title: Early life adversity in piglets induces long-term upregulation of the enteric cholinergic nervous system and heightened, sex-specific secretomotor neuron responses.
abstract: BACKGROUND
  Early life adversity (ELA) is a risk factor for the later-life onset of gastrointestinal (GI) diseases such as irritable bowel syndrome (IBS); however, the mechanisms are poorly understood. Here, we utilized a porcine model of ELA, early weaning stress (EWS), to investigate the influence of ELA on the development and function of the enteric nervous system (ENS).
  
  
  METHODS
  Female and castrated male (Male-C) piglets were weaned from their sow either at 15 days of age (EWS) or 28 days of age (late weaning control, LWC). At 60 and 170 days of age, ileal mucosa-submucosa preparations were mounted in Ussing chambers and veratridine- and corticotropin releasing factor (CRF)-releasing factor-evoked short circuit current (Isc ) responses were recorded as indices of secretomotor neuron function. Enteric neuron numbers and the expression of select neurotransmitters and their receptors were also measured.
  
  
  RESULTS
  Compared with LWC pigs, female, but not Male-C EWS, pigs exhibited heightened veratridine-induced Isc responses at 60 and 170 days of age that were inhibited with tetrodotoxin and atropine. Ileum from EWS pigs had higher numbers of enteric neurons that were choline acetyltransferase positive. Markers of increased cholinergic signaling (increased acetylcholinesterase) and downregulated mucosal muscarinic receptor 3 gene expression were also observed in EWS pigs.
  
  
  CONCLUSIONS
  This study demonstrated that EWS in pigs induces lasting and sex-specific hypersensitivity of secretomotor neuron function and upregulation of the cholinergic ENS. These findings may represent a mechanistic link between ELA and lifelong susceptibility to GI diseases such as IBS.
authors.affiliation: Comparative Biomedical Sciences Program, North Carolina State University, College of Veterinary Medicine, Raleigh, NC, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Medland
authors.affiliation: Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Pohl
authors.affiliation: Department of Population Health and Pathobiology, North Carolina State University, College of Veterinary Medicine, Raleigh, NC, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: Edwards
authors.affiliation: Department of Population Health and Pathobiology, North Carolina State University, College of Veterinary Medicine, Raleigh, NC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Frandsen
authors.affiliation: Department of Population Health and Pathobiology, North Carolina State University, College of Veterinary Medicine, Raleigh, NC, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bagley
authors.affiliation: Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Gastrointestinal Stress Biology Laboratory, Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA.|Neuroscience Program, Michigan State University, East Lansing, MI, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Moeser
mesh_terms: D000818:Animals; D059329:Cholinergic Neurons / Q000378:metabolism*; D004195:Disease Models, Animal; D017615:Enteric Nervous System / Q000378:metabolism*; D005260:Female; D043183:Irritable Bowel Syndrome / Q000378:metabolism; D008297:Male; D009046:Motor Neurons / Q000378:metabolism*; D012737:Sex Factors; D013315:Stress, Psychological / Q000378:metabolism*; D013552:Swine; D015854:Up-Regulation; D014886:Weaning
keywords: cholinergic neurons; early life adversity; enteric nervous system development; irritable bowel syndrome; porcine model