ileal cholinergic‐mediated I sc responses ( p <0.05) that was more pronounced in female pigs compared with males. Coinciding with elevated cholinergic activity in EWS pigs were increased numbers of intestinal mast cells which were found in close‐proximity to submucosal and myenteric ganglia. Further, EWS pigs exhibited elevated mast cell mediator release compared to non‐stressed controls. Together, these studies demonstrate that ELA induces a persistent upregulation of proteins involved in acetylcholine synthesis and trafficking, which coincided with heightened motility, secretomotor function, and mast cell hyperplasia. The combination of heightened cholinergic signaling and mast cell hyperplasia and hyperactivity may contribute to the mechanism which links ELA to adult FGIDs. Future studies will investigate possible cholinergic nerve, mast cell nerve circuits that may develop and induce intestinal dysfunction and increased GI disease risk following ELA. Support or Funding Information Michigan State University Matilda Wilson Endowment; NICHD R01 HD072968 AJM; NIDDK R03 DK097462 AJM; NIDDK K08 DK084313 AJM