Brainstem control of apneic reflexes relating to respiratory deaths in neurological disorders - PROJECT SUMMARY Research: This proposal aims to investigate the fatal failures to gasp and autoresuscitate following an obstructive reflexive apnea (i.e., choking stimulus) in the pons and medulla. These failures are believed to underly sudden respiratory deaths in epilepsy (SUDEP), infants (SIDS), and children (SUDC). More broadly, the neural control of choking stimuli, apnea, and gasps is relevant to episodes of “mini-choking” and dysphagia – which then cause aspiration pneumonia, the #1 cause of death in neurological disorders. The literature record of reflexive apnea, gasps, and autoresuscitation have long implicated the carotid bodies and their afferent targets in the caudal solitary nucleus (cNTS), however recent work has established a specific genetic identity of these neurons (cNTS-Grp+). This proposal will utilize intersection genetics tools like a variety of transgenic lines, neuronal tracers, viral vectors, in-situ hybridization techniques, histology, Neuropixel high density probes, and dynamics modeling techniques in order to analyze the role of cNTS-Grp+ neurons with high precision. In Aim 1 I will utilize a modern suite of physiological and genetics tools to map the network connectivity and activation profile across multiple reflexive apnea stimuli in order to isolate shared downstream targets. In Aim 2 I will utilize optogenetic stimulation or chemogenetic inhibition of the cNTS-Grp+ neurons to establish if they are necessary and sufficient for the gasping and autoresuscitation drive following reflexive apnea. In Aim 3 I will utilize Neuropixel probes to collect data from hundreds of respiratory neurons simultaneously across gasping and autoresuscitation paradigms. I will utilize cutting edge dynamical systems modeling to establish the role and hierarchy of cNTS-Grp+ neurons in the gasping behavior, including the ability to produce cardiac resuscitation. Training: This proposal will also strongly develop the trainee, who is an engineer by training, into a world class neuroscientist. The trainee comes from a medical device biomedical engineering lab with a focus on epilepsy and neurostimulation and will be joining Norcliffe Center for Integrative Brain Research at Seattle Children's Research Institute, in the lab of Dr. Jan-Marino Ramirez. The lab and the Center are established leaders in infant sudden deaths, neurorespiratory control, and have recently established a leading position on the use of Neuropixels in complex medullary neural dynamics of respiration. The trainee will expand his computational and quantitative expertise while gaining a new suite of skills, including the use of transgenic mice, viral vectors, DREADDs, optogenetics, opto-tagging, in-situ hybridization, neuronal tracers, and more, all in a collaborative, translation focused Center, supported by numerous technical and professional resources.
