Brainstem circuits of corticospinal neurons

皮质脊髓神经元的脑干回路

• 批准号: 9977340
• 负责人: Gordon M Shepherd
• 金额: $ 69.32万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977340
• 关键词: Anatomy; Animals; Axon; Bar Codes; Behavioral; Brain Stem; Cell Nucleus; Cells; Cerebrovascular Disorders; Communication; Complement; Demyelinating Diseases; Disease; Electrophysiology (science); Foundations; Future; Goals; Health; Image; Individual; Inferior; Label; Lead; Length; Mammals; Maps; Mediating; Methods; Midbrain structure; Mission; Modeling; Molecular; Monitor; Motor; Motor Cortex; Multiplexed Analysis of Projections by Sequencing; Mus; Muscle; Neurons; Olives - dietary; Pathology; Pathway interactions; Pontine structure; Process; Property; Public Health; Pyramidal Tracts; Research; Resolution; Role; Sampling; Sensory; Signal Transduction; Slice; Source; Spinal; Spinal Cord; Spinal cord injury; Structure of nucleus cuneatus; Surveys; Synapses; System; Techniques; Textbooks; United States National Institutes of Health; Viral; base; cell type; connectome; disability; improved; in vivo; interest; locus ceruleus structure; motor behavior; motor control; motor impairment; nerve supply; nervous system disorder; neuroregulation; noradrenergic; optogenetics; postsynaptic; postsynaptic neurons; programs; reconstruction; somatosensory; subcellular targeting; systems research; tool

PROJECT SUMMARY Corticospinal axonal projections are critical for mammalian motor control. Their length and complexity makes them vulnerable to an exceptionally wide range of neurological disease processes including cerebrovascular disorders, demyelinating diseases, ALS, spinal cord injury, and more. Corticospinal research has naturally focused on cortical and spinal mechanisms. However, corticospinal axons, like those of other types of pyramidal tract neurons, can send branches to the midbrain, pons, and medulla along the way to the spinal cord. The anatomical “projectome” of corticospinal axonal branching to brainstem targets has not been systematically investigated. Even less is known about the synaptic “connectome”; i.e., the cellular circuits formed by corticospinal input to postsynaptic neurons in various brainstem nuclei. Elucidating the brainstem circuits of corticospinal axons will be important for understanding the cellular basis of mammalian motor control. For example, there very likely are as-yet unrecognized subtypes of corticospinal neurons that, through differential innervation of brainstem targets, mediate specific sensorimotor, neuromodulatory, or other functions essential for motor coordination and control. We propose a two-pronged approach to investigate the brainstem branches and circuits of corticospinal axons in the mouse. In Aim 1, we will use a high-throughput molecular barcoding technique, MAPseq, to characterize the diversity and complexity of corticospinal projections to the brainstem, with single-axon resolution and large-scale sampling. In Aim 2, we will use optogenetic, electrophysiological, imaging, and viral labeling tools to characterize the cell-type-specific synaptic connectivity in these circuits. The projections and connections of corticospinal axons’ brainstem branches will be both broadly surveyed across regions (midbrain, pons, medulla) and analyzed in a more focused manner at the level of specific types of projection neurons in key nuclei, including those associated with sensorimotor, neuromodulatory, and other systems (reticular, pontine, cuneate, locus coeruleus, and more). Results from this discovery-oriented research program will lay the groundwork for future hypothesis-oriented studies to investigate – at the mechanistically important level of specific cell types and their synaptic connectivity – how the brainstem circuits of corticospinal neurons contribute to mammalian motor function.

项目概要 皮质脊髓轴突投射对于哺乳动物的运动控制至关重要，其长度和复杂性使得。 他们很容易受到各种神经系统疾病的影响，包括脑血管疾病 疾病、脱髓鞘疾病、肌萎缩侧索硬化症、脊髓损伤等等。 然而，皮质脊髓轴突与其他类型的锥体轴突一样。 束神经元，可以将分支发送到中脑、脑桥和延髓，然后再到达脊髓。 皮质脊髓轴突分支到脑干目标的解剖学“投影组”尚未被系统地研究 关于突触“连接组”（即由其形成的细胞回路）的研究更是少之又少。 皮质脊髓对各种脑干核团中突触后神经元的输入阐明了脑干回路。 皮质脊髓轴突对于理解哺乳动物运动控制的细胞基础非常重要。 例如，很可能存在尚未识别的皮质脊髓神经元亚型，通过差异化 脑干目标的神经支配，介导特定的感觉运动、神经调节或其他重要功能 我们提出了一种双管齐下的方法来研究脑干分支。 在目标 1 中，我们将使用高通量分子条形码。 MAPseq 技术来表征皮质脊髓投射到脑干的多样性和复杂性， 具有单轴突分辨率和大规模采样，在目标 2 中，我们将使用光遗传学、电生理学、 成像和病毒标记工具来表征这些回路中细胞类型特异性的突触连接。 皮质脊髓轴突脑干分支的投射和连接将在各个领域进行广泛调查 区域（中脑、脑桥、延髓），并在特定类型的水平上以更有针对性的方式进行分析 关键核中的投射神经元，包括与感觉运动、神经调节和其他相关的神经元 系统（网状系统、脑桥系统、楔形系统、蓝斑系统等）。 该计划将为未来以假设为导向的研究奠定基础，以机械方式进行调查 特定细胞类型及其突触连接的重要水平——皮质脊髓的脑干回路如何 神经元有助于哺乳动物的运动功能。