The Role of the Transcallosal Pathway in Neuroplasticity Following Nerve Injury

描述(申请人提供)：周围神经损伤导致感觉功能障碍，被认为不仅可归因于周围神经中发生的功能、细胞和生化事件，还可归因于周围区域大脑皮质表现中的功能变化。证据表明，周围神经损伤导致位于剥夺的(患肢的对侧)和健康的(患肢的同侧)躯体感觉皮质的皮质表征重组。这些研究表明，双侧的重组可能起源于大脑半球间的改变，即跨痂通路。此外，最近的人类康复研究表明，事实上，这些新发现的跨痂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(失神经)导致双侧皮质表达的重组。我们的结果表明，这些神经元的变化可以用功能磁共振成像(FMRI)、电生理学、免疫染色和激光散斑对比光学成像(LSI)来监测。我们的研究结果表明，确实是通过跨痂通路调节了双侧皮质的重组，结果是位于被剥夺的皮质(受损肢体的对侧)的抑制性中间神经元的活动增加。我们假设，在被剥夺的皮质中观察到的皮质抑制的增加可能是患者观察到的恢复不良的基础。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的方法来确定周围神经损伤后重塑神经元行为的关键跨痂神经机制。此外，我们还建议开发一种新的“引导可塑性”策略，通过使用光遗传学(光遗传学)技术来控制跨痂连接的活动，以促进周围神经损伤后的恢复。这将通过光激活位于健康的、未受影响的皮质中的神经元中的氯泵(卤视紫红质)来瞬时地减少跨颧骨的通信来实现。最后，我们建议开发一个使用功能磁共振成像的非侵入性平台，以监测光遗传学操作对损伤后皮质重组的影响。这项动物研究的结果可以直接转化为临床应用，以改进基于经膝盖骨的手法的康复策略。我们期望这将促进一种新颖而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：本研究的目标是调查大脑半球间神经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。从动物研究中获得的结果可以直接转化为临床应用，以改进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.