Longitudinal structure of spinal premotor circuits

脊髓前运动回路的纵向结构

• 批准号: 10577360
• 负责人: Martha W Bagnall
• 金额: $ 39.08万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577360
• 关键词: Ablation; Animals; Anterior Horn Cells; Axon; Behavioral; Biological; Biological Assay; Charge; Clinical; Computer Models; Contralateral; Data; Ensure; Exhibits; GATA3 gene; Head; Home; Horns; Injury; Ipsilateral; Leg; Locomotion; Logic; Mammals; Maps; Measures; Modeling; Morphology; Motor; Motor Neurons; Movement; Muscle Contraction; Natural regeneration; Neurons; Organism; Output; Pattern; Physiological; Population; Positioning Attribute; Publishing; Sensory; Slice; Spinal; Spinal Cord; Stimulus; Structure; Synapses; Synaptic Potentials; Tail; Target Populations; Testing; Translating; V1 neuron; Vertebral column; Walking; Whole-Cell Recordings; Work; Zebrafish; arm; dorsal horn; experimental study; in vivo; inhibitory neuron; optogenetics; postsynaptic; predictive modeling; spinal cord repair; spine bone structure

Project Summary As animals locomote, they constantly coordinate activity between the rostral and caudal ends of the body. This coordination relies on neurons in the spinal cord that send long ascending or descending axonal projections. Although several studies have shown that ablation of these neurons leads to deficits in coordination, it is largely unknown whether these long-range circuits are similar or different from local circuits. In recently published data in larval zebrafish, we demonstrated that at least one genetically defined class of spinal neurons, the V1 (En1+) population, changes its synaptic targets as its axon ascends in the spinal cord. Specifically, V1 neurons form synaptic connections with motor neurons and other ventral horn neurons nearby, but switch to inhibiting a dorsal horn sensory population at longer range. Here we propose to extend this analysis to five additional sets of ventral horn neurons, the dI6, V0 excitatory and inhibitory, V2a, and V2b populations. To create this large-scale circuit map, we use localized optogenetic activation of identified spinal populations while carrying out whole-cell recording of identified potential postsynaptic partners. By translating the optogenetic stimuli up and down the spinal cord, we can build a physiological map of the strength of the synaptic connection at various rostrocaudal positions. Normalization of the synaptic charge transfer allows comparisons across target populations, providing a comprehensive grid of connectivity among spinal neuron classes at various rostrocaudal distances. We will then build a computational model of spinal cord connectivity that reflects biological reality, as measured in these experiments. Using this model, we will test the consequences of shifting synaptic connections in the rostrocaudal axis, in order to understand the logic of spinal circuit organization. Finally, we will selectively ablate long-range or local V2a neurons to determine the behavioral effects of long-range vs local projections. Together, these experiments will provide a circuit map of genetically identified spinal neurons.

项目概要 当动物运动时，它们不断协调身体的头端和尾端之间的活动。这 协调依赖于脊髓中的神经元发送长的上升或下降轴突投射。 尽管一些研究表明这些神经元的消融会导致协调性缺陷，但 很大程度上不知道这些远程电路与本地电路是否相似或不同。在最近 在斑马鱼幼虫中发表的数据中，我们证明至少一类基因定义的脊髓 神经元，即 V1 (En1+) 群体，随着其轴突在脊髓中上升而改变其突触目标。 具体来说，V1 神经元与附近的运动神经元和其他腹角神经元形成突触连接， 但改为在更远的范围内抑制背角感觉群。在此我们建议延长此 对另外五组腹角神经元（dI6、V0 兴奋性和抑制性、V2a 和 V2b）的分析 人口。为了创建这个大规模的电路图，我们使用已识别的脊髓的局部光遗传学激活 群体，同时对已识别的潜在突触后伙伴进行全细胞记录。通过翻译 通过脊髓上下的光遗传学刺激，我们可以构建一个强度的生理图 不同头尾位置的突触连接。突触电荷转移的标准化允许 跨目标人群的比较，提供脊髓神经元之间的全面连接网格 不同体尾距离的课程。然后我们将建立脊髓连接的计算模型 正如这些实验中所测量的那样，这反映了生物现实。使用这个模型，我们将测试 轴尾轴突触连接转移的后果，以便理解 脊髓回路组织。最后，我们将选择性地消融远程或局部 V2a 神经元，以确定 远程与局部预测的行为影响。这些实验将共同提供一个电路图 基因鉴定的脊髓神经元。