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

总结 慢性疼痛不仅仅是一种持续性的感觉障碍，而是一种情感功能障碍的神经系统疾病 对超过1亿人的精神状态、职业目标和个人关系产生负面影响 美国人理性引导的行为，如避免痛苦和寻求快乐，来自于 由大脑边缘系统产生的价信息。价电路的能力，分类外部和 内部感觉信息，无论是“愉快的”或“不愉快的”是必不可少的行为选择，保护 学习和生存。然而，由于这些神经元内的病理可塑性， 效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。杏仁核是处理情绪效价的关键大脑区域， 影响动机驱动力。然而，杏仁核效价加工的功能相关性， 享乐感知和行为选择的产生主要由其输出连通性来定义， 边缘系统和皮质区域的效应器结构。最近的证据表明存在先天的和独特的 在基底外侧核中用于对抗正和负价处理的神经元回路 杏仁核（BLA）也基于下游靶结构（如丘脑核）而分叉 （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被破坏了。 未开发的在这里，我建议揭示BLA价电路的动态相互作用，以确定其 对疼痛和享乐影响的贡献，无论是在BLA内的局部还是在NAc中的长期目标。 在辅导K99阶段，我的职业发展和培训将由我的共同导师监督， Drs.格雷戈里·谢勒和马克·施尼策，在罗伯特·马伦卡博士、肖恩·麦基博士的额外支持下， 和布莱恩·科比尔卡研究神经网络机制驱动疼痛不愉快和共病 快感缺失，我将接受光遗传学引导的脑切片电生理学和时间推移方面的专家培训， 自由行为小鼠体内钙离子成像，揭示神经系综编码的功能相互作用 在慢性疼痛的整个发展过程中，伤害性和食欲性感觉信息。期间 独立的R 00阶段，我将确定是否BLA价电路，不同地支配NAc定义 阿片类神经回路中功能和解剖学上不同的“享乐区”。我会进一步调查 这些区域与急性和慢性疼痛期间的行为选择和强化以及 药物使用条件。我将在K99/R 00获奖期间接受的高级培训将为 我未来的研究计划和国家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 能力，并支持我作为一个成功的，独立的研究科学家和导师的职业生涯。成功 这项工作的完成也将具有重要的公共卫生效益，因为它将指导未来在新的 镇痛策略，以减少疼痛和减少对处方阿片类药物的需求。

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.