Dissecting motor cortex circuits underyling chronic pain relief

项目摘要 超过1亿美国人患有慢性疼痛。选择处方止痛的形式， 阿片类药物的人长时间一直有争议，由于成瘾的风险和报告有限， 控制慢性非恶性疼痛的功效（例如，神经性疼痛）。慢性疼痛的沉重负担 美国提出了非成瘾性镇痛替代方法的需求。一种潜在的缓解方法 疼痛是通过对大脑的非侵入性电刺激或磁刺激产生的。在人类患者中， 非侵入性刺激的目标是运动皮层。运动皮层最著名的作用是 引发随意运动，并具有在整个大脑中广泛连接的躯体运动地图 和脊髓，包括与前扣带皮层（ACC），中背 丘脑（MD）、基底外侧杏仁核（BLA）和导水管周围灰质（PAG）。这些电机之间的连接 皮质和已知对疼痛的情感成分很重要的区域可能是潜在的回路 其在患有慢性疼痛的人类患者的运动皮层刺激（MCS）期间引起镇痛。到 为了充分剖析MCS的机制，我建议使用慢性神经病理性疼痛的小鼠模型。在目标1中， 将首先确定运动皮层神经元，当小鼠经历疼痛时， 与疼痛区域如ACC、MD、BLA和PAG的下游连接。在目标2中，我将想象活动 在慢性疼痛的发展过程中和在MCS诱导的疼痛缓解过程中，运动皮层神经元的变化。在Aim中 3，我将使用光遗传学刺激来选择性地将MCS靶向神经元亚群，并确定 会产生镇痛作用该数据集将包括伤害感受运动皮层神经元的活动模式 以及它们在其他疼痛相关脑区的神经元靶点的细胞身份。此信息将 可供临床医生优化MCS治疗方案，以激活特定亚群，并调整为 神经元活动模式该项目将在Mark Schnitzer教授的协作环境中进行 斯坦福大学的实验室，一个创新神经科学和成像技术的专家环境。一起 在领先的疼痛神经科学家的指导下，教授。Greg Scherrer和Sean Mackey（共同赞助人）， 拟议的培训计划为我提供了一个极好的机会，使我能够将联合收割机新的科学思想与尖端技术结合起来。 技术.我将获得宝贵的经验，利用临床治疗提出科学问题，并创造 有用的实验设计。这个项目将有助于制定我成为一个可持续发展的科学家，并定位我， 开始我自己的实验室项目，研究疼痛回路及其与运动回路和行为结果的交叉。 总的来说，我们将解剖目前有效的慢性疼痛非侵入性治疗的基础电路 缓解和揭示更广泛的图片疼痛戒律是如何产生的大脑。

Project Abstract More than 100 million Americans suffer from chronic pain. The choice to prescribe pain relief in the form of opioids to people for long periods of time has been controversial due to the risk of addiction and reports of limited efficacy to manage chronic nonmalignant pain (e.g., neuropathic pain). The heavy burden of chronic pain in America prompts the need for alternative methods of non-addictive analgesia. One potential method of relieving pain is through non-invasive electrical or magnetic stimulation of the brain. In human patients, the most effective target of noninvasive stimulation is, surprisingly, the motor cortex. Motor cortex is best known for its role in eliciting voluntary movements and has a somatotopic motor map with broad connections throughout the brain and spinal cord, including understudied connections with the anterior cingulate cortex (ACC), mediodorsal thalamus (MD), basolateral amygdala (BLA), and periaqueductal gray (PAG). These connections between motor cortex and the regions known to be important for the affective component of pain may be the underlying circuits that cause analgesia during motor cortex stimulation (MCS) of human patients suffering from chronic pain. To fully dissect the mechanism of MCS, I propose to use a mouse model of chronic neuropathic pain. In Aim 1, I will first identify the motor cortex neurons that respond when mice experience pain and further quantify their downstream connections with pain regions like the ACC, MD, BLA, and PAG. In Aim 2, I will image the activity of neurons in motor cortex during the development of chronic pain and during MCS-induced pain relief. In Aim 3, I will use optogenetic stimulation to selectively target MCS to subpopulations of neurons and determine which are inducing analgesia. This resulting dataset will include activity patterns of nociceptive motor cortex neurons and the cellular identity of their neuronal targets in other pain-relevant brain regions. This information will be available for clinicians to optimize MCS treatment protocols to activate specific subpopulations and tuned to neuronal activity patterns. This project will take place in the collaborative environment of Prof. Mark Schnitzer’s (sponsor) lab at Stanford, an expert environment for innovative neuroscience and imaging techniques. Together with the mentorship of leading pain neuroscientists, Profs. Greg Scherrer and Sean Mackey (co-sponsors), the proposed training plan provides an excellent opportunity for me to combine new scientific ideas with cutting-edge technology. I will gain valuable experience in using clinical treatments to ask scientific questions and create useful experimental designs. This project will help to formulate me into an intendent scientist and position me to start my own lab program studying pain circuitry and its intersect with motor circuits and behavioral outcomes. Collectively, we will dissect the circuits underlying a currently effective, noninvasive treatment for chronic pain relief and uncover a broader picture of how pain precept is generated in the brain.