Cellular mechanisms underlying how early life stressors disrupt respiratory control
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Date
2024-08-07
Authors
Beyeler, Sarah
Journal Title
Journal ISSN
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Publisher
University of Oregon
Abstract
Sufficient breathing is essential to maintaining homeostatic blood gases, yet stressors early in life undermine neural circuits controlling breathing in neonates, leading to potentially life-threatening respiratory insufficiency. Further, since respiratory control circuitry continues to develop postnatally, many early life stressors have lasting negative consequences for adult breathing and can increase risk for developing adult ventilatory control disorders, such as sleep apnea. For instance, neonatal inflammation acutely disrupted neonatal central respiratory activity and caused lasting disruption in adult respiratory control by abolishing respiratory motor plasticity, which disrupts the ability of the neural networks controlling breathing to learn and adapt. Yet, identifying mechanisms mediating this loss of adult plasticity and the extent of impairments to the neural control of breathing beyond plasticity are still necessary to understand how neonatal inflammation contributes to adult ventilatory insufficiencies and the risk for developing ventilatory control disorders. Additionally, infants exposed to maternal opioids have diverse negative health consequences, including respiratory distress. However, many factors contribute to these negative health outcomes, confounding the ability to understand how maternal opioids directly impact the neonatal respiratory system. Thus, this dissertation focuses on (1) identifying lasting disruptions in adult breathing after neonatal inflammation, (2) cellular mechanisms contributing to these impairments in adults after neonatal inflammation and (3) mechanisms underlying how maternal opioids impairs neonatal respiratory circuits.
I will begin by providing an overview of respiratory control circuitry and development, introducing microglia and their role in neuroinflammatory signaling, and why it is important to understand how early life stressors disrupt respiratory control in Chapter I. Our laboratory previously identified that neonatal inflammation caused lasting abolishment of adult respiratory motor plasticity, where loss of plasticity has the potential to disrupt the ability of the neural networks controlling breathing to learn and adapt. Chapter II of this dissertation extends this work by identifying medullary microglia (primary immune cells in the brain) as a key cell type likely contributing to this loss of adult plasticity. Further, we determined neonatal inflammation sex-dependently impaired respiratory control beyond plasticity, increasing our understanding of how neonatal inflammation may contribute to adult ventilatory insufficiencies and the risk for developing ventilatory control disorders. We identified that neonatal inflammation caused lasting augmentation of adult male hypercapnic responses, consistent with males being at increased risk for sleep apnea. Chapter III of this dissertation focuses on understanding how a subsequent adult inflammatory challenge affects breathing in adults after neonatal inflammation to determine their risk for breathing disruptions during illness and disease. This research significantly advances our understanding of how impairments in microglial inflammatory responses may contribute to adult breathing vulnerability after neonatal inflammation.
Finally, Chapter IV of this dissertation investigated mechanisms underlying how neonatal breathing is impaired by maternal opioids, another early life stressor. We determined maternal opioids directly impaired neonatal respiratory control networks, likely contributing to neonatal breathing deficits after maternal opioids, which we identified previously. Together this dissertation significantly advances our understanding of cellular mechanisms underlying how two early life stressors, neonatal inflammation and maternal opioids, disrupt respiratory control. Such an understanding is necessary to develop novel therapeutic strategies to support breathing at all ages. This dissertation includes previously published, co-authored material.
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Keywords
inflammation, microglia, neurodevelopment, opioids, physiology, respiratory control