Organization of Central Sympathetic Pathways

University Of Virginia, Charlottesville VA

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Abstract

DESCRIPTION (provided by applicant): The neural mechanisms that automatically regulate breathing and the circulation during sleep reside primarily within the lower brainstem. These mechanisms are implicated in many human diseases or conditions such as obstructive sleep apnea (OSA), the treatment of pain with opiates, central sleep apnea, sudden infant death syndrome (SIDS), and rare diseases such as congenital central hypoventilation syndrome (CCHS). Under the auspices of this grant, we have extensively studied the brainstem network that mediates the cardio respiratory adjustments to changes in blood gases. An important component of this network consists of modified catecholaminergic neurons called the C1 neurons that innervate the spinal cord and regulate sympathetic tone to the heart and blood vessels. The contribution of the C1 neurons to blood pressure stabilization, including during hypoxia, is well established, thanks in part to our work. However, the commonly held view that these neurons merely regulate the activity of the sympathetic system is outdated because these cells also obviously play a major role in the activation of the hypothalamo-pituitary axis during stresses such as infection, hypotension, pain and hypoxia and they also contribute to the regulation of glucose metabolism. Collectively, these data suggest that the C1 cells mediate neuroendocrine responses (sympathoadrenal activation, CRF/ACTH/corticosteroid release) to acute stresses. We think that this view is closer to reality but still falls short of fully describing the role of the C1 neurons, especially during asphyxia and sleep. The present project is designed to test three novel hypotheses. First, activation of the C1 neurons contributes to the arousal effect of acute asphyxia/hypoxia. Second, the breathing stimulation caused by acute hypoxia/asphyxia is partly due to an excitatory input from the C1 neurons to the retrotrapezoid nucleus, a nearby collection of lower brainstem neurons that play a major role in the involuntary regulation of breathing. Third, the C1 neurons also regulate the circulation via the control that they exert over lower brainstem noradrenergic neurons (A5 and locus coeruleus). These hypotheses are supported by neuroanatomical evidence and by preliminary physiological evidence that stimulation of the C1 neurons increases breathing, causes EEG desynchronization and activates wake-promoting neurons such as the locus coeruleus. Our experimental approach is unique as it brings to bear the power of optogenetics to the study of cardiorespiratory integration. This approach, recently developed under the auspices of this grant, allows us to study the effects produced by selective activation of the C1 neurons in conscious rats in a time-controlled and artifact-free manner. The forthcoming results will have a significant impact on current knowledge of cardiorespiratory integration and of the mechanisms by which acute asphyxia produces arousal. These issues are paramount to understanding the effects of hypoxia on the cardiovascular system and the pathology of OSA, particularly the hypertension associated with this disease.