Neonatal inflammation induces lasting sex- and region-dependent microglia activation and sex-dependent impairments in chemoreflexes

Neonatal inflammation is common and has lasting detrimental consequences for the health of the adult nervous system, including on the neural control of breathing. Our previous work demonstrated that neonatal inflammation abolished adult respiratory motor plasticity; yet, the mechanisms underlying this impairment or the broader impact of neonatal inflammation on control of breathing were unknown. Since microglia are key immune cells in the brain and contribute to lasting sex-specific disruptions in nonrespiratory behaviors, we hypothesized that neonatal inflammation would induce lasting sex-dependent activation of adult microglia in respiratory control regions and contribute to broader breathing impairments. In support of this hypothesis, neonatal inflammation increased adult male medullary microglia number and TNF-α gene expression. In adult females, microglia number was unchanged, but neonatal inflammation increased female medullary microglial IL-6 gene expression. Surprisingly, changes in adult microglia were confined to the medulla and cortex, with no changes in ventral cervical spinal microglia, suggesting that the origins of impaired respiratory motor plasticity after neonatal inflammation are likely outside the spinal cord. Neonatal inflammation also augmented adult male hypercapnic ventilatory responses and hypoxic ventilatory responses, and decreased sighs in females, consistent with neonatal inflammation increasing adult risks for ventilatory control disorders. Thus, lasting increases in microglia number and inflammatory gene expression likely contribute to abolished adult respiratory motor plasticity after neonatal inflammation, with distinct inflammatory mechanisms likely underlying abolishment in males and females.<b>NEW & NOTEWORTHY</b> Neonatal inflammation is common, yet our understanding of the mechanisms underlying impairment is poorly understood. Here, we demonstrate for the first time that adult medullary microglia sex- and region-specifically contribute to lasting adult inflammation after neonatal inflammation. Sex-specific activation of adult medullary microglia emphasizes that distinct inflammatory mechanisms underlie male versus female impairments in respiratory control after neonatal inflammation. Such lasting microglia activation likely contributes to abolished adult respiratory motor plasticity and chemoreflexes after neonatal inflammation.