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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.

项目摘要这个职业发展奖将允许候选人，博士内森Baertsch，建立一个独立的他的研究生涯集中在揭示大脑如何适应疾病期间保持呼吸。的该奖项中概述的培训计划结合候选人在运动可塑性，呼吸，生理学和节奏生成使他非常适合成功地遵循这一职业发展道路。呼吸节律是由前Bötzinger区兴奋性中间神经元的周期性同步产生的 Complex（preBötC）.寻找基本的节律发生机制一直是研究的中心问题。控制呼吸场超过二十年。虽然这次搜索揭示了许多重要的发现，它忽略了网络的一个最基本的特征--适应能力。的 preBötC神经元之间的同步量不是固定的，而是取决于它们之间的动态相互作用。兴奋性和抑制性连接，以及preBötC神经元的内在膜特性。怎么会这样- 维持神经网络调节突触和内在属性的精确平衡，以确保呼吸保持强健还不是很清楚。根据初步数据，我们假设产生灵感的网络的分布是自适应的，并且突触兴奋，抑制和内在的爆发特性可以被稳态调节以补偿慢性的威胁节奏发生和呼吸的扰动。这个项目将建立在候选人的事先通过引入最先进的化学遗传学，成像和分子技术。结合这些策略将允许候选人使用多层次描述吸气活动（Aim 1）分布变化的方法，并确定突触和内在特性（Aim 2）在preBötC神经元活动的慢性中断后。这些使用新型脑干切片制备物的体外实验将与体内实验相补充，探索呼吸如何适应完整动物中preBötC活性的慢性抑制（Aim 3）。帮助候选人实现本建议书的研究和职业发展目标，他将获得强有力的来自Nino Ramirez博士的指导，他是呼吸节律生成领域的领导者，拥有成功的指导轨迹- 记录候选人还将获得咨询委员会的研究和职业发展支持已经过渡到独立的知名教授和前K奖获得者。这些PI都能工作他们与候选人关系密切，是化学遗传学、成像和分子技术方面的专家，本建议的培训内容。有了充分的机构支持和额外的培训，指导，这一K奖将提供的经验，候选人将处于有利地位，成功竞争 R 01-资助并建立一个有影响力的独立研究计划。