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SCI临床上恢复运动功能的恢复表现出了很大的希望 和动物模型。尽管它成功地激活了低于伤害水平的沉默电路 瘫痪的肢体运动，导致其长期影响的机制尚不清楚。中央模式 腰脊髓中的发电机（CPG）控制着运动的节奏和模式。 CPG在下面 大多数伤害的水平，因此，ES相对完好无损。我们实验室的最新努力 确定ES在脊柱运动电路水平上发挥其有益作用的机制 在SCI之后，已经揭示了运动途径的变化，这要么阻止 或ES在阈值激活（子电动机阈值ES）的强度上逆转，而 鼠标在跑步机上。在完整的横断科学模型中，尽管有 在跑步机上显然缺乏与运动相关的后肢活动。我们目前的建议将直接测试 单独的子运动阈值是否足以诱导有益的可塑性和/或防止适应不良 小鼠脊柱运动电路水平的可塑性。在人类中，仅ES就不支持没有行走 由于ES激活传入，广泛的伴随康复训练是正常的 本体感知信号。此外，尽管可能有一个伤害后的关键窗口可最大 在这些早期时间点，通常无法使用可塑性，广泛的基于活动的康复。如果电路 在没有运动训练的情况下发生的可塑性发生，这将表明亚运动阈值ES为 一种可用于卧铺患者的方法，作为未来康复的桥梁。为了第二个目标 提案，我们将确定运动途径改变的神经底物 SCI后和ES之后的电路。我们将专注于CPG神经元和抑制​​性神经元 在CpG神经元和主要传入之间。我们共同提议揭示子运动阈值是否 是在可行的疗法之前改变脊柱回路的潜在策略。如果是 案例，它将提出一种治疗策略，可以代替或用作桥梁直到活动 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人群， 从而提出了未来细胞特异性治疗剂的特定靶标。

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.