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.

项目摘要 当动物移动时，它们不断地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，这些神经元发送长的上行或下行轴突投射。 虽然一些研究表明，这些神经元的消融导致协调缺陷，但这是不可能的。 很大程度上不知道这些远程电路是否与本地电路相似或不同。在最近 发表的数据在幼体斑马鱼，我们证明，至少有一个遗传定义类的脊髓 V1（En1+）神经元群随着其轴突在脊髓中上升而改变其突触靶点。 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， 而是切换到在更远距离抑制背角感觉群体。在这里，我们建议将其扩展到 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，我们使用了识别的脊髓神经元的局部光遗传学激活。 群体，同时进行识别的潜在突触后伴侣的全细胞记录。通过平移 光遗传学刺激向上和向下的脊髓，我们可以建立一个生理地图的强度， 在不同的吻尾位置的突触连接。突触电荷转移的正常化允许 在目标人群之间进行比较，提供脊髓神经元之间的全面连接网格 在不同的rostrocaudal距离类。然后我们将建立一个脊髓连接的计算模型 这反映了生物学上的现实，正如这些实验所测量的那样。使用这个模型，我们将测试 的后果转移突触连接在rostrocaudal轴，为了理解的逻辑 脊髓回路组织最后，我们将选择性地消融长程或局部V2a神经元，以确定V2a神经元的功能。 行为影响的长期与本地的预测。总之，这些实验将提供一个电路图， 基因鉴定的脊髓神经元