title: Decreased neuroinflammation correlates to higher vagus nerve activity fluctuations in near-term ovine fetuses: a case for the afferent cholinergic anti-inflammatory pathway?
abstract: Neuroinflammation in utero may contribute to brain injury resulting in life-long neurological disabilities. The pivotal role of the efferent cholinergic anti-inflammatory pathway (CAP) in controlling inflammation, e.g., by inhibiting the HMGB1 release, via the macrophages' α7 nicotinic acetylcholine receptor (α7nAChR) has been described in adults, but its importance in the fetus is unknown. Moreover, it is unknown whether CAP may also exert anti-inflammatory effects on the brain via the anatomically predominant afferent component of the vagus nerve.
  
  
  
  We measured microglial activation in the ovine fetal brain near term 24 h after the umbilical cord occlusions mimicking human labor versus controls (no occlusions) by quantifying HMGB1 nucleus-to-cytosol translocation in the Iba1+ and α7nAChR+ microglia. Based on multiple clinical studies in adults and our own work in fetal autonomic nervous system, we gauged the degree of CAP activity in vivo using heart rate variability measure RMSSD that reflects fluctuations in vagus nerve activity.
  
  
  
  RMSSD correlated to corresponding plasma IL-1β levels at R = 0.57 (p = 0.02, n = 17) and to white matter microglia cell counts at R = -0.89 (p = 0.03). The insult increased the HMGB1 translocation in α7nAChR+ microglia in a brain region-dependent manner (p < 0.001). In parallel, RMSSD at 1 h post insult correlated with cytosolic HMGB1 of thalamic microglia (R = -0.94, p = 0.005), and RMSSD at pH nadir correlated with microglial α7nAChR in the white matter (R = 0.83, p = 0.04). Overall, higher RMSSD values correlated with lower HMGB1 translocation and higher α7nAChR intensity per area in a brain region-specific manner.
  
  
  
  Afferent fetal CAP may translate increased vagal cholinergic signaling into suppression of cerebral inflammation in response to near-term hypoxic acidemia as might occur during labor. Our findings suggest a new control mechanism of fetal neuroinflammation via the vagus nerve, providing novel possibilities for its non-invasive monitoring in utero and for targeted treatment.
authors.affiliation: Department of Obstetrics and Gynaecology, CHU Ste-Justine Research Centre, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada. mfrasch@uw.edu.|Department of Neurosciences, CHU Ste-Justine Research Centre, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada. mfrasch@uw.edu.|Animal Reproduction Research Centre (CRRA), Faculty of Veterinary Medicine, Université de Montréal, Montréal, QC, Canada. mfrasch@uw.edu.|Department of Obstetrics and Gynaecology, Lawson Health Research Institute, University of Western Ontario, London, ON, Canada. mfrasch@uw.edu.|Department of Obstetrics and Gynecology, University of Washington, 1959 NE Pacific St, Box 356460, Seattle, WA, 98195, USA. mfrasch@uw.edu.
authors.forename: M G
authors.initials: MG
authors.lastname: Frasch
authors.affiliation: Department of Obstetrics and Gynaecology, Lawson Health Research Institute, University of Western Ontario, London, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Szynkaruk
authors.affiliation: Department of Obstetrics and Gynaecology, Lawson Health Research Institute, University of Western Ontario, London, ON, Canada.
authors.forename: A P
authors.initials: AP
authors.lastname: Prout
authors.affiliation: Microscopy Imaging@Biotron, University of Western Ontario, London, ON, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Nygard
authors.affiliation: Department of Obstetrics and Gynaecology, CHU Ste-Justine Research Centre, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.|Department of Neurosciences, CHU Ste-Justine Research Centre, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Cao
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Veldhuizen
authors.affiliation: Department of Pathology, University of Western Ontario, London, ON, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Hammond
authors.affiliation: Department of Obstetrics and Gynaecology, Lawson Health Research Institute, University of Western Ontario, London, ON, Canada.|Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors.forename: B S
authors.initials: BS
authors.lastname: Richardson
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D003936:Diagnosis, Computer-Assisted; D004195:Disease Models, Animal; D004660:Encephalitis / Q000097:blood / Q000209:etiology* / Q000628:therapy*; D005260:Female; D005311:Fetal Hypoxia / Q000097:blood / Q000150:complications* / Q000628:therapy; D005333:Fetus; D005786:Gene Expression Regulation / Q000502:physiology; D024243:HMGB1 Protein / Q000378:metabolism; D006339:Heart Rate / Q000502:physiology; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008840:Microfilament Proteins; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012756:Sheep; D014630:Vagus Nerve / Q000196:embryology / Q000502:physiology*; D055536:Vagus Nerve Stimulation; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: C112986:AIF1 protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D008840:Microfilament Proteins; D016760:Proto-Oncogene Proteins c-fos; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: CHRNA7; Fetus; HMGB1; HRV; Labor; Microglia; RMSSD; Vagus