The role of inhibitory microcircuits in the neural control of breathing

项目总结/摘要 在理解特定抑制性群体中的神经元功能或功能障碍是如何发生的方面存在着根本性的差距。 哺乳动物中枢神经系统中的神经传导转化为正常或改变的行为。自然行为，往往 表达为运动，由兴奋性网络产生，其功能由抑制性γ-氨基- 丁酸（GABA）能神经元和甘氨酸能神经元。抑制功能障碍是许多致残性神经元的基础， 发育障碍-许多，例如，雷特综合征，合并运动障碍。确定如何 抑制形状基本运动程序代表了理解正常网络功能 以及如何在临床上修复/治疗故障网络。在基本的运动行为中，只有 呼吸有一个局部的节律网络，前BötC（preBötC），已被确定。内 前BötC是GABA能和甘氨酸能神经元，这为研究前BötC的作用提供了一个独特的机会。 抑制;这可以在体外切片中进行，这呈现出相当大的技术优势。现行办法 用于研究抑制的ches从小样本外推或忽略神经元内重要的异质性 人口。被忽视的是抑制性微电路--GABA能和甘氨酸能的局部嵌入网络 这些神经元以附近的抑制性和兴奋性神经元为目标。解决这一问题的两个长期障碍是： 抑制性微电路的作用是神经元网络中可能出现的动态复杂性， 动态操纵抑制性微电路的能力。为了克服这些障碍，我们将联合收割机的概念与 联盟创新的方法，专注于最小的微电路，与技术创新的解决方案，全息 光刺激，能够兴奋或抑制特定群体的神经元内的人群，除了， 时空分辨率在转基因小鼠的节律性髓质切片中使用这些方法， 测试我们的中心假设，即突触和网络特性决定了preBötC抑制微电路 在三个特定的AIMS中控制与谋杀相关的行为的动态库。在AIM 1中，我们确定 preBötC抑制微电路如何塑造呼吸输出。在AIM 2中，我们确定了突触和网络- 工作机制是preBötC抑制性微电路激活效应的基础。在AIM 3中，我们确定如何 微电路-微电路的相互作用扩展了preBötC的动态功能。的贡献 拟议的研究预计将阐明呼吸控制的具体机制， BötC抑制微电路。这一贡献是重要的，因为确定这些机制是必要的- 了解抑制性微电路如何在健康和疾病中塑造呼吸， 作为其他回路的目标进行调节，以产生复杂的与免疫相关的行为。的总体影响 这个建议将揭示控制生命行为的基本神经回路机制，证明 潜在的动态模式操作解剖神经回路，铺平了道路，了解 更复杂的行为，并可能揭示抑制性微电路功能的一般原理。

Project Summary/Abstract There is a fundamental gap in understanding how neuronal function or dysfunction in specific inhibitory popula- tions in mammalian central nervous system translates into normal or altered behavior. Natural behavior, often expressed as movement, is generated by excitatory networks whose function is shaped by inhibitory γ-amino- butyric acid (GABA)-ergic and glycinergic neurons. Inhibitory dysfunction underlies a number of disabling neu- rodevelopmental disorders–many, e.g., Rett syndrome, with comorbid motor disturbances. Determining how inhibition shapes basic motor programs represents a strategy for understanding both normal network function and how malfunctioning networks might be repaired/treated clinically. Among basic motor behaviors, only for breathing has a localized rhythmogenic network, the preBötzinger Complex (preBötC), been identified. Within the preBötC are GABAergic and glycinergic neurons, presenting an inimitable opportunity to study the role of inhibition; that this can be done in a slice in vitro presents considerable technical advantages. Current approa- ches for studying inhibition extrapolate from small samples or ignore important heterogeneity within neuronal populations. Overlooked are inhibitory microcircuits–local, embedded networks of GABAergic and glycinergic neurons that target nearby inhibitory and excitatory neurons. Two long-standing obstacles to addressing the role of inhibitory microcircuits are the dynamic complexity that can emerge in neuronal networks and the inabi- lity to dynamically manipulate inhibitory microcircuits. To overcome these obstacles, we combine a conceptu- ally innovative approach, focused on minimal microcircuits, with a technically innovative solution, holographic photostimulation, capable of exciting or inhibiting specific groups of neurons within a population with excep- tional spatiotemporal resolution. Using these approaches in rhythmic medullary slices from transgenic mice, we test our central hypothesis that synaptic and network properties determine how preBötC inhibitory microcircuits control the dynamic repertoire of respiratory-related behaviors in three specific AIMS. In AIM 1, we determine how preBötC inhibitory microcircuits shape respiratory output. In AIM 2, we determine how synaptic and net- work mechanisms underlie the effects of preBötC inhibitory microcircuit activation. In AIM 3, we determine how microcircuit-microcircuit interactions expand the dynamic repertoire of the preBötC. The contribution of the proposed research is expected to be elucidation of specific mechanisms underlying control of breathing by pre- BötC inhibitory microcircuits. This contribution is significant because determining these mechanisms is neces- sary for understanding how inhibitory microcircuits shape breathing in health and disease and are themselves regulated as targets of other circuits to generate complex respiratory-related behaviors. The overall impact of this proposal will be to reveal basic neural circuit mechanisms controlling a vital behavior, demonstrate the potential of dynamic patterned manipulations for dissecting neural circuits, pave the way for understanding more complex behaviors, and possibly uncover general principles of inhibitory microcircuit function.