Decreased neuroinflammation correlates to higher vagus nerve activity fluctuations in near-term ovine fetuses: a case for the afferent cholinergic anti-inflammatory pathway?

Abstract

BackgroundNeuroinflammation 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.MethodsWe 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.ResultsRMSSD 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.ConclusionsAfferent 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0567-x) contains supplementary material, which is available to authorized users.

Neuromonitoring of delirium with quantitative pupillometry in sedated mechanically ventilated critically ill patients

“…The autonomous nervous system, through cholinergic activation, has an innate counterregulatory role against increased neuro-inflammation [3], via an inhibition of cytokine release and increased inflammatory neurotransmitters [4][5][6][7]. Growing evidence demonstrates that reduced functioning of the cholinergic antiinflammatory reflex is implicated in the pathophysiology of secondary critical illness-related brain dysfunction [8], which in turn can be attenuated by therapeutic vagus nerve stimulation [9][10][11][12][13].…”

Vagus Nerve Stimulation for Treatment of Inflammation: Systematic Review of Animal Models and Clinical Studies

“…Lastly, we found no studies on developing organisms, from perinatal to juvenile age, where putative salutary effects of VNS would be investigated, although CAP is active as early as in the late-gestation fetus (55,56). There is a continued need to provide better treatments for sepsis, severe infection and cardiovascular compromise in early life (55,57).…”

Neuroautonomic activity evidences parturition as a complex and integrated neuro–immune–endocrine process

“…Other contributions suggest that the fetal HRV analysis can track the temporal profile of fetal inflammation and discriminate between normal and inflammatory processes across time . For example, a decreased neuroinflammation has been correlated with higher activity of the vagus nerve fluctuations in near‐term ovine fetuses . Thus, these results highlight a potential role of the fetal HRV analysis to explore noninvasively the inflammatory response in the perinatal period.…”

“…In the same line, low vagal activity was associated with impaired stress recovery of TNF‐α levels; this study concluded that the vagus strongly affects the cardiovascular function and may play an inhibitory role in the regulation of inflammatory processes and HPA activity. In addition, the identification of an increased vagal cholinergic activity to suppress cerebral inflammation in response to hypoxic acidemia provides evidence of a neuroimmunological link in near‐term ovine fetuses . Hence, maternal and fetal HRV analysis could be considered as a mean to explore and understand the interactions of the neuro‐immuno‐endocrine system at parturition according to the vagal nerve activation.…”