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.

抽象的 硬膜外刺激 (ES) 在临床上显示出对于 SCI 后运动功能恢复的巨大希望 以及在动物模型中。尽管它成功地激活了受伤水平以下的沉默电路，从而允许 瘫痪肢体的运动，导致其长期影响的机制尚不清楚。中央图案 腰脊髓中的发生器（CPG）控制着运动的节律和模式。 CPG 如下 大多数伤害的程度，因此相对完整且可通过 ES 进行访问。我们实验室最近的努力 确定 ES 在脊髓运动回路水平发挥有益作用的机制 揭示了 SCI 后运动 CPG 的感觉通路的改变，这些改变要么被阻止 或由 ES 以运动激活亚阈值（亚运动阈值 ES）的强度逆转，而 鼠标在跑步机上。在完整的横断 SCI 模型中，尽管 跑步机上明显缺乏与运动相关的后肢活动。我们当前的提案将直接测试 单独的亚运动阈值 ES 是否足以诱导有益的可塑性和/或防止适应不良 小鼠脊髓运动回路水平的可塑性。对于人类来说，仅 ES 不支持步行 由于 ES 的传入激活遮挡了正常的神经活动，因此需要进行广泛的伴随康复训练 本体感觉信号。此外，尽管受伤后可能存在一个关键窗口，可以最大限度地发挥作用。 在这些早期时间点，可塑性、广泛的基于活动的康复通常是不可能的。如果电路 在没有运动训练的情况下观察到 ES 的可塑性，这表明亚运动阈值 ES 为 这种方法可用于卧床不起的患者，作为未来康复的桥梁。为了第二个目标 根据该提案，我们将确定脊髓感觉通路改变的神经基质 SCI 和 ES 后明显的电路。我们将重点关注 CPG 神经元和介入的抑制性神经元 CPG 神经元和初级传入神经元之间。我们共同建议揭示子运动阈值 ES 是在基于活动的疗法可行之前改变脊髓回路的潜在策略。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桥梁，直到积极 康复是可能的。此外，我们建议识别参与这种可塑性的关键神经元群体， 从而提出未来细胞特异性治疗的特定目标。

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.