Harnessing cortical neuromodulation to disrupt pain perception

项目摘要 慢性疼痛是美国的一个主要健康危机，影响超过1亿美国人和数百万人 国际吧此外，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因素， 已经席卷全国开发具有相似或更高疗效的新类别治疗药物 相对于阿片类药物治疗疼痛，但缺乏处方阿片类药物的成瘾性， 这对治疗疼痛患者和减轻国家阿片类药物危机的负担都有影响。一个重大障碍 在实现这一目标的过程中，我们对大脑回路和通路的了解很少， 由慢性疼痛引起的痛苦。我们的目标是确定潜在的疼痛情感的神经回路元件 感知，解码他们的神经计算在慢性疼痛期间如何演变，并试图使这些正常化。 病理动力学与精确的基于电路的光学干预。在这里，我们将通过以下方式实现这一目标： 使用自动化大规模单神经元分辨率可视化新皮层内的关键阿片回路 成像、光遗传学操作和机器视觉行为分析。通过实现这一目标，我们将 产生新的动态框架来模拟慢性疼痛的出现。这些框架将为 我们的翻译目标策略使用当代电路中断技术，最终目标是 促进内源性阿片肽释放仅在所需的脑区，电路，和突触相关， 疼痛处理，具有时间上的按需控制。因此，成功实施我们的战略， 释放用于破坏皮质和/或皮质下回路特异性病理的技术， 慢性疼痛患者的痛苦。拟议的研究非常适合NIH新创新者的目标 奖励计划。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 项目包括一些重大的进步，无论是在概念和技术， 从根本上改变旨在改变神经回路的镇痛药的基本原理设计方法 潜在的对疼痛的负面情感感知。我在疼痛神经生物学，阿片类药物 药理学和系统神经科学，以及我在鉴定结构方面的成功， 神经回路的功能逻辑是技能的精确组合，使我非常适合完全执行一个 这个野心的计划。NIH主任的新创新者奖将为我的研究提供一个宝贵的起点。 早期的职业生涯，并支持我的研究计划的持续发展，以解构大脑的疼痛 发展非传统战略的系统，以治疗慢性病患者的不愉快影响和痛苦， 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.