Neonatal inflammation impairs control of breathing

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PROJECT SUMMARY/ABSTRACT Bacterial-induced infections and inflammation in newborns are common clinical problems, and with continued health care improvements, more infants (including those born preterm) are surviving. We have only recently begun to understand the lasting impact of neonatal inflammation on adult physiology. Specifically, understanding the impact of neonatal inflammation on adult breathing, a vital homeostatic behavior, is largely unexplored, and is the focus of this proposal. Based on exciting preliminary data, we hypothesize that neonatal inflammation significantly impairs the respiratory control network in adulthood. Three specific hypotheses will be tested to advance our understanding in this developing field: 1) Neonatal inflammation abolishes multiple known pathways to adult respiratory motor plasticity; 2) Adult subthreshold inflammatory challenges have stimulus-specific effects on respiratory control following neonatal inflammation; 3) Neonatal inflammation differentially alters adult microglial and astrocytic inflammatory responses in the spinal cord. An innovative, multidisciplinary approach will be used to test these hypotheses. Experimental approaches include: phrenic nerve recordings in anesthetized rats, plethysmography in unanesthetized rats, and transcriptome profiling in isolated cells from respiratory-related central nervous system (CNS) regions. After bacterial-induced neonatal inflammation, preliminary data indicate severe deficits in adult respiratory motor plasticity (an important form of learning and adaptability critical for compensation to lung or neural injury). Interestingly, acute treatment with anti-inflammatory drugs in adults after neonatal inflammation differentially restores one of two main pathways to respiratory motor plasticity, suggesting persistent adult inflammation as a consequence of the neonatal inflammation. Since organisms rarely experience only a single inflammatory challenge in life, we are testing the vulnerability of the adult respiratory system to subsequent low-level, innocuous inflammatory challenges. Our preliminary data indicate increased vulnerability of the adult male respiratory control network (plasticity, chemosensitivity, and mortality) to otherwise innocuous bacterial stimuli after neonatal inflammation, correlating with increased incidence of adult pathology in males. Since viral infections are common in adults, we will also investigate the effects of neonatal bacterial inflammation + adult viral inflammation in both sexes. At a mechanistic level, we find opposing responses to neonatal inflammation in two CNS cell types, astrocytes and microglia. Astrocytes, which compose the majority of cells in the CNS, show increased inflammatory gene expression lasting into adulthood, while microglia (CNS resident immune cells) display a blunted or unchanged gene response. Results from these studies will significantly advance our understanding of neonatal inflammation-induced impairments persisting into adulthood, and shed light on the sensitivity of the respiratory control network to neonatal inflammation. This understanding is necessary to identify new therapeutic targets and to develop new treatment strategies for adults with ventilatory control disorders.