  The efferent and afferent effects of the vagus nerve on the developing brain
have remained enigmatic. Here we review the evidence of such effects on
microglial plasticity in the sheep model of human fetal development, one of the
most recognized and deployed models of human fetal physiology. We show that
vagotomy alters microglial phenotype and that this effect is hormetic under
conditions of mild systemic inflammation, as may occur antepartum with
chorioamnionitis. We present the methodology to assess not only biomarker-based
microglial activation but also the morphometric features of the microglia.
Together, these assessments provide a more comprehensive toolbox of glial
phenotypical characterizations, especially in the context of investigating the
locoregional vagal control of glial function. The presented findings support
the earlier discoveries in preclinical and clinical models of adult physiology
whereby vagotomy appeared neuroprotective for Parkinson disease, explained, at
least in part, by the effects on microglia. In addition, we present the
approach to measure and the findings on regional cerebral blood flow changes in
relation to vagus nerve manipulation. In summary, the body of evidence
underscores the importance of both the efferent and the afferent vagal
pathways, via the vagus nerve, in the programming of microglial phenotype in
the developing brain. The significance of these relationships for developing
and treating early susceptibility to neuroinflammatory and neurodegenerative
disorders in later life requires further studies.
