Somatosensory corticospinal neurons as a biomarker for mind-body pain management strategies

项目总结/摘要 神经性疼痛是一个重要的公共卫生问题，影响生活质量，其中非神经性疼痛是一个重要的公共卫生问题。 传统的治疗方法，如电刺激，大麻，或冥想已经出现， 慢性疼痛管理的有前途的策略。尽管试图建立标准化的 团，效率仍然很不稳定。很明显，目前的经验观察是 不足以对这些较温和的治疗对个体化疼痛感知的结论性评价， 这可能被诸如注意力和情绪的精神状态的动态变化所掩盖。这 这种限制促使需要鉴定和利用新的机制生物标志物。 波士顿儿童医院的何志刚和克利福德·伍尔夫博士最近的证据显示， 一个处理轻触的关键自上而下的调节器，躯体感觉皮层（S1）皮质脊髓 神经元（CSN），其在神经损伤后变得敏感。作为世界上最著名的 大脑皮层细胞与直接下行轴突投射到脊髓，CSNs可以是 精神状态和脊椎触觉处理之间缺失的环节因此，这一目标 一个建议是研究S1 CSNs作为监测触觉敏感性的生物标志物及其作用 减轻疼痛的策略。更具体地说，我们打算监测S1 CSN的功能活动， 与行为敏感性平行，同时探测直接皮质皮层回路或应用 备用神经损伤后的神经调节治疗，一种可再现的神经性疼痛 动物模型初步证据表明，S1 CSN皮质连接的存在 近端和远端突触前连接在三个离散的区域：初级运动 皮质（M1）、次级躯体感觉皮质（S2）和压后皮质（RSC）。M1和 S2与触觉有关，RSC显示出更广泛的记录作用， 多模态感觉和认知计算。因此，我们提出的目标是调查 1）近端抑制性连接和2）远端突触前投射的功能贡献， 以及3）表征硬膜外电刺激或大麻二酚（CBD）的影响 给药对S1 CSN活性和行为敏感性的影响。为了实现这些目标，我们将使用 病毒示踪剂或Cre小鼠系与光遗传学刺激和功能性钙结合 显像研究结果将解决皮层的轻触感觉处理，并评估 S1 CSN作为疼痛管理策略的生物标志物的潜力。此外，这种支持 将直接促进下一代的技术和科学知识发展 神经科学家，从而促进职业发展的独立研究。

PROJECT SUMMARY/ABSTRACT Neuropathic pain is an important public health issue compromising quality of life, where non- conventional treatments like electrical stimulation, cannabis, or meditation have emerged as promising strategies for chronic pain management. Yet despite attempts to establish standardized regiments, efficiency remains highly variable. It is evident current empirical observation is insufficient for conclusive evaluation of these milder treatments on individualized pain perception, which may be masked by dynamic changes in mental states such as attention and mood. This limitation precipitates the need for identification and leverage of new mechanistic biomarkers. Recent evidence from Drs. Zhigang He and Clifford Woolf at Boston Children's Hospital revealed a key top-down regulator in processing light touch, somatosensory cortex (S1) corticospinal neurons (CSNs), which become sensitized following nerve injury. As one of the most prominent cerebral cortical cells with direct descending axonal projections to the spinal cord, CSNs could be the missing link between mental states and spinal tactile processing. Thus, the objective of this proposal is to investigate S1 CSNs as a biomarker for monitoring tactile sensitivity and their role in pain-reducing strategies. More specifically, we intend to monitor S1 CSN functional activity in parallel with behavioral sensitivity while probing direct corticocortical circuitry or applying neuromodulatory treatments following spared nerve injury, a reproducible neuropathic pain animal model. Preliminary evidence mapping S1 CSN cortical connectivity indicates the existence of both proximal and distal pre-synaptic connections in three discrete regions: primary motor cortex (M1), secondary somatosensory cortex (S2), and retrosplenial cortex (RSC). While M1 and S2 have been linked to tactile sensation, the RSC displays a more broadly documented role in polymodal sensory and cognitive computation. Thus, our proposed aims intend to investigate the functional contribution of 1) proximal inhibitory connections and 2) distal pre-synaptic projections, as well as 3) characterize the impact of epidural electrical stimulation or cannabidiol (CBD) administration on S1 CSN activity and behavioral sensitivity. To address these aims, we will use viral tracers or Cre mouse lines in combination with optogenetic stimulation and functional calcium imaging. Study outcomes will address light touch sensory processing in the cortex and evaluate the potential of S1 CSNs as a biomarker for pain management strategies. In addition, this support will contribute directly to the technical and scientific knowledge development of a next generation neuroscientist, thereby fostering career growth towards independent research.