Interneuron circuits in the spinal motor system

脊髓运动系统中的中间神经元回路

• 批准号: 10405025
• 负责人: Jay Benjamin Bikoff
• 金额: $ 44.88万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405025
• 关键词: Acute; Address; Adolescent; Adult; Behavior; Brain; Data; Development; Electrophysiology (science); Elements; Embryo; Exhibits; FOXP2 gene; Forelimb; Foundations; Future; Gene Expression; Genetic; Goals; Interneuron function; Interneurons; Knowledge; Limb structure; Link; Locomotion; Logic; Mediating; Methods; Molecular; Motor; Motor Neurons; Motor Pathways; Motor output; Movement; Mus; Muscle Contraction; Mutant Strains Mice; Nature; Neonatal; Nervous System control; Neurodegenerative Disorders; Neurons; Output; Pathway interactions; Periodicity; Physiological; Play; Population; Positioning Attribute; Rabies; Research; Role; Series; Shapes; Spatial Distribution; Speed; Spinal; Spinal Cord; Spinal cord injury; Stereotyping; System; Testing; Transgenic Organisms; Trauma; Viral; base; brain pathway; cell type; disability; experimental study; limb movement; motor behavior; motor control; motor disorder; motor impairment; mutant; neonatal mice; neural circuit; neuroregulation; novel therapeutic intervention; programs; reconstruction; selective expression; transcription factor

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.

项目总结： 脊髓中的神经回路是神经系统控制肌肉的管道。 收缩以实现行为。因此，定义脊椎回路组织是理解 运动的神经控制。解决脊髓回路如何引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 基本的运动和熟练的前肢动作。因为我们分解不同中间神经元细胞的能力 类型仍然有限，对脊髓中间神经元的突触和回路组织或其 对电机输出的功能贡献。我们最近发现，脊髓中最大的V1中间神经元 脊髓运动系统中的抑制性中间神经元群体，构成了一个分子上的异质性群体 可以分为至少四个相互排斥的子集(分支)，这些子集由 转录因子Foxp2、Mafa、Pou6f2和Sp8。V1分支表现出受限和高度刻板印象 在脊髓的位置，和几个显示不同的电生理特征。因此，V1 中间神经元代表了一个理想的系统，在其中探索中间神经元识别的一般原理和 支配运动输出的回路，与其他类型的脊髓中间神经元相关。受我们的激励 V1中间神经元多样性的发现，本建议旨在(1)定义V1中间神经元多样性的分子和细胞特性 这些分支和这种多样性产生的机制，(2)检验了这种下降的假设 来自大脑的运动通路不同地支配V1分支，以及(3)研究V1中间神经元是如何 影响电机控制的一个关键方面--有节奏的运动输出的速度。总而言之，建议的 实验解决了在有关身份、电路组织和功能方面的基本知识差距 脊髓运动系统中的中间神经元，并为未来旨在解剖 特定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。