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（IN）。然而，下行轴突靶向数千个脊髓IN并形成复杂的神经回路。这种复杂性限制了常规调查技术的效用和效率。为了解决这一障碍并加快进展，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的活动刺激皮层下下行系统。这种新的方法使我们能够研究下行网络中的突触连接，其效率和吞吐量在哺乳动物中以前是不可能的。在这个建议中，我们专注于运动协调的主要参与者，网状脊髓（RS）下行系统。我们建议，以确定RS神经元和人口连合IN与下行轴突预测称为dCINs之间的功能连接。CINs策略性地插入RS输入和运动输出之间，在运动节律产生和肢体间协调中发挥重要作用。然而，它们在递质表型、输入输出连接性和运动过程中的功能作用方面是异质的。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）两组不同的延髓RS神经元，差异激活轴和后肢运动神经元，和（ii）三个亚群的dCIN，响应RS组或两者。因此，RS神经元被组织成选择性募集dCIN的离散组。在这里，在目标1中，我们提出测试RS 神经元可以用来募集dCIN。首先，我们将测试节段选择性利用已知的脊髓节段性差异的组成轴，屈和伸肌运动神经元。然后，我们将使用转基因方法测试递质表型选择性。在目标2和3中，我们将确定RS-dCIN募集依赖于脊髓运动网络的兴奋性和行为状态的程度。这些目标的成功完成将显着推进我们的RS系统的功能组织的理解，在安静期间，并在一个复杂的运动行为的积极参与。我们的长期目标是确定脑干下行系统通过脊髓中间神经元控制运动输出的组织原则。这些知识无疑将提供更深入的了解电路功能障碍后，受伤和援助确定合理的策略，摩托车恢复。

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.