Specific spinal locomotor circuit alterations induced by epidural stimulation

硬膜外刺激引起的特定脊髓运动回路改变

• 批准号: 10041067
• 负责人: Kimberly J Dougherty
• 金额: $ 41.59万
• 依托单位: DREXEL UNIVERSITY
• 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/10041067
• 关键词: Adult; Afferent Neurons; Afferent Pathways; Animal Model; Cells; Chest; Clinical; Data; Electrophysiology (science); Equilibrium; Feedback; Future; Goals; Hindlimb; Human; Injury; Interneurons; Label; Limb structure; Locomotion; Locomotor Recovery; Long-Term Effects; Lumbar spinal cord structure; Maintenance; Methods; Modeling; Motor; Movement; Mus; Muscle; Neuronal Plasticity; Neurons; Paralysed; Pathway interactions; Patients; Pattern; Population; Property; Rattus; Reflex action; Rehabilitation therapy; Sensory; Signal Transduction; Slice; Spinal; Spinal Cord transection injury; Spinal cord injury; Spinal cord injury patients; Synapses; System; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Transgenic Mice; Transgenic Organisms; Traumatic injury; Walking; active method; base; cell type; central pattern generator; evidence base; experimental study; functional restoration; inhibitory neuron; insight; motor function improvement; mouse model; prevent; recruit; relating to nervous system; restoration; sensory feedback; sensory input; severe injury; spasticity; success; transcription factor; treadmill; treadmill training; treatment strategy

ABSTRACT Epidural stimulation (ES) has shown great promise for the restoration of motor functioning after SCI both clinically and in animal models. Despite its success in activating silenced circuits below the level of the injury allowing for movement of paralyzed limbs, the mechanisms contributing to its long-term effects are unknown. Central pattern generators (CPG) in the lumbar spinal cord control both the rhythm and pattern of locomotion. CPGs are below the level of most injuries, and, therefore, relatively intact and accessible by ES. Recent efforts in our lab to determine the mechanisms by which ES exerts its beneficial effects at the level of the spinal locomotor circuit have revealed alterations in sensory pathways to the locomotor CPG following SCI which are either prevented or reversed by ES at intensities that are subthreshold for motor activation (sub-motor-threshold ES) while the mouse is on a treadmill. In a complete transection SCI model, these circuit alterations are evident despite the apparent lack of locomotor-related hindlimb activity on the treadmill. Our current proposal will directly test whether sub-motor-threshold ES alone is sufficient to induce beneficial plasticity and/or prevent maladaptive plasticity at the level of spinal locomotor circuits in mice. In humans, ES alone does not support walking without extensive concomitant rehabilitative training since the afferent activation by ES occludes the normal proprioceptive sensory signal. Additionally, although there may be a post-injury critical window for maximum plasticity, extensive activity-based rehabilitation is often not possible at these early time points. If the circuit plasticity observed with ES occurs in the absence of motor training, this will suggest sub-motor-threshold ES as a method that could be used for bedridden patients as a bridge for future rehabilitation. For the second aim of the proposal, we will determine the neural substrates of the alterations in spinal sensory pathways to locomotor circuits that are evident after SCI and after ES. We will focus on CPG neurons and inhibitory neurons interposed between CPG neurons and primary afferents. Together, we propose to reveal whether sub-motor-threshold ES is a potential strategy to alter spinal circuits prior to the time when activity-based therapies are feasible. If this is the case, it will suggest a treatment strategy that can be used either in place of or as a bridge until active rehabilitation is possible. Further, we propose to identify a key population of neurons involved in this plasticity, thereby suggesting a specific target of future cell-specific therapeutics.

摘要 硬膜外刺激（ES）在临床上已显示出恢复SCI后运动功能的巨大希望， 和动物模型。尽管它成功地激活了低于受伤水平的沉默电路， 虽然它对瘫痪肢体的运动有很大影响，但其长期影响的机制尚不清楚。中枢模式 腰脊髓中的神经元发生器（CPG）控制运动的节奏和模式。CPG在下面 大多数伤害的水平，因此相对完整且可通过ES访问。我们实验室最近的努力是 确定ES在脊髓运动回路水平发挥其有益作用的机制 揭示了SCI后运动CPG的感觉通路的改变， 或通过ES以运动激活的亚阈值（亚运动阈值ES）的强度反转，而 老鼠在跑步机上。在一个完整的横断脊髓损伤模型中，这些电路的改变是明显的，尽管 在跑步机上明显缺乏与运动相关的后肢活动。我们目前的提案将直接测试 亚运动阈值ES单独是否足以诱导有益的可塑性和/或防止适应不良 在小鼠脊髓运动回路水平的可塑性。在人类中，ES单独不支持行走， 广泛的伴随康复训练，因为ES的传入激活阻断了正常的 本体感觉信号此外，虽然可能有一个受伤后的关键窗口， 可塑性，广泛的基于活动的康复往往是不可能的，在这些早期的时间点。如果电路 ES观察到的可塑性发生在缺乏运动训练的情况下，这将表明亚运动阈值ES作为 一种可以用于卧床不起的病人作为未来康复的桥梁的方法。第二个目标是 根据这项建议，我们将确定脊髓感觉通路运动改变的神经基质。 在SCI和ES之后明显的电路。我们将重点放在CPG神经元和抑制神经元之间 CPG神经元和初级传入神经之间的联系总之，我们建议揭示亚运动阈值ES是否 是一种潜在的策略，可以在基于活动的治疗可行之前改变脊髓回路。如果这是 在这种情况下，它将建议一种治疗策略，可以用来代替或作为一个桥梁，直到积极的 康复是可能的。此外，我们建议确定参与这种可塑性的关键神经元群体， 从而提示了未来细胞特异性治疗的特异性靶点。

项目成果

Spinal Inhibitory Interneurons: Gatekeepers of Sensorimotor Pathways.

• DOI: 10.3390/ijms22052667
• 发表时间: 2021-03-06
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Stachowski NJ;Dougherty KJ
• 通讯作者: Dougherty KJ

Identification of adult spinal Shox2 neuronal subpopulations based on unbiased computational clustering of electrophysiological properties.

• DOI: 10.3389/fncir.2022.957084
• 发表时间: 2022
• 期刊: Frontiers in neural circuits
• 影响因子: 3.5

The role of V3 neurons in speed-dependent interlimb coordination during locomotion in mice.

• DOI: 10.7554/elife.73424
• 发表时间: 2022-04-27
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Zhang, Han;Shevtsova, Natalia A.;Deska-Gauthier, Dylan;Mackay, Colin;Dougherty, Kimberly J.;Danner, Simon M.;Zhang, Ying;Rybak, Ilya A.
• 通讯作者: Rybak, Ilya A.