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

项目摘要/摘要 神经病理性疼痛是一个重要的公共卫生问题，影响生活质量，其中非 像电刺激、大麻或冥想这样的传统疗法已经出现 有希望的慢性疼痛管理策略。然而，尽管试图建立标准化的 各团，效率仍然高度不稳定。很明显，目前的经验观察是 不足以对这些较温和的治疗方法在个性化疼痛感知方面进行结论性评估， 这可能被精神状态的动态变化所掩盖，例如注意力和情绪。这 局限性催生了识别和利用新的机械性生物标记物的需要。 波士顿儿童医院何志刚博士和克利福德·伍尔夫博士最近的证据显示 躯体感觉皮层(S1)是处理光触摸的关键自上而下的调节器 神经元(CSN)，在神经损伤后变得敏感。作为最突出的 具有直接向脊髓下行轴突投射的大脑皮质细胞，CSNS可能是 精神状态和脊椎触觉处理之间缺失的一环。因此，这一行动的目标是 建议研究S1 CSNS作为监测触觉敏感度的生物标志物及其作用 在减轻疼痛的策略上。更具体地说，我们打算监控S1CSN在 在探测直接皮质回路或应用时与行为敏感性平行 备用神经损伤后的神经调节治疗--一种可复制的神经病理性疼痛 动物模型。初步绘制S1 CSN皮质连接图表明存在 三个离散区域的近端和远端突触前连接：初级运动 皮质(M1)、次级躯体感觉皮质(S2)和脾后皮质(RSC)。而M1和 S2与触觉有关，RSC在 多通道感觉和认知计算。因此，我们提议的目标是调查 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)描述硬膜外电刺激或大麻二醇(CBD)的影响 给药对S1CSN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小鼠品系与光遗传刺激和功能钙的结合 成像。研究结果将涉及大脑皮层的光触摸感觉处理，并评估 S1 CSNS作为疼痛管理策略生物标记物的潜力。此外，这一支持 将直接为下一代的技术和科学知识发展做出贡献 神经科学家，从而促进了独立研究的职业发展。

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.