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。选择以长期以来对人的opioids由于成瘾的风险和有限的报告而引起了争议控制慢性非恶性疼痛的功效（例如，神经性疼痛）。慢性疼痛的重灼伤美国促使人们需要采取非成瘾性镇痛的替代方法。一种缓解的潜在方法疼痛是通过对大脑的非侵入性电或磁刺激而进行的。在人类患者中，最有效令人惊讶的是，非侵入性刺激的靶标是运动皮层。运动皮层以其在引发自愿运动，并具有一个体型电动机图和脊髓，包括与前扣带回皮层（ACC），培养基的联系丘脑（MD），基底外侧杏仁核（BLA）和灰灰色（PAG）。电机之间的这些连接皮质和已知对受影响的疼痛组成部分很重要的区域可能是基础电路这会导致患有慢性疼痛的人类患者运动皮层刺激（MC）。到完全解剖了MC的机制，我建议使用慢性神经性疼痛的小鼠模型。在AIM 1中，我将首先识别当小鼠经历疼痛并进一步量化其的运动皮质神经元与ACC，MD，BLA和PAG等疼痛区域的下游连接。在AIM 2中，我将对活动进行映像慢性疼痛和MCS诱导的疼痛缓解期间，运动皮层中的神经元的神经元。目标 3，我将使用光遗传刺激有选择地将MC靶向神经元的亚群，并确定哪个是诱导的镇痛。所得的数据集将包括伤害性运动皮质神经元的活动模式以及其他与疼痛相关的大脑区域中神经元靶标的细胞身份。这些信息将是可供临床医生优化MCS治疗方案以激活特定的亚群并调整为神经元活动模式。该项目将在Mark Schnitzer教授的合作环境中进行（赞助商）斯坦福大学的实验室，这是创新神经科学和成像技术的专家环境。一起借助领先的疼痛神经科学家的精神，教授。 Greg Scherrer和Sean Mackey（共同提案国），拟议的培训计划为我提供了将新科学思想与尖端结合起来的绝佳机会技术。我将在使用临床治疗提出科学问题并创建临床治疗方面获得宝贵的经验有用的实验设计。这个项目将有助于使我成为有意的科学家，并将我定位为启动我自己的实验室计划，研究止痛电路及其与电机电路和行为结果相交。总的来说，我们将剖析目前有效的无创治疗方法的电路缓解和揭示了更广泛的了解大脑中疼痛戒律的方式。