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

基本信息

批准号：
10455666
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10455666
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

项目摘要

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.

项目摘要再生神经科学的重大努力是改善中枢神经受伤后的轴突生长系统（CNS）。但是，一旦实现增长，改善功能的第二个障碍就是重生轴突必须成功形成突触接触，并使用适当的突触后神经元组。挑战恢复有效电路特别是在损伤皮质脊髓区域（CST）的脊柱损伤之后尤其是急性的。良好电机控制至关重要的途径。 CST通过突触特定的脊柱神经元的子集，在人类和啮齿动物中，它们都包括一组不同的中间神经元到表征灵长类动物的直接CST运动神经元接触。该领域取得了越来越多的成功在促进CST轴突生长时，行为恢复的收益却滞后。这项工作将满足需求监视重生的CST轴突的连通性，并优化其行为输出。为此，我们会采用啮齿动物的脊柱损伤模型，并大写了干细胞桥接和病毒表达促进基因称为klf6，我们最近发现它唤起了强大的再生CST生长。在此外，我们还将利用最近开发的跨突触病毒标记技术可视化突触后目标选择的前所未有的能力。首先，我们将渲染KLF6表达式可控和可逆的，以便在再生后沉默KLF6，以确定是否是否延长的KLF6表达本身会干扰行为恢复。这将解决一个紧迫的问题亲获得生长机制的程度可能是以有效的突触为代价的细化或目标选择。接下来，我们将通过再生CST并改善其行为输出。最后，我们将采用电气和化学发生在再生CST轴突中长期提升活性的方法，我们假设这两个都将增强CST 发芽并改善突触区域的竞争。这些补充方法将创造最佳最大化可从再生CST轴突中提取的行为益处的策略。