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Homeostatic Plasticity of the Respiratory Rhythm Generating Network

呼吸节律生成网络的稳态可塑性

基本信息

批准号：
10615743
负责人：
Nathan Andrew Baertsch
金额：
$ 24.9万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10615743
关键词：
Acute Advisory Committees Animals Award Behavioral Binding Blood gas Brain Brain Stem Breathing Characteristics Chronic Compensation Complement Complex Contracts Data Disease Electrophysiology (science)Ensure Equilibrium Exhibits Feedback Funding Generations Genetic Goals Health Homeostasis Image Immunoprecipitation In Vitro Institution Interneurons K-Series Research Career Programs Life Membrane Mentors Mentorship Metabolic Molecular Motor Mus Neurons Organism Pathology Periodicals Periodicity Pharmacology Phase Positioning Attribute Preparation Property Proteins Recurrence Regulation Research Respiration Disorders Respiratory Failure Respiratory physiology Role Slice Synapses Techniques Testing Training Transfection Viral Work career career development central pattern generator excitatory neuron experience experimental study genetic approach in vivo inhibitory neuron nervous system disorder neural network novel optogenetics pH Homeostasis pharmacologic postsynaptic preBotzinger complex professor programs research and development respiratory response synaptic inhibition ventilation

项目摘要

PROJECT SUMMARY This career development award will allow the Candidate, Dr. Nathan Baertsch, to establish an independent research career focused on unravelling how the brain adapts to maintain breathing during disease. The training plan outlined in this award combined with the Candidate’s background in motor plasticity, respiratory physiology and rhythm generation make him ideally suited to successfully follow this career development path. The breathing rhythm is generated by periodic synchronization of excitatory interneurons in the preBötzinger Complex (preBötC). The search for the essential rhythmogenic mechanism has been a central question in the control of breathing field for over two decades. Although this search has revealed many important discoveries, it has overlooked perhaps one of the most fundamental characteristics of the network – its ability to adapt. The amount of synchronization among preBötC neurons is not fixed, but depends on a dynamic interplay between excitatory and inhibitory connections, and the intrinsic membrane properties of preBötC neurons. How this life- sustaining neural network regulates this precise balance of synaptic and intrinsic properties to ensure breathing remains robust is not well understood. Based on preliminary data, we hypothesize that the distribution of the network generating inspiration is adaptable, and the balance between synaptic excitation, inhibition, and intrinsic bursting properties can be homeostatically tuned to compensate for chronic perturbations that threaten rhythmogenesis and breathing. This project will build on the candidate’s prior training in electrophysiology, pharmacology, and optogenetics by introducing state-of-the-art chemogenetic, imaging, and molecular techniques. Combining these strategies will allow the Candidate to use a multi-level approach to characterize changes in the distribution of inspiratory activity (Aim1) and identify changes in synaptic and intrinsic properties (Aim2) in the preBötC following chronic disruptions in neuronal activity. These in vitro experiments using a novel brainstem slice preparation will be complemented with in vivo experiments to explore how breathing adapts to chronic suppression of preBötC activity in the intact animal (Aim3). To help the Candidate achieve the research and career development goals of this proposal, he will receive strong mentorship from Dr. Nino Ramirez, a leader in respiratory rhythm generation with a successful mentoring track- record. The Candidate will also receive research and career development support from an advisory committee of established professors and former K-awardees that have transitioned to independence. These PIs all work closely with the Candidate and are experts in the chemogenetic, imaging, and molecular techniques that will be training components of this proposal. With full institutional support and the additional training, mentorship, and experience that this K-award will provide, the Candidate will be well positioned to successfully compete for R01-funding and establish an impactful independent research program.

项目总结