Dissecting motor cortex circuits underyling chronic pain relief

剖析缓解慢性疼痛的运动皮层回路

基本信息

批准号：
10401494
负责人：
Nicole Mercer Lindsay
金额：
$ 1.76万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-09-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401494
关键词：
Absence of pain sensation Affective American Americas Amygdaloid structure Anterior Area Basic Science Behavior Biological Models Brain Brain Stem Brain region Calcium Chronic Clinical Clinical Treatment Clozapine Complement Data Set Designer Drugs Development Enterobacteria phage P1 Cre recombinase Environment Experimental Designs Genetic Head Human Image Imaging Techniques Individual Knowledge Light Magnetism Mammals Maps Mentorship Methods Motivation Motor Motor Cortex Motor output Movement Mus Neurons Neurosciences Nociception Nociceptors Non-Malignant Opioid Opsin Output Oxides Pain Pain Clinics Pain intensity Patients Pattern Persons Play Population Positioning Attribute Process Protocols documentation Rabies virus Reporting Research Project Grants Risk Rodent Role Scientist Sensory Signal Transduction Spinal Cord Structure Synapses Techniques Technology Thalamic structure Therapeutic Time Training Travel Treatment Protocols Viral Virus Work addiction behavioral outcome chronic neuropathic pain chronic pain chronic pain management chronic pain relief cingulate cortex collaborative environment connectome designer receptors exclusively activated by designer drugs excitatory neuron experience improved in vivo calcium imaging innovation midbrain central gray substance mouse model optogenetics pain relief painful neuropathy programs response tool training opportunity

项目摘要

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.

项目摘要超过 1 亿美国人患有慢性疼痛，他们选择服用止痛药。由于存在成瘾风险，并且有报道称，长期使用阿片类药物一直存在争议。治疗慢性非恶性疼痛（例如神经性疼痛）的功效慢性疼痛的沉重负担。美国提示需要一种非成瘾性镇痛的替代方法。疼痛是通过非侵入性的电或磁刺激人类患者的大脑来实现的。令人惊讶的是，无创刺激的目标是运动皮层，运动皮层以其在运动中的作用而闻名。引发随意运动，并具有与整个大脑广泛连接的体位运动图和脊髓，包括尚未研究的与前扣带皮层 (ACC)、内侧皮质的连接丘脑 (MD)、基底外侧杏仁核 (BLA) 和导水管周围灰质 (PAG)。皮层和已知对疼痛情感成分很重要的区域可能是潜在的电路在患有慢性疼痛的人类患者的运动皮层刺激（MCS）过程中引起镇痛。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。将首先识别当小鼠经历疼痛时做出反应的运动皮层神经元，并进一步量化它们与 ACC、MD、BLA 和 PAG 等疼痛区域的下游连接在目标 2 中，我将想象该活动。慢性疼痛发展过程中和 MCS 诱导的疼痛缓解过程中运动皮层神经元的变化。 3，我将使用光遗传学刺激选择性地将 MCS 靶向神经元亚群，并确定哪些产生的数据集将包括伤害性运动皮层神经元的活动模式。以及其他与疼痛相关的大脑区域的神经目标的细胞身份。可供登山者优化 MCS 治疗方案以激活特定亚群并进行调整该项目将在 Mark Schnitzer 教授的协作环境中进行。（赞助商）斯坦福大学实验室，一个创新神经科学和成像技术的专家环境。在领先的疼痛神经科学家 Greg Scherrer 教授和 Sean Mackey（共同发起人）的指导下，拟议的培训计划为我提供了将新的科学思想与前沿技术相结合的绝佳机会我将获得利用临床治疗提出科学问题和创造的宝贵经验。有用的实验设计将帮助我成为一名理想的科学家，并使我能够开始我自己的实验室计划，研究疼痛回路及其与运动回路和行为结果的交叉点。我们将共同剖析目前有效的慢性疼痛无创治疗方法的回路缓解疼痛并揭示大脑如何产生疼痛的更广泛的图景。