Sensory and Supraspinal Control of Locomotion

运动的感觉和椎上控制

• 批准号: 9207795
• 负责人: Martyn D Goulding
• 金额: $ 45.18万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207795
• 关键词: Acute; Address; Adult; Afferent Neurons; Back; Behavior; Behavioral; Brain; Cells; Cholecystokinin; Cutaneous; Defect; Dorsal; Electric Stimulation; Electrophysiology (science); Feedback; Generations; Genetic; Goals; Income; Interneurons; Label; Locomotion; Maps; Methods; Motor; Motor Activity; Motor Pathways; Motor output; Movement; Mus; Neuroanatomy; Neurons; Neurosciences; Nuclear Orphan Receptor; Output; Parkinson Disease; Pathway interactions; Periodicity; Play; Population; Positioning Attribute; Rabies; Rabies virus; Recovery of Function; Reflex action; Reporter; Role; Sensory; Shapes; Signal Transduction; Source; Spinal; Spinal Cord; Spinal cord injury; Stimulus; Synapses; System; Tactile; Target Populations; Techniques; Testing; behavior test; cell type; dorsal horn; excitatory neuron; experimental study; genetic analysis; genetic manipulation; hindbrain; insight; locomotor control; motor control; motor disorder; novel; novel therapeutic intervention; optogenetics; programs; prospective; public health relevance; sensor; sensory feedback; spinal reflex

DESCRIPTION (provided by applicant): A fundamentally important question in neuroscience is how sensory feedback and supraspinal commands control the spinal motor programs that control movement. This study will begin to address this issue by examining the connectivity and function of excitatory neurons in the dorsal spinal cord, focusing primarily on cells that express the nuclear orphan receptor RORa. Preliminary findings from the Goulding lab indicate that these sensory interneurons receive convergent inputs from descending motor pathways and from cutaneous sensory afferents. More importantly, loss of the RORa interneurons results in a pronounced motor defect, suggesting these cells form an important excitatory relay that connects sensory and descending pathways to the spinal motor system. In this study, we will use the RORa interneurons to address three important questions that are required to understand how sensory and descending control pathways interface with the spinal motor circuitry. The first involves identifying the source of inputs to the RORa interneurons, using a new genetic transsynaptic tracing system that was developed in the Goulding lab. This will lead to a better understanding of how neurons in the dorsal horn integrate sensory and descending commands (Aim 1). The second is to identify the neurons in the spinal cord that are innervated by RORa interneurons, with a particular focus on neurons that have previously been demonstrated to be key components of the locomotor circuitry (Aim 2). Finally, the role that RORa neurons and other dorsal interneuron cell types play in eliciting and shaping movement will be analyzed by genetic manipulations that use conditional reporter mice to either ablate and silence neurons, or activate them optogenetically (Aim 3). This study, when completed, will be the first to comprehensively analyze the contribution that a population of sensory interneurons makes to motor control. It will provide insights into how the spinal cord integrates tactile sensor stimuli with descending signals from motor centers in the brain to control locomotor movements. The information gained from these studies will aid the generation of new therapeutic approaches for functional recovery following spinal cord injury. It will also provide novel insight into the descending command pathways that control movement and locomotion, whose functioning is compromised in motor disorders such as Parkinson's Disease.

描述（由申请人提供）：神经科学中的一个根本重要问题是感觉反馈和脊髓上命令如何控制控制运动的脊髓运动程序。这项研究将通过检查背侧脊髓兴奋性神经元的连接性和功能来解决这个问题，主要关注表达核孤儿受体 RORa 的细胞。古尔丁实验室的初步研究结果表明，这些感觉中间神经元接收来自下行运动通路和皮肤感觉传入的汇聚输入。更重要的是，RORa 中间神经元的缺失会导致明显的运动缺陷，这表明这些细胞形成了一个重要的兴奋性中继，将感觉和下行通路与脊髓运动系统连接起来。在这项研究中，我们将使用 RORa 中间神经元来解决理解感觉和下行控制通路如何与脊髓运动回路相互作用所需的三个重要问题。第一个涉及使用古尔丁实验室开发的新型遗传跨突触追踪系统来识别 RORa 中间神经元的输入来源。这将有助于更好地理解背角神经元如何整合感觉和下行命令（目标 1）。第二个目标是识别脊髓中受 RORa 中间神经元支配的神经元，特别关注先前已被证明是运动回路关键组成部分的神经元（目标 2）。最后，RORa 神经元和其他背侧中间神经元细胞类型在引发和塑造运动中所起的作用将通过基因操作进行分析，使用条件报告小鼠来消融和沉默神经元，或通过光遗传学激活它们（目标 3）。这项研究完成后，将是第一个全面分析感觉中间神经元群体对运动控制的贡献的研究。它将深入了解脊髓如何将触觉传感器刺激与来自大脑运动中心的下行信号相结合以控制运动。从这些研究中获得的信息将有助于产生脊髓损伤后功能恢复的新治疗方法。它还将为控制运动和运动的下行命令通路提供新的见解，这些通路的功能在帕金森病等运动障碍中受到损害。