Harnessing cortical neuromodulation to disrupt pain perception

项目总结 慢性疼痛是美国的一项主要健康危机，影响着1亿美国人和数百万人 全世界。此外，使用阿片类药物治疗慢性疼痛一直是阿片类药物流行的主要驱动力， 已经席卷了全国。开发具有类似或更高疗效的新疗法 相对于阿片类药物用于治疗疼痛但缺乏成瘾倾向的处方类阿片类药物可能会有深远的影响 对于治疗疼痛患者和减轻国家阿片类药物危机的负担都有效果。一个重要的障碍 在实现这一目标方面，我们对大脑回路和通路知之甚少，这些回路和通路有助于 慢性疼痛引起的痛苦。我们的目标是确定疼痛情感性背后的神经回路元素 感知，解码他们的神经计算在慢性疼痛过程中是如何演变的，并试图将这些正常化 精确的基于电路的光学干预的病理动力学。在这里，我们将通过以下方式实现这一目标 使用自动大规模单神经元分辨技术可视化新皮质内的关键阿片类药物回路 成像、光遗传操作和机器视觉行为分析。通过实现这一目标，我们将 生成新的动态框架，用于模拟慢性疼痛的出现。这些框架将通知 我们使用现代电路中断技术的翻译目标定位策略的最终目标是 促进内源性阿片肽的释放仅在所需的脑区、环路和突触中进行 疼痛处理，具有临时按需控制。因此，我们的战略的成功实施可以 释放破坏皮质和/或皮质下电路特异性病理的技术，以缓解 慢性疼痛患者的痛苦。这项拟议的研究非常适合NIH新创新者的目标 颁奖计划。这些技术和高风险战略的创新组合有可能 改变我们对慢性疼痛如何调节大脑网络以及如何严格控制它们的理解。我们的 项目包含了许多重大的进步，无论是在概念上还是在技术上，都可能 从根本上改变旨在改变神经回路的止痛药的基本设计方法 对疼痛的负面情感知觉的基础。我在疼痛神经生物学、阿片类药物方面的跨学科背景 药理学和系统神经科学，再加上我在鉴定结构上的成功- 神经电路的功能逻辑是技能的精确组合，使我非常适合完全执行 这一雄心壮志的项目。美国国立卫生研究院院长的新创新者奖将为我的 早期的职业生涯，并支持我解构大脑疼痛的研究计划的继续轨迹 制定非传统战略以治疗慢性疾病的不良影响和痛苦的系统 疼痛患者，并减少对阿片类药物处方的依赖。

PROJECT SUMMARY Chronic pain is a major health crisis in the United States, affecting >100 million Americans and millions more worldwide. In addition, the use of opioids to treat chronic pain has been a major driver in the opioid epidemic that has swept over the country. Development of new classes of therapeutics that have a similar or higher efficacy relative to opioids for treating pain but lack the addictive liability of prescription opioids could have profound effects both for treating pain patients and for reducing the burden of the national opioid crisis. A significant barrier in achieving this goal is that we have little understanding of the brain circuits and pathways that contribute to the suffering caused by chronic pain. Our goal is to identify the neural circuit elements underlying pain affective perception, decode how their neural computations evolve during chronic pain, and attempt to normalize these pathological dynamics with precise circuit-based optical interventions. Here, we will achieve this goal by visualizing critical opioid circuits within the neocortex using automated large-scale single-neuron resolution imaging, optogenetic manipulations, and machine-vision behavior analysis. By achieving this goal, we will generate new dynamic frameworks for modeling the emergence of chronic pain. These frameworks will inform our translational targeting strategies using contemporary circuit disruption technologies with the ultimate goal of promoting endogenous opioid peptide release only in the desired brain region, circuit, and synapses relevant to pain processing, with temporal on-demand control. Therefore, successful implementation of our strategy could unleash technologies for disrupting cortical and/or sub-cortical circuit-specific pathologies that alleviate the suffering of chronic pain patients. The proposed research is well suited to the goals of the NIH New Innovator Award program. The innovative combination of these technical and high-risk strategies has the potential to transform our understanding of how chronic pain modulates brain networks and how to tightly-control them. Our projects encompass a number of significant advances, both in concept and in techniques that might fundamentally change the approach toward the rationale design of analgesics aimed at altering the neural circuits underlying the negative affective perception of pain. My interdisciplinary background in pain neurobiology, opioid pharmacology, and systems neuroscience, together with my demonstrated success in identifying the structure- function logic of neural circuits is the precise combination of skills that make me well suited to fully execute a project of this ambition. The NIH Director’s New Innovator Award would provide an invaluable jumpstart to my early career and support the continued trajectory of my research program into deconstructing the brain’s pain systems for the development of non-traditional strategies to treat the unpleasant affect and suffering of chronic pain patients, and lessen the reliance on prescription of opioids.