Functional organization of a reticulospinal motor connectome

描述（由申请人提供）：运动控制领域的一个核心挑战是了解下行系统如何控制脊髓中间神经元（INs）。然而，下行轴突针对数千个脊髓INs并形成复杂的神经回路。这种复杂性限制了传统调查技术的有效性和效率。为了解决这一障碍并加速进展，我们最近开发了将功能连接研究转移到体外小鼠的替代方法。我们使用光学成像记录个体和群体神经元活动后刺激皮层下下降系统。这种新颖的方法使我们能够以一种以前在哺乳动物中不可能的效率和吞吐量研究下行网络中的突触连接。在这篇文章中，我们将重点关注运动协调中的一个主要参与者，网状脊髓（RS）下降系统。我们建议确定RS神经元和具有下行轴突投射的互交神经元之间的功能连接，称为dCINs。中枢神经网络在RS输入和运动输出之间有策略地介入，在运动节律的产生和肢体间协调中发挥重要作用。然而，它们在递质表型、输入输出连通性和运动过程中的功能角色方面是异质的。我们已经开始阐明RS-dCIN系统的组织原理，并取得了两个重要的初步发现。我们发现;(i)两组不同的髓质RS神经元不同地激活轴向和后肢运动神经元，以及（ii） dCINs的三个亚群对RS组或两者都有反应。因此，RS神经元被组织成离散的组，选择性地招募dCINs。在这里，在目标1中，我们建议测试RS的两种形式的选择性

DESCRIPTION (provided by applicant): A central challenge in the field of motor control is to understand how descending systems control spinal cord interneurons (INs). However, descending axons target thousands of spinal INs and form complex neural circuits. This complexity limits the usefulness and efficiency of conventional investigation techniques. To solve this roadblock and accelerate progress, we recently developed alternative approaches that transfer functional connectivity studies to the in vitro mouse. We use optical imaging to record individual and population neuronal activity following stimulation of subcortical descending systems. This novel approach allows us to study synaptic connections in descending networks with an efficiency and throughput that has not been possible previously in mammals. In this proposal, we focus on a major player in motor coordination, the reticulospinal (RS) descending system. We propose to identify the functional connections between RS neurons and a population of commissural INs with descending axonal projections called dCINs. CINs are strategically interposed between RS input and motor output to play an important role in locomotor rhythm generation and interlimb coordination. However, they are heterogeneous with respect to transmitter phenotype, input-output connectivity and functional role during movement. We have begun to elucidate organizational principles of RS-dCIN system and made two important preliminary findings. We found; (i) two distinct groups of medullary RS neurons that differentially activate axial and hindlimb motoneurons, and (ii) three subpopulations of dCINs that respond to either RS group or to both. Thus, RS neurons are organized in discrete groups that recruit dCINs selectively. Here, in Aim 1, we propose to test two forms of selectivity that RS neurons may use to recruit dCINs. First, we will test segmental selectivity by taking advantage of the known spinal segmental differences in composition of axial, flexor and extensor motoneurons. Then, we will test transmitter phenotype selectivity using transgenic approaches. In Aims 2 and 3, we will determine the extent to which RS-dCIN recruitment depends on the excitability and behavioral state of the spinal motor network. Successful completion of these aims will significantly advance our understanding of the functional organization of the RS system both during quiescence and during the active engagement of a complex motor behavior. Our long-term goal is to define organizational principles by which brainstem descending systems control motor output via spinal interneurons. Such knowledge will undoubtedly provide greater insight into circuit dysfunction after injury and aid identify rational strategies for moto recovery.