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.

项目摘要 皮质脊髓轴突投射对于哺乳动物运动控制至关重要。他们的长度和复杂性使 它们容易受到包括脑血管在内的极广泛的神经系统疾病过程 疾病，脱髓鞘疾病，ALS，脊髓损伤等。皮质脊髓研究自然 专注于皮质和脊柱机制。但是，皮质脊髓轴突，例如其他类型的金字塔 区域神经元可以将分支发送到中脑，熊和延髓，并沿着脊髓发送到脊髓。这 皮质脊髓轴突分支到脑干目标的解剖学“ Projectome”尚未系统地。 调查。关于突触的“连接组”的知之甚少。即，由 各种脑干核中突触后神经元的皮质脊髓输入。阐明脑干电路 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。为了 例如，很可能是尚未识别的皮质脊髓神经元的亚型，这些亚型通过差异 脑干目标的神经，介导特定的感觉运动，神经调节剂或其他功能必不可少的 用于运动协调和控制。我们提出了一种两种普通的方法来研究脑干分支 和小鼠中皮质脊髓轴突的圆圈。在AIM 1中，我们将使用高通量分子条形码 MAPSEQ的技术，以表征皮质脊髓项目对脑干的多样性和复杂性， 具有单轴分辨率和大规模采样。在AIM 2中，我们将使用光遗传学的电生理学， 成像和病毒标记工具，以表征这些电路中细胞型特异性突触连通性。 皮质脊髓轴突的脑干分支的预测和连接都将在各个方面进行广泛调查 区域（中脑，PON，髓质），并以更集中的方式分析特定类型的水平 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，蓬托，cunate，coeruleus基因座等）。这项面向发现的研究的结果 计划将为未来的以假设为导向的研究奠定基础，以便在机械上进行研究 特定细胞类型的重要水平及其突触连通性 - 皮质脊髓的脑干电路如何 神经元有助于哺乳动物运动功能。