Use Dependent Plasticity of Spinal Inhibition

实验动物和人类都可以在完全脊髓横断后重新获得站立或行走的能力。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。低胸横断和随后的训练导致腰椎脊髓总抑制能力的持续增加，表现为GAD67 （gaba合成酶）及其mRNA，以及甘氨酸受体α -1亚基和甘氨酸受体相关蛋白gephyrin的增加。然而，重复后肢训练，如步行，可使GAD67和甘氨酸受体水平恢复正常。该建议的中心假设是，特定任务的重复性训练选择性地调节与任务执行相关的感觉运动通路中的抑制作用。使用机器人装置，我们将在新生横切（T12-13）大鼠中进行定义明确的站立任务来验证这一假设。站立训练使我们能够比较训练引起的与跖屈（促进比目鱼肌运动池）和背屈（抑制胫前肌运动池）相关的神经元的变化。我们将测试三个假设：(1)站立训练降低了与踝关节背屈肌（胫前肌）相关的特定神经元的抑制能力；(2)训练选择性地改变了与比目鱼肌相关的运动池中单个运动神经元的体上抑制性突触和兴奋性突触的比例；(3)药物诱导的脊髓横断大鼠运动表现的变化反映了前两个假设中提到的跖屈和背屈相关神经元中gaba能和甘氨酸能抑制的变化。这项工作的一个主要创新是训练运动任务的能力，并使用新开发的机器人设备量化站立和行走的运动学。这个装置将使我们能够严格地进行重复训练，并非常精确地评估单个动物的进步。提出的研究解决了可塑性的解剖学和分子基础，可能是脊髓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训练策略和相关的药理学干预的有效性。

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.