Neurobiological Mechanisms of Sympathetic Regulation in Sleep Apnea
Dates: 9/1/2015 - 6/30/2018
Mentors: Anne Fink, David Carley
Abstract: The long-term objective of my research is to determine the neurobiological mechanisms underlying the significant and independent risk for cardiovascular (CV) morbidity 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 tegmentum (PPT), a cluster of neurons in the rostral pons. The PPT has an established role in controlling respiratory patterning. PPT neurons also control rapid eye movement (REM) sleep, a behavioral state associated with autonomic instability. My research findings support a novel role for the PPT in the regulation of the sympathetic nervous system. I found that pharmacologic stimulation of neurons throughout the rostral-caudal extent of the PPT can evoke increases in renal sympathetic nerve activity and blood pressure in an anesthetized rat model. Experiments using carbachol and muscimol indicated that cholinergic PPT neurons play a role in the sympathoexcitatory responses to acute intermittent hypoxia. In the independent/R00 phase, I will expand on my previous approaches to PPT manipulations. Using novel telemetry technology to assess sleep, breathing, and CV function, I will study rats exposed to chronic intermittent hypoxia (CIH; a commonly used rodent model of OSA). I will determine the impact of excitotoxic PPT lesions in conscious/behaving rats to elucidate CV pathogenic mechanisms relevant to OSA. My R00 studies are important for understanding how neurons of the PPT modulate sympathetic/CV activities across wakefulness, REM sleep, and non-REM sleep in an experimental model of OSA. Also, because CV and respiratory variables demonstrate circadian/diurnal variability, I will examine variations in breathing and CV variables (e.g., blood pressure, heart rate variability metrics) throughout the circadian day. This study represents the foundation for future R01 initiatives for defining OSA neurobiology and its CV consequences.