Pontine Mechanisms For Hypertension Pathogenesis With Experimental Sleep Apnea: A Feasibility Study Using An Optogenetic Approach In The Behaving Rat
Dates: 3/3/2016 - 8/31/2017
Co-Investigators: Anne Fink, David Carley, Kamal Sharma
Abstract: The >18 million Americans afflicted with sleep apnea syndrome have a significantly elevated risk for developing hypertension and other cardiovascular diseases.1 Patients do not always tolerate the available surgical and non-surgical interventions for sleep apnea (e.g., uvulopalatoplasty, continuous positive airway pressure), 2 and none of the available therapies specifically target cardiovascular disease prevention. Although there is a dire need for interventions that prevent the cardiovascular consequences of sleep apnea, efforts to devise new therapies have been thwarted by an inadequate understanding of the mechanisms underlying hypertension pathogenesis resulting from sleep apnea. My research addresses this need by investigating the neurobiological mechanisms that underlie sympathetic nervous system over-activity with sleep apnea. I have demonstrated that a population of cholinergic neurons in the pedunculopontine tegmentum (PPT) has a role in blood pressure (BP) regulation in anesthetized rats.3 Previous research also demonstrated that cholinergic PPT neurons regulate sleep and breathing.4,5 In an ongoing study (R00NR014369) I am creating PPT lesions to determine how the loss of these neurons influences sleep, breathing, and cardiovascular activities in conscious rats with experimental sleep apnea. Lesioning experiments have limitations, however, so to ensure that I develop highly competitive R01-supported studies, I must include more sophisticated approaches. This Internal Research Support Program (IRSP) application is focused on using optogenetics, an approach that combines genetic engineering and fiber optic technology to permit the nearly instantaneous activation/inactivation of neurons. In collaboration with Drs. Kamal Sharma and David Carley, I will develop a system for optogenetically manipulating cholinergic PPT neurons to define their role in hypertension pathophysiology. This will be important for bringing a novel methodology into my laboratory, generating preliminary data, and making sample size estimates for R01-supported investigations. Upon completion of this pilot study, my team will be the only group employing optogenetics to probe brainstem structures in rats with experimental sleep apnea along with the real-time assessment of physiologic responses using telemetry.