Homeostatic Plasticity of the Respiratory Rhythm Generating Network

项目概要 该职业发展奖将使候选人 Nathan Baertsch 博士能够建立一个独立的 研究生涯的重点是揭示大脑在疾病期间如何适应维持呼吸。的 该奖项概述的培训计划结合候选人在运动可塑性、呼吸系统方面的背景 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 中兴奋性中间神经元的周期性同步产生的 复杂（preBötC）。寻找基本的节律发生机制一直是该领域的一个中心问题。 控制呼吸场二十多年。尽管这次搜索揭示了许多重要的发现， 它可能忽视了网络最基本的特征之一——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。这一生如何—— 维持神经网络调节突触和内在特性的精确平衡，以确保 呼吸仍然强劲尚不清楚。根据初步数据，我们假设 产生灵感的网络分布具有适应性，并且突触兴奋之间的平衡， 抑制和内在的爆发特性可以通过稳态调整来补偿慢性 威胁节律发生和呼吸的扰动。该项目将建立在候选人之前的基础上 通过引入最先进的化学遗传学，进行电生理学、药理学和光遗传学方面的培训， 成像和分子技术。结合这些策略将使候选人能够使用多层次的 方法来表征吸气活动分布的变化（目标1）并识别吸气活动的变化 神经元活动慢性破坏后 preBötC 中的突触和内在特性 (Aim2)。这些 使用新型脑干切片制剂的体外实验将与体内实验相补充，以 探索完整动物的呼吸如何适应 preBötC 活动的长期抑制（目标 3）。帮助 候选人实现本提案的研究和职业发展目标，他将获得强有力的 Nino Ramirez 博士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 已过渡到独立的知名教授和前 K 奖获得者。这些 PI 都有效 与候选人密切合作，并且是化学遗传学、成像和分子技术方面的专家。 本提案的培训部分。凭借全面的机构支持和额外的培训、指导和 该 K 奖将提供的经验，候选人将处于有利地位，能够成功竞争 R01 资助并建立有影响力的独立研究计划。

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.