Functional Dissection of Medullary Respiratory Microcircuits

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Delineating neurons that underlie complex behaviors is of fundamental interest. We will exploit a powerful method, optogenetics, for inducing extremely rapid changes in excitability of genetically targeted neurons to affect a robust and vita ongoing regulatory behavior in mice, i.e., breathing. Breathing is a remarkable behavior that mediates gas exchange to support metabolism and regulate pH. A reliable and robust rhythmic pattern of respiratory muscle activity is essential for breathing in mammals. Failure to maintain a normal breathing pattern in humans suffering from sleep apnea, apnea of prematurity, congenital central hypoventilation syndrome, hyperventilation syndrome, Rett syndrome, and perhaps Sudden Infant Death Syndrome, leads to serious adverse health consequences, even death. Various neurodegenerative diseases, such as Parkinson's disease, multiple systems atrophy and amyotrophic lateral sclerosis, are associated with sleep disordered breathing that we hypothesize results from the loss of neurons in brain areas controlling respiration. If breathing is to be understood in normal and in pathological conditions, the mechanisms for respiratory central pattern generation must be revealed. We focus on two brain sites essential for generation of the normal breathing pattern, the preBötzinger Complex and the retro trapezoid nucleus/parafacial respiratory group. Using a viral delivery system, we will express genetically encoded opsins in several key subpopulations of neurons in these regions. A totally unexplored aspect of the organization of the respiratory central pattern generator is the actions of these critical populations at their axonal target sites. Rapid changes in excitability of these neurons by administration of light pulses delivered via an optical fiber implanted in these sites i mice should produce noticeable, even profound perturbations in breathing. Analysis of such perturbations will provide an extraordinary window into understanding mechanisms of respiratory rhythm and pattern generation.