The Role of the Transcallosal Pathway in Neuroplasticity Following Nerve Injury

经胼胝体通路在神经损伤后神经可塑性中的作用

• 批准号: 8023948
• 负责人: Galit Pelled
• 金额: $ 32.35万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8023948
• 关键词: Affect; Animals; Appearance; Behavior; Behavioral; Bilateral; Biochemical; Brain; Cells; Cerebrum; Chemicals; Chloride Ion; Chlorides; Communication; Contralateral; Denervation; Development; Electrophysiology (science); Engineering; Epilepsy; Event; FOS gene; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Goals; Halorhodopsins; Human; Imaging Techniques; Injury; Interneurons; Ipsilateral; Lasers; Light; Limb structure; Measurement; Mediating; Modeling; Modification; Monitor; Motor Cortex; Movement; Neuronal Plasticity; Neurons; Optics; Outcome; Parkinson Disease; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral nerve injury; Population; Potassium Channel; Pump; Rattus; Recovery; Rehabilitation therapy; Research; Resolution; Role; Sensory; Somatosensory Cortex; Techniques; Testing; Time; Translating; Vibrissae; Viral Vector; attenuation; base; cell type; clinical application; excitatory neuron; expectation; improved; in vivo; injured; nerve injury; neuronal circuitry; neurophysiology; novel; novel strategies; optical imaging; promoter; public health relevance; rehabilitation strategy; response; transcription factor

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.

描述（由申请人提供）：周围神经损伤导致感觉功能障碍，这被认为不仅归因于周围神经中发生的功能、细胞和生化事件，而且还归因于周围神经的大脑皮层表征中发生的功能变化。地区。有证据表明，周围神经损伤导致位于受损（受伤肢体的对侧）和健康（受伤肢体的同侧）体感皮层的皮质表征的重组。这些研究表明，双侧重组可能源于半球间、胼胝体通路中发生的改变。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）会导致双侧皮质表征的重组。我们的结果表明，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）来监测这些神经元变化。我们的研究结果表明，经胼胝体通路确实介导双侧皮质重组，因此位于受损皮质（受伤肢体的对侧）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，我们建议结合使用高分辨率电生理学测量和功能磁共振成像来确定重塑周围神经损伤后神经元行为的关键经胼胝体神经元机制。此外，我们建议开发一种新颖的“引导可塑性”策略，通过使用光遗传学（光遗传学）技术操纵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、未受影响的皮层的神经元中的氯泵（盐视紫红质）来暂时减少跨胼胝体通讯来实现。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来监测光遗传学操作对损伤后皮质重组的影响。从这项动物研究中获得的结果可以直接转化为临床应用，以改善基于经胼胝体操作的康复策略。我们期望这将有助于采用原创且有效的方法来恢复周围神经损伤后的正常皮质功能。 公共健康相关性：本研究的目的是调查半球间神经元通路行为的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改善和开发新的康复策略的临床应用。