The Role of the Transcallosal Pathway in Neuroplasticity Following Nerve Injury

 描述(申请人提供)：2000万美国人患有周围神经损伤，导致皮质和皮质下神经元活动的显著变化。来自人类成像研究的证据表明，损伤后的可塑性和皮质重新映射的程度可能是不适应的，并与感觉功能障碍和幻肢疼痛的程度呈正相关。在周围神经损伤的动物模型中，我们证明了损伤后功能磁共振成像(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性的增加延迟了神经康复。然而，目前的神经康复策略大多集中在外科神经修复上，而忽视了脑水平发生的剧烈变化。事实上，研究表明，尽管接受了神经修复手术，患者仍在继续遭受感觉功能障碍的折磨。我们最近已经证明，成年大鼠的肢体损伤会导致短期和长期的可塑性变化，影响S1的活性；这种影响可以很容易地通过非侵入性、超高场和高分辨率的fMRI进行定位。这种可塑性表现为受影响的初级躯体感觉皮质(S1)中皮层5层抑制中间神经元兴奋性的变化，并通过经颧骨投射进行调节。我们使用光遗传学方法来调节损伤大鼠的皮质活动，并成功地恢复了兴奋和抑制之间的平衡。因此，损伤后神经元的变化导致兴奋-抑制平衡的改变，有可能通过神经调节策略来重塑。这项提议的目标是开发最先进的神经调节策略来增强康复，包括经颅磁刺激(TMS)和一种新的、微创的神经元特异性技术。利用多模式技术方法，我们将确定损伤如何在分子、细胞、网络和行为水平上影响可塑性机制，以及这里采用的神经调节策略是否可以将与损伤相关的感觉功能障碍降至最低，并促进康复。我们预计，这些策略可以作为传统外科神经修复的替代或辅助手段应用于临床，也可用于调节其他神经系统疾病的神经功能。

 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.