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，认为其不仅可归因于周围神经中发生的功能、细胞和生物化学事件，还可归因于周围区域的大脑皮质表征中发生的功能变化。有证据表明，周围神经损伤导致位于被剥夺的（受伤肢体的对侧）和健康的（受伤肢体的同侧）躯体感觉皮层中的皮层表示的重组。这些研究表明，双边重组可能源于发生在半球间的修改，trans胼胝体通路。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。与人类研究相似，大鼠外周神经损伤（去神经支配）导致双侧皮质表征重组。我们的研究结果表明，这些神经元的变化，可以使用功能磁共振成像（fMRI），电生理学，免疫染色和激光散斑对比光学成像（LSI）监测。我们的研究结果表明，确实transcallosal途径介导的双边皮层重组，因此有位于剥夺皮层（对侧受伤肢体）的抑制性中间神经元的活动增加。我们推测，在剥夺皮层中观察到的皮层抑制增加可能是在患者中观察到的恢复不良的基础。 在这里，我们建议使用高分辨率的电生理测量和功能磁共振成像相结合，以确定关键的trans胼胝体神经元的机制，重塑周围神经损伤后的神经元行为。此外，我们建议开发一种新的“引导可塑性”的策略，以促进周围神经损伤后的恢复，通过操纵活动的transcallosa连接使用光遗传学（光遗传学）技术。这将通过在位于健康的未受影响的皮层中的神经元中通过光激活Cl-泵（盐视紫红质）来暂时减少经胼胝体通信来实现。最后，我们建议开发一个非侵入性的平台，使用功能磁共振成像来监测损伤后皮质重组的光遗传学操作的效果。从这项动物研究中获得的结果可以直接转化为临床应用方面的改善康复策略，这是基于经胼胝体的操作。我们期望这将有助于一个原始的和有效的方法来恢复周围神经损伤后的正常皮质功能。 公共卫生相关性：本研究的目的是研究半球间神经元通路的行为改变如何影响周围神经损伤后的恢复，以及如何操纵这些通路以促进恢复。从这项动物研究中获得的结果可以直接转化为临床应用，以改善和开发新的康复策略。

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.