Interneuron circuits in the spinal motor system

项目摘要： 脊髓中的神经回路充当神经系统控制肌肉的管道 收缩以实现行为。因此，定义脊髓回路组织对于理解 运动的神经控制解决脊髓回路如何指导运动输出的一个主要挑战是 脊髓中间神经元的高度异质性，它塑造了肢体运动的基本要素 潜在的运动和熟练的前肢行为。因为我们能够分辨不同的中间神经元细胞 类型仍然有限，对脊髓中间神经元的突触和电路组织或其 对运动输出的功能性贡献。我们最近发现，脊髓V1中间神经元，最大的 脊髓运动系统中的抑制性中间神经元群体，构成分子异质性群体 其可以被分离成至少四个互斥的子集（进化枝），所述子集（进化枝）由 转录因子Foxp 2、MafA、Pou 6 f2和Sp 8。V1进化枝表现出限制性和高度定型 在脊髓中的位置，并且有几个显示出不同的电生理特征。因此，V1 interneurons代表了一个理想的系统，在其中探索interneurons身份的一般原则， 控制运动输出的电路，与其他类型的脊髓中间神经元相关。受我们的 V1中间神经元多样性的发现，该建议旨在（1）定义V1中间神经元的分子和细胞身份， 这些分支和这种多样性产生的机制，（2）测试假设，下降 来自大脑的运动通路差异地支配V1分支，以及（3）研究V1中间神经元如何 影响运动控制的一个关键方面-节奏运动输出的速度。在一起，拟议的 实验解决了关于以下物质的身份、电路组织和功能的知识方面的根本差距 脊髓运动系统中的中间神经元，并作为未来旨在解剖脊髓运动系统的基础。 特定的中间神经元细胞类型对运动行为的贡献，与发育运动相关 疾病和脊髓损伤。

Project Summary: Neural circuits in the spinal cord serve as the conduit through which the nervous system controls muscle contraction to implement behavior. Defining spinal circuit organization is therefore central to understanding the neural control of movement. One major challenge in resolving how spinal circuits direct motor output is the highly heterogeneous nature of spinal interneurons, which shape fundamental elements of limb movement underlying locomotion and skilled forelimb behaviors. Because our ability to resolve distinct interneuron cell types remains limited, little is known about the synaptic and circuit organization of spinal interneurons or their functional contributions to motor output. We recently discovered that spinal V1 interneurons, the largest inhibitory interneuron population in the spinal motor system, constitute a molecularly heterogeneous group that can be segregated into at least four mutually exclusive subsets (clades) defined by expression of the transcription factors Foxp2, MafA, Pou6f2, and Sp8. V1 clades exhibit restricted and highly stereotyped positions in the spinal cord, and several show distinct electrophysiological signatures. As such, V1 interneurons represent an ideal system in which to explore general principles of interneuron identity and circuitry governing motor output, of relevance to other classes of spinal interneurons. Motivated by our discovery of V1 interneuron diversity, this proposal aims to (1) define the molecular and cellular identity of these clades and the mechanisms through which this diversity arises, (2) test the hypothesis that descending motor pathways from the brain differentially innervate V1 clades, and (3) investigate how V1 interneurons influence one key aspect of motor control – the speed of rhythmic locomotor output. Together, the proposed experiments address a fundamental gap in knowledge about the identity, circuit organization, and function of interneurons in the spinal motor system, and serve as a foundation for future efforts aimed at dissecting the contributions of specific interneuron cell types to motor behavior, of relevance for developmental motor disorders and spinal cord injury.