Strategies to maximize the functional benefit of regenerated corticospinal tract axons

最大化再生皮质脊髓束轴突功能效益的策略

• 批准号: 10200919
• 负责人: Murray G Blackmore
• 金额: $ 33.03万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200919
• 关键词: Acute; Address; Aftercare; Animals; Axon; Back; Behavior; Behavioral; Brain; Cells; Cervical; Cervical spinal cord injury; Chronic; Corticospinal Tracts; Critical Pathways; Data; Developmental Gene; Electric Stimulation; Electrophysiology (science); Fiber; Forelimb; Genes; Goals; Growth; Hand functions; Human; Individual; Injury; Interneurons; Intervention; Label; Lesion; Mediating; Monitor; Motor Neurons; Natural regeneration; Nerve Fibers; Neuraxis; Neuronal Injury; Neurons; Neurosciences; Output; Pathway interactions; Patients; Primates; Recovery; Recovery of Function; Rehabilitation therapy; Rodent; Rodent Model; Site; Spinal; Spinal Cord; Spinal Injuries; Spinal cord injury; Synapses; Techniques; Technology; Testing; Tissues; Training; Trauma; United States; Viral; Work; axon growth; axon injury; base; cellular targeting; central nervous system injury; combinatorial; embryo tissue; improved; improved functioning; injured; motor control; mouse model; novel strategies; optogenetics; postsynaptic neurons; regenerative; regenerative growth; rehabilitation paradigm; relating to nervous system; repaired; restoration; reverse genetics; stem cell therapy; stem cells; success; synergism; therapy design; tool; transcription factor

PROJECT SUMMARY A major effort in regenerative neuroscience is to improve axon growth after injury to the central nervous system (CNS). Once growth is achieved, however, a second hurdle to improving function is that regenerated axons must succeed in forming synaptic contacts with appropriate sets of post-synaptic neurons. The challenge of restoring effective circuitry is especially acute after spinal injuries that damage the corticospinal tract (CST), a pathway critical for fine motor control. The CST mediates descending motor control by synapsing on specific subsets of spinal neurons, which in humans and rodents alike include a diverse set of interneurons in addition to the direct CST-motor-neuron contacts that characterize primates. The field has achieved increasing success in promoting CST axon growth, yet gains in behavioral recovery have lagged. This work will address the need to monitor the connectivity of regenerated CST axons, and to optimize their behavioral output. To do so we will employ rodent models of spinal injury and capitalize on combined stem cell bridging and viral expression of a pro-regenerative gene called KLF6, which we recently found to evoke robust regenerative CST growth. In addition, we will leverage a recently developed trans-synaptic viral labeling technique that enables an unprecedented ability to visualize post-synaptic target selection. First, we will render KLF6 expression controllable and reversible, in order to silence KLF6 after regeneration occurs in order to determine whether prolonged KLF6 expression itself interferes with behavioral recovery. This will address the pressing question of the degree to which pro-regenerative growth mechanisms may come at the expense of effective synaptic refinement or target selection. Next, we will test the ability of rehabilitative training to sculpt target selection by regenerating CSTs and improve their behavioral output. Finally, we will employ both electrical and chemogenetic means to chronically elevate activity in regenerating CST axons, which we hypothesize will both enhance CST sprouting and improve competition for synaptic territory. These complementary approaches will create optimal strategies to maximize the behavioral benefit that can be extracted from regenerated CST axons.

项目概要 再生神经科学的一项主要工作是改善中枢神经损伤后轴突的生长 系统（中枢神经系统）。然而，一旦实现生长，改善功能的第二个障碍是再生 轴突必须成功地与适当的突触后神经元组形成突触接触。挑战 在脊髓损伤导致皮质脊髓束 (CST) 受损后，恢复有效回路的速度尤其急迫，这是一种 对精细运动控制至关重要的通路。 CST 通过突触特定的信号来介导下行运动控制 脊髓神经元的子集，在人类和啮齿类动物中还包括一组不同的中间神经元 灵长类动物特有的 CST-运动神经元直接接触。该领域取得了越来越大的成功 促进 CST 轴突生长，但行为恢复方面的进展却滞后。这项工作将解决这一需求 监测再生 CST 轴突的连接性，并优化其行为输出。为此，我们将 采用脊髓损伤的啮齿动物模型，并利用干细胞桥接和病毒表达的组合 称为 KLF6 的促再生基因，我们最近发现它可以激发强劲的 CST 再生生长。在 此外，我们将利用最近开发的跨突触病毒标记技术，该技术能够 前所未有的可视化突触后目标选择的能力。首先，我们将渲染 KLF6 表达式 可控且可逆，以便在再生发生后使KLF6沉默，以确定是否 延长 KLF6 表达本身会干扰行为恢复。这将解决以下紧迫问题 促再生生长机制可能以牺牲有效突触为代价的程度 细化或目标选择。接下来，我们将通过以下方式测试康复训练塑造目标选择的能力： 再生 CST 并改善他们的行为输出。最后，我们将同时采用电学和化学遗传学 意味着长期提高 CST 轴突再生的活性，我们假设这都会增强 CST 发芽并改善突触区域的竞争。这些互补的方法将创造最佳的 最大化可从再生 CST 轴突中提取的行为益处的策略。