Homeostatic Plasticity of the Respiratory Rhythm Generating Network

呼吸节律生成网络的稳态可塑性

• 批准号: 10392515
• 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
• 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/10392515
• 关键词: Acute; Advisory Committees; Animals; Award; Behavioral; Blood gas; Brain; Brain Stem; Breathing; Characteristics; Chronic; Complement; Complex; Contracts; Data; Disease; Electrophysiology (science); Ensure; Equilibrium; Exhibits; Feedback; Financial compensation; Funding; Generations; Goals; Health; Homeostasis; Image; In Vitro; Interneurons; K-Series Research Career Programs; Life; Membrane; Mentors; Mentorship; Metabolic; Molecular; Motor; Mus; Neurologic; Neurons; Organism; Pathology; Periodicity; Pharmacology; Phase; Positioning Attribute; Preparation; Property; Proteins; Recurrence; Regulation; Research; Respiration Disorders; Respiratory Failure; Respiratory physiology; Role; Slice; Synapses; Techniques; Testing; Training; Viral; Work; base; career; career development; central pattern generator; excitatory neuron; experience; experimental study; in vivo; inhibitory neuron; nervous system disorder; neural network; novel; optogenetics; pH Homeostasis; postsynaptic; preBotzinger complex; professor; programs; research and development; respiratory; response; synaptic inhibition; ventilation

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 这一职业发展奖将允许候选人Nathan Baertsch博士建立一个独立的 研究生涯专注于解开大脑在疾病期间如何适应以维持呼吸。这个 该奖项中概述的培训计划结合候选人在运动可塑性、呼吸方面的背景 生理和节奏的产生使他非常适合成功地沿着这条职业发展道路前进。 呼吸节律是由Prebötzinger中兴奋性中间神经元的周期性同步产生的 复合体(PrebötC)。对基本节律发生机制的研究一直是心电领域的中心问题。 控制呼吸场长达二十多年。虽然这次搜索发现了许多重要的发现， 它忽视了这个网络最基本的特征之一--它的适应能力。这个 PrebötC神经元之间的同步量并不是固定的，而是取决于两者之间的动态相互作用 兴奋性和抑制性联系，以及PrebötC神经元的固有膜特性。这种生活是如何- 维持神经网络调节这种突触和固有属性的精确平衡，以确保 人们还不能很好地理解呼吸是否保持旺盛。根据初步数据，我们假设 产生灵感的网络的分布是适应性的，突触兴奋， 抑制和内在猝发特性可以通过自平衡调节来补偿慢性 对节律和呼吸构成威胁的干扰。该项目将建立在候选人的先前 电生理学、药理学和光遗传学方面的培训，介绍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应聘者使用多层次的 描述吸气活动分布变化(Aim1)和确定吸气活动分布变化的方法 慢性神经元活动中断后PrebötC的突触和固有特性(AIM2)。这些 使用一种新的脑干切片制剂的体外实验将与体内实验相辅相成 探索呼吸如何适应正常动物体内PrebötC活性的慢性抑制(Aim3)。帮助 如果应聘者达到这一建议的研究和职业发展目标，他将获得强有力的 来自尼诺·拉米雷斯博士的指导，他是呼吸节律生成方面的领导者，拥有一条成功的指导曲目- 唱片。候选人还将得到一个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都能正常工作 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 本提案的培训内容。有了全面的机构支持和额外的培训、指导和 这个K奖将提供的经验，候选人将处于有利地位，成功竞争 R01-资助并建立一个有影响力的独立研究计划。