Bringing the clinic to the lab: the effects of forced and non-forced rehabilitation on functional recovery after spinal cord injury

基于感觉的康复有助于改善动物和人类脊髓损伤(SCI)后的功能。人类患者的临床计划利用组合强迫运动(FE)和非强迫运动(NFE)训练计划来促进功能改善(想想跑步机与在跑道上行走)。对于FE，人们认为传入的环境线索在脊柱水平上局部发挥作用，以减轻功能缺陷。而NFE，允许试错，将运动的可变性引入神经系统。可变性有助于微调下行的大脑指令，以提高运动能力。然而，关键问题仍然存在：不同的训练模式如何改变脊髓回路，并有助于运动恢复？答案将有助于微调这些感觉康复策略，以优化功能恢复。该方案的假设是FE和NFE在脊髓损伤后的功能恢复中启动了不同的神经重连策略和可表征的差异。我将使用老鼠的遗传策略来说明重新连接过程中的解剖学变化。具体地说，我将研究运动前网络，脊髓深背角小白蛋白+神经元(DPV)的神经回路的变化。DPV接受会聚的触摸、本体感觉和棘上信息，并在任务依赖型运动行为中进行差异性参与。因此，dPV的投入或产出的变化反映了矛盾训练(FE/NFE)在调解恢复方面的贡献。具体目标1将测试这样的假设，即FE将引起感觉神经重新连接的升高，而NFE将导致大脑输入的下行增加。我将把遗传学方法与定量突触分析结合起来，从解剖学的角度将皮质脊髓和触摸/本体感觉输入映射到dPV上。目的1‘S的训练潜力在于学习小鼠遗传学，高分辨率定量突触分析，并进一步磨练我的生物统计学训练。具体目标2将检验这样一种假设，即NFE促进平稳的自然运动，行为状态图与损伤前状况的关系比FE更密切。我将把肌肉活动记录与高灵敏度的计算机视觉/机器学习结合起来，研究训练(1)对肌肉反应(EMG)和关节活动的影响，以及(2)从整体上对自然行为的影响。我还将使用遗传方法来表征dPV对运动神经元的输出，并用植入的电极标记支配腿部肌肉的受影响的运动神经元。目的2 S的训练潜力植根于尖端的计算技术、肌肉记录和数据解释。这些共同的结果将使我们了解(1)脊柱上和感觉的整合和诱发的运动反应，以及(2)NFE在复杂运动行为中的功能优势。我的研究将打破目前翻译性临床前研究的障碍，帮助指导临床康复。这些目标的高培训潜力是精心设计的，以填补我基于空白的知识。这一奖学金的影响将培养我在SCI领域成功的、有影响力的和持久的独立研究生涯。

Sensory-based rehabilitation facilitates functional improvements after spinal cord injury (SCI) in animals and humans. Clinical programs for human patients utilize combinatorial Forced Exercise (FE) and Non-Forced Exercise (NFE) training programs to facilitate functional improvements (think treadmill vs. walking on a track). For FE, it is believed that incoming environmental cues work locally on the spinal level to mitigate functional deficits. While NFE, which enables for trial and error, introduces motor variability into the neural system. Variability helps fine tune descending brain commands to improve motor performance. However, key questions remain: How do different training paradigms change spinal cord circuits and contribute to motor recovery? Answers will help to fine tune these sensory-rehabilitation strategies to optimize functional recovery. The hypothesis of this proposal is that FE and NFE initiate distinct neural rewiring strategies and characterizable differences in functional recovery following SCI. I will use mouse genetic strategies to illuminate anatomical changes in rewiring. Specifically, I will examine the changes in neural circuitry of a premotor network, Deep Dorsal horn spinal cord ParvalBumin+ neurons (dPVs). dPVs receive convergent touch, proprioceptive, and supraspinal information, and are differentially engaged during task-dependent motor behaviors. Changes in inputs onto or outputs from dPVs therefore reflect the contributions of paradoxical training (FE/NFE) in mediating recovery. Specific Aim 1 will test the hypothesis that FE will evoke elevated sensory neural rewiring, while NFE will result in increased descending brain inputs. I will couple genetic approaches with quantitative synaptic analysis to anatomically map corticospinal and touch/proprioceptive inputs onto dPVs. Aim 1’s training potential lies in learning mouse genetics, high resolution quantitative synaptic analysis, and to further hone my biostatistics training. Specific Aim 2 will test the hypothesis that NFE facilitates smooth naturalistic motor movements and behavioral state maps more closely related to the preinjury condition than FE. I will couple muscle activity recordings with highly sensitive computer vision/machine learning to investigate the influence of training (1) granularly on muscle responses (EMGs) and joint activity and (2) holistically on naturalistic behavior. I will also characterize dPVs outputs onto motor neurons using genetic approaches and label affected motor neurons innervating leg muscles with implanted electrodes. Aim 2’s training potential is rooted in cutting-edge computational techniques, muscle recordings, and data interpretation. The collective results will provide an understanding of the (1) supraspinal and sensory integration and evoked motor responses involved in NFE and (2) functional benefits of NFE in complex motor behaviors. My research will break down current barriers of translational preclinical research to help instruct clinical rehabilitation. The high training potential for these Aims has been carefully designed to fill my gap-based knowledge. The impact of this fellowship will foster my successful, impactful, and enduring independent research career in the field of SCI.