The Role of the Transcallosal Pathway in Neuroplasticity Following Nerve Injury

描述（由申请人提供）：周围神经损伤引起感觉功能障碍，被认为不仅可归因于周围神经发生的功能，细胞和生化事件，还可归因于周围区域大脑皮层表征发生的功能变化。有证据表明，周围神经损伤导致位于被剥夺（对侧损伤肢体）和健康（同侧损伤肢体）体感觉皮层的皮层表征重组。这些研究表明，双侧重组可能源于发生在半球间、经胼胝体通路的修饰。此外，最近的人类康复研究表明，事实上，这些新发现的经胼胝体神经可塑性机制可能决定了周围神经损伤后的恢复程度。与人类研究类似，大鼠周围神经损伤（去神经支配）导致双侧皮层表征重组。我们的研究结果表明，这些神经元的变化可以通过功能磁共振成像（fMRI）、电生理学、免疫染色和激光散斑对比光学成像（LSI）来监测。我们的研究结果表明，经胼胝体通路确实介导了双侧皮层的重组，因此位于被剥夺皮层（对侧受伤肢体）的抑制性中间神经元的活性增加。我们假设，在被剥夺的皮层中观察到的皮质抑制增加可能是在患者中观察到的不良恢复的基础。在这里，我们建议使用高分辨率电生理测量和功能磁共振成像相结合来确定周围神经损伤后重塑神经元行为的关键经叶神经元机制。此外，我们建议开发一种新的“引导可塑性”策略，通过使用光遗传学技术操纵经胼胝体连接的活动来促进周围神经损伤后的恢复。这将通过光激活位于健康的、未受影响的皮层的神经元中的Cl-泵（盐视紫红质），短暂地减少跨胼胝体通信来实现。最后，我们建议开发一个非侵入性平台，利用fMRI来监测光遗传学操作对损伤后皮层重组的影响。这项动物研究的结果可以直接转化为临床应用，以改善基于经胼胝体操作的康复策略。我们期望这将促进一种原始和有效的方法来恢复周围神经损伤后的正常皮质功能。

DESCRIPTION (provided by applicant): Peripheral nerve injury causes sensory dysfunctions that are thought to be attributable not only to the functional, cellular and biochemical events occurring in the peripheral nerve, but also to the functional changes occurring in the cerebral cortical representations of the peripheral regions. Evidence shows that peripheral nerve injury results in reorganization of cortical representation located in the deprived (contralateral to the injured limb) and healthy (ipsilateral to the injured limb) somatosensory cortices. These studies suggest that the bilateral reorganization may originate from modifications occurring in the inter-hemispheric, transcallosal pathway. Moreover, recent human rehabilitation studies suggest that in fact, these newly identified transcallosal neuroplasticity mechanisms may dictate the degree of recovery following peripheral nerve injury. Similar to human studies, peripheral nerve injury (denervation) in the rat results in bilateral reorganization of cortical representations. Our results demonstrate that these neuronal changes can be monitored using functional magnetic resonance imaging (fMRI), electrophysiology, immunostaining and laser speckle contrast optical imaging (LSI). Our findings suggest that indeed the transcallosal pathways mediate the bilateral cortical reorganization and as a result there are increases in the activity of inhibitory interneurons located in the deprived cortex (contralateral to the injured limb). We hypothesize that the increased cortical inhibition observed in the deprived cortex may be the foundation of the poor recovery observed in patients. Here we propose to use a combination of high-resolution electrophysiology measurements and fMRI to identify the key transcallosal neuronal mechanisms that reshape the neuronal behavior following peripheral nerve injury. In addition we propose to develop a novel "guided plasticity" strategy to promote recovery following peripheral nerve injury by manipulating the activity of the transcallosal connections using optical-genetic (optogenetics) techniques. This will be achieved by transiently reducing transcallosal communication by light activating Cl- pumps (halorhodopsin) in neurons located in the healthy, unaffected cortex. Finally, we propose to develop a non-invasive platform using fMRI to monitor the effect of the optogenetics manipulations on cortical reorganization following injury. Results obtained from this animal study could be directly translated into clinical applications in terms of improving rehabilitation strategies which are based on transcallosal manipulations. It is our expectation that this will facilitate an original and effective approach to restore normal cortical functions following peripheral nerve injury. PUBLIC HEALTH RELEVANCE: The goal of this research is to investigate how modifications in the behavior of inter-hemispheric neuronal pathways affect recovery following peripheral nerve injury and how these pathways can be manipulated in order to promote recovery. Results obtained from this animal study could be directly translated into clinical applications in terms of improving and developing new rehabilitation strategies.