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: 8963913
• 负责人: Galit Pelled
• 金额: $ 34.77万
• 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 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963913
• 关键词: Accidents; Address; Adjuvant; Adult; Affect; American; Amputees; Animal Model; Animals; Autoimmune Diseases; Behavioral; Brain; Characteristics; Chloride Channels; Clinical; Contralateral; Diabetes Mellitus; Dopa-Responsive Dystonia; Electromagnetic Fields; Electromagnetics; Electrophysiology (science); Equilibrium; Fishes; Fluorescence; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Goals; Grant; Grooming; Human; Image; Injury; Interneurons; Ion Channel; Lead; Limb structure; Long-Term Depression; Long-Term Potentiation; Maps; Mediating; Membrane; Metabolic Diseases; Methods; Molecular; Nerve; Neuronal Injury; Neuronal Plasticity; Neurons; Neurorehabilitation; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Peripheral Nerves; Peripheral nerve injury; Phantom Limb Pain; Protocols documentation; Rattus; Recovery; Rehabilitation therapy; Resolution; Rodent; Role; Sensory; Slice; Somatosensory Cortex; Source; Synaptic plasticity; Technology; Testing; Transcranial magnetic stimulation; Translating; United States; Up-Regulation; War; base; behavior test; chronic pain; excitatory neuron; functional outcomes; improved; in vivo; inhibitory neuron; injured; limb injury; minimally invasive; neglect; nerve injury; nervous system disorder; neurophysiology; neuroregulation; novel; optical imaging; optogenetics; painful neuropathy; promoter; public health relevance; repaired; response

 DESCRIPTION (provided by applicant): Twenty million Americans suffer from peripheral nerve injury that leads to significant changes in cortical and subcortical neuronal activity. Evidence from human imaging studies suggests that the degree of post- injury plasticity and cortical remapping may be maladaptive and positively correlated to the levels of sensory dysfunctions and phantom limb pain. In an animal model of peripheral nerve injury we demonstrated that post-injury increases in functional magnetic resonance imaging (fMRI) responses reflect in fact, increases in inhibitory interneurons activity. Thus, we hypothesize that post-injury increase in inhibitory interneurons activity delays neurorehabilitation. However, the majority of current neurorehabilitation strategies focus on surgical nerve repair which neglect to address the dramatic changes occurring in the brain level. Indeed, studies show that patients continue to suffer from sensory dysfunctions despite nerve repair surgeries. We have recently demonstrated that limb injury in adult rats induces short- and long-term plasticity changes that affect S1 activity; an effect that can be readily mapped with non-invasive, ultra-high field, and high-resolution fMRI. The plasticity was manifested in changes in the excitability of cortical laye 5 inhibitory interneurons in the affected primary somatosensory cortex (S1), and was mediated via the transcallosal projections. We used optogenetics methods to modulate cortical activity in the injured rats and successfully restored the balance between excitation and inhibition. Therefore, post-injury neuronal changes leading to a shift in the excitation-inhibition balance have the potential to be reshaped with neuromodulation strategies. The goal of this proposal is to develop state-of-the-art neuromodulation strategies to augment recovery including transcranial magnetic stimulation (TMS) and a novel, minimally-invasive, neuronal-specific technology. Utilizing multimodal technical approaches we will determine how injury affects plasticity mechanisms in the molecular, cellular, network and behavioral levels, and whether the neuromodulation strategies employed here can minimize sensory dysfunctions associated with injury and facilitate rehabilitation. We anticipate that these strategies could be translated into he clinical setting as alternatives or adjuvants to traditional surgical nerve repairs, and also be usd to modulate neuronal function in other neurological disorders.

 描述（由申请人提供）：两千万美国人患有周围神经损伤，导致皮质和皮质下神经元活动发生显着变化。来自人类影像学研究的证据表明，损伤后可塑性和皮质重新映射的程度可能是适应不良的，并且与感觉功能障碍和幻肢痛的水平呈正相关。在周围神经损伤的动物模型中，我们证明，损伤后功能性磁共振成像（fMRI）反应的增加实际上反映了抑制性中间神经元活动的增加。因此，我们假设 损伤后抑制性中间神经元活动的增加会延迟神经康复。然而，目前大多数神经康复策略都集中在外科神经修复上，而忽视了大脑水平发生的巨大变化。事实上，研究表明，尽管进行了神经修复手术，患者仍然患有感觉功能障碍。我们最近证明，成年大鼠的肢体损伤会引起影响 S1 活性的短期和长期可塑性变化；这种效应可以通过非侵入性、超高场和高分辨率功能磁共振成像轻松绘制。可塑性表现为受影响的初级体感皮层 (S1) 中皮质第 5 层抑制性中间神经元的兴奋性变化，并通过胼胝体投射介导。我们利用光遗传学方法来调节受伤大鼠的皮质活动，并成功恢复了兴奋和抑制之间的平衡。因此，导致兴奋-抑制平衡转变的损伤后神经元变化有可能通过神经调节策略进行重塑。该提案的目标是开发最先进的神经调节策略来促进康复，包括经颅磁刺激 (TMS) 和一种新颖的微创神经元特异性技术。利用多模式技术方法，我们将确定损伤如何影响分子、细胞、网络和行为水平的可塑性机制，以及这里采用的神经调节策略是否可以最大限度地减少与损伤相关的感觉功能障碍并促进康复。我们预计这些策略可以转化为临床环境，作为传统外科神经修复的替代品或辅助剂，也可用于调节其他神经系统疾病的神经元功能。