Neurobiological Mechanisms of Sympathetic Regulation in Sleep Apnea

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The long-term objective of my research is to determine the neurobiological mechanisms underlying the significant and independent risk for cardiovascular (CV) morbidity/mortality resulting from obstructive sleep apnea (OSA). Aberrant sympathetic activation is a pathophysiologic hallmark of OSA, but the neurobiological mechanisms that regulate sympathetic activities across sleep-wake states are poorly understood. This lack of knowledge has thwarted attempts to devise specific therapeutic strategies for the CV consequences of OSA. My research is focused on the pedunculopontine tegmental nucleus (PPT), a cluster of neurons in the rostral pons. The PPT has a well-established role in controlling rapid eye movement (REM) sleep, a state associated with autonomic instability. Our laboratory developed novel data indicating that local stimulation of PPT neurons elicits CV and sympathoexcitatory activities (e.g., elevated blood pressure, tachycardia, and increased renal sympathetic nerve activity). I hypothesize that there is a sympathetic modulating region of the PPT (i.e., a PPT- SMR) that significantly and differentially regulates sympathetic activities across sleep-wake states (such as REM sleep) and that altered PPT-SMR function in OSA represents a mechanistic link between OSA and aberrant activation of the sympathetic nervous system. I have a strong foundation of knowledge/competency relevant to studying CV pathophysiology, and in this Pathway to Independence Award application I propose two years of additional training in neuroscience and the assessment of CV reflexes, which will be important for launching an innovative R00 investigation to determine how the PPT-SMR modulates CV function across behavioral states in an experimental model of OSA. In the K99 phase, I will conduct experiments in anesthetized rats to determine the location(s), neurochemical phenotype, and projections of PPT-SMR neurons. I will also define the role of PPT-SMR neurons in mediating/modulating sympathetic responses to acute hypoxia. In the R00 phase, I will determine the impact of PPT-SMR lesion and chronic intermittent hypoxia (CIH) on CV function across behavioral states (non-REM sleep, REM sleep, and wakefulness) in rats. Both the K99 and R00 phase investigations represent important foundations for my future R01 initiatives to define neurobiology of the CV consequences of OSA.