Deconstructing the network mechanisms of chronic pain and reward in the amygdala

摘要 慢性疼痛不仅是一种持续性的感觉障碍，而且是一种情感障碍的神经系统疾病 这对超过1亿人的精神状态、职业目标和人际关系产生了负面影响 美国人。情感引导的行为，如避免痛苦和寻求快乐，源于 由边缘脑产生的配价信息。价电路对外部和外部的分类能力 “愉快”或“不愉快”的内部感觉信息对于行为选择、保护 学习和生存。然而，由于这些细胞内的病理可塑性，感觉信息的错误编码 价回路会产生不必要的心理影响，包括痛苦和抑郁。 与慢性疼痛有关。杏仁核是大脑中处理情绪的关键区域， 影响激励的动力。然而，杏仁核的配价处理与 享乐主义知觉和行为选择的产生主要由其输出与 边缘和皮质区域的效应器结构。最近的证据表明，存在先天的和不同的 大鼠基底外侧核内反向正价和负价处理的神经元回路 杏仁核(BLA)，也基于下游的靶结构，如伏隔核 (NAC)。然而，这些相反的BLA价电路之间的网络级接口在很大程度上 未被开发的。在这里，我建议揭示BLA价电路的动态相互作用，以确定它们 对疼痛和享乐情绪的贡献，无论是在BLA的局部还是在NAC的远程目标。 在被指导的K99阶段，我的职业发展和培训将由我的合作导师监督， Gregory Scherrer博士和Mark Schnitzer博士，以及Robert Malenka博士，Sean Mackey博士， 还有布莱恩·科比尔卡。探讨驱动疼痛、不适和共病的神经网络机制 快感缺乏症，我将接受光遗传引导脑片电生理学和时间推移方面的专家培训 自由活动小鼠体内钙离子成像揭示神经系综编码的功能相互作用 在慢性疼痛的发展过程中，伤害性和食欲的感觉信息。在.期间 独立的R00阶段，我将确定不同神经支配NAC的BLA价电路是否定义 在功能和解剖学上不同的“享乐区”在阿片能回路。我将进一步调查 这些区域与急性和慢性疼痛期间的行为选择和强化的相关性 毒品使用情况。我将在K99/R00奖项期间接受的高级培训将为 我未来的研究计划和国立卫生研究院的拨款申请。这个奖项将帮助我推进我自己的科学研究 能力，并支持我作为一名成功的独立研究科学家和导师的职业生涯。成功者 这项工作的完成也将对公众健康产生重要的好处，因为它将指导未来关于新技术的努力 减轻疼痛和减少处方阿片类药物需求的止痛策略。

Summary Chronic pain is not merely a persistent sensory disorder, but a neurological disease of affective dysfunction that negatively impacts the mental state, professional goals, and personal relationships of over 100 million Americans. Emotionally-guided behaviors, such as avoiding pain and seeking pleasure, are derived from valence information generated by the limbic brain. The ability of valence circuits to categorize external and internal sensory information as either ‘pleasant’ or ‘unpleasant’ is essential for behavior selection, protective learning, and survival. However, miscoding of sensory information due to pathological plasticity within these valence circuits can produce unwanted psychological effects, including the suffering and depression associated with chronic pain. The amygdala is a brain region critical for processing emotional valence and influencing motivational drive. However, the functional relevance of amygdalar valence processing to the generation of hedonic perception and behavior-selection is defined primarily by its output connectivity with effector structures in limbic and cortical regions. Recent evidence proposes the existence of innate and distinct neuronal circuits for opposing positive and negative valence processing in the basolateral nucleus of the amygdala (BLA) that also diverge based on the downstream target structures, such as the nucleus accumbens (NAc). However the network-level interface between these opposing BLA valence circuits has been largely unexplored. Here, I propose to uncover the dynamic interactions of BLA valence circuits to determine their contribution to pain and hedonic affect, both locally within the BLA and at their long-range targets in the NAc. During the mentored K99 phase, my career development and training will be supervised by my co-mentors, Drs. Gregory Scherrer and Mark Schnitzer, with additional support from Drs. Robert Malenka, Sean Mackey, and Brian Kobilka. To investigate the neural network mechanisms driving pain unpleasantness and comorbid anhedonia, I will receive expert training in optogenetic-guided brain slice electrophysiology and time-lapse in vivo Ca2+ imaging in freely behaving mice to uncover the functional interactions of neural ensembles encoding nociceptive and appetitive sensory information throughout the development of chronic pain. During the independent R00 phase, I will determine whether BLA valence circuits that differently innervate the NAc define functionally and anatomically distinct “hedonic zones” within opioidergic circuits. I will further investigate the relevance of these zones to behavior-selection and reinforcement during acute and chronic pain, and during drug use conditions. The advanced training I will receive during this K99/R00 award will lay the foundations for my future research program and NIH grant applications. This award will help me advance my own scientific capabilities, and bolster my career as a successful, independent research scientist and mentor. The successful completion of this work will also have important public health benefits as it will guide future efforts on novel analgesic strategies to reduce pain and lessen the need for prescription opioids.