Use Dependent Plasticity of Spinal Inhibition

使用脊髓抑制的依赖性可塑性

• 批准号: 6477871
• 负责人: ALLAN J TOBIN
• 金额: $ 34.66万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6477871
• 关键词: biomechanics; electromyography; electron microscopy; fluorescent dye /probe; gait; gamma aminobutyrate; glycine receptors; immunocytochemistry; in situ hybridization; laboratory rat; limb movement; motor neurons; neural plasticity; neuromuscular system; neuropsychology; psychomotor function; robotics; sensorimotor system; sensory signal detection; spinal cord; spinal cord injury; spinal cord surgery; spinal nerves; synapses; training

Both experimental animals and humans can regain the ability to stand or to step after a complete spinal cord transection. The ability to execute these tasks depends on specific training regimens, illustrating the importance of motor leading in the spinal cord. Low-thoracic transection and subsequent training leads to a persistent increase in the total inhibitory capacity of the lumbar spinal cord, exhibited by increases in GAD67, a GABA-synthesizing enzyme, and its mRNA, as well as in the alpha-1 subunit of glycine receptor and in gephyrin, a protein associated with glycine receptors. However, repetitive hindlimb training, such as stepping, returns the levels of GAD67 and glycine receptors towards normal. The central hypothesis of this proposal is that task-specific, repetitive training selectively modulates the inhibition within sensorimotor pathways associated with the execution of that task. Using a robotic device, we will test this hypothesis with a well-defined standing task in neonatally transected (T12-13) rats. Stand training allows us to compare training-induced changes in neurons associated with plantarflexion (facilitation of the soleus motor pool) and neurons associated with dorsiflexion (inhibition of the tibialis anterior motor pool). We will test three hypotheses: (1) that stand training decreases the inhibitory capacity of specific neurons associated with the ankle dorsiflexor (tibialis anterior); (2) that training selectively alters the ratio of inhibitory and excitatory synapses on the somata of individual motoneurons in motor pools associated with soleus, and (3) that pharmacologically induced changes in motor performance of spinally transected rats reflect these alterations in GABAergic and glycinergic inhibition in plantarflexion- and dorsiflexor-associated neurons as noted in the first two hypotheses. A major innovation in this work is the ability to train motor tasks, and to quantify the kinematics of standing and stepping using a newly developed robotic device. This device will allow us to impose strictly repetitive training and to assess the progress of individual animals with great precision. The proposed studies address the anatomical and molecular bases of the plasticity that may underlie rehabilitative training after spinal injury. This work will lead to better ways of testing the effectiveness of alternative training strategies and associated pharmacological interventions.

实验动物和人类都可以在脊髓完全横断后恢复站立或行走的能力。执行这些任务的能力取决于特定的训练方案，这说明了脊髓运动领导的重要性。下胸横断和随后的训练导致腰髓总抑制能力的持续增加，表现为GAD 67（GABA合成酶）及其mRNA的增加，以及甘氨酸受体α-1亚基和桥蛋白（与甘氨酸受体相关的蛋白质）的增加。然而，重复的后肢训练，如踏步，使GAD 67和甘氨酸受体的水平恢复正常。这个建议的中心假设是，任务特定的，重复的训练选择性地调节与执行该任务相关的感觉运动通路内的抑制。使用机器人设备，我们将在新生儿横切（T12-13）大鼠中通过明确定义的站立任务来测试这一假设。站立训练使我们能够比较与跖屈相关的神经元（促进比目鱼肌运动池）和与背屈相关的神经元（抑制胫骨前运动池）的训练诱导的变化。我们将测试三个假设：（1）站立训练降低了与踝背屈肌相关的特定神经元的抑制能力。（胫骨前肌）;（2）训练选择性地改变比目鱼肌运动池中单个运动神经元胞体上抑制性和兴奋性突触的比例，以及（3）脊髓横断大鼠运动功能的变化反映了GABA能和甘氨酸能抑制的这些变化，跖屈和背屈相关的神经元，如前两个假设所述。这项工作的一个主要创新是能够训练运动任务，并使用新开发的机器人设备来量化站立和踏步的运动学。这个装置将使我们能够进行严格的重复训练，并以极高的精度评估个别动物的进展。拟议的研究解决了可塑性的解剖学和分子基础，可能是脊柱损伤后康复训练的基础。这项工作将导致更好的方法来测试替代培训战略和相关的药物干预措施的有效性。