A patch circuit dissection of opioid addiction

项目总结/摘要 阿片类药物危机仍然是一个主要的健康问题，数百万美国人对阿片类药物上瘾， 每年有数千例阿片类药物相关死亡。可悲的现实是，虽然药物辅助治疗是高度 有效，复发率仍然很高。需要更多地了解阿片类药物的神经生物学和回路 寻找新的治疗方法。阿片类药物通过作用于肌肉， 阿片受体（莫尔）。莫尔在整个神经系统中广泛表达， 与药物奖赏有关的神经元它存在于一种特殊的神经解剖学中， 被称为“斑块”或“纹状体”的组织，具有位于岛屿网络中的密集区域表达 遍布背侧纹状体和丘脑核。这些岛之外的区域称为矩阵。 这种神经解剖学组织水平的功能相关性是神秘的， 使用障碍几乎完全未知。虽然纹状体组织的直接和间接途径 揭示了与物质使用相关的动机行为和病理变化的重要见解 在某些疾病中，它仍然是不完整的，特别是在腹侧纹状体的区域，如延髓核。的 “补丁”与“矩阵”的神经解剖学，以及每个隔室中包含的细胞类型，打开了 一个复苏的透镜的可能性，通过它来看神经核的功能组织， 动机行为和成瘾。最近，小鼠遗传学的力量揭示了两个独立的种群， 直接通路介质多刺神经元容纳在莫尔阳性补丁网络内。进一步的研究表明， 当一个群体编码积极的效价和积极的强化时，另一个群体编码消极的 价和负强化，挑战传统的教条的直接途径。这项建议 重新提交开始定义这些细胞群在阿片类药物滥用临床前模型中的作用，研究 贴剂在阿片类药物效价和戒断、阿片类药物消耗、维持、消退方面的性质 和复职输入和输出电路将被定义在细胞核内的每种细胞类型中 快来这项工作将结合联合收割机阿片类药物自我管理，行为经济学分析，病毒 神经解剖学技术、光遗传学和化学遗传学操作以及纤维细胞型神经成像 测光法这项工作将是在阿片类药物使用的背景下研究莫尔（+）贴片电路的第一批工作之一 disorder.通过这种职能组织的新透镜，可以揭示可能导致新的 治疗阿片类药物使用障碍对健康和社会的破坏性影响。

PROJECT SUMMARY/ABSTRACT The opioid crisis remains a major health concern with millions of Americans addicted to opioid drugs and thousands of opioid related deaths per year. The sad reality is that while medication assisted therapies are highly effective, relapse rates remain high. More understanding is needed into the neurobiology and circuits of opioid addiction to identify new therapies. Opioids exert their rewarding and addictive effects through action at the mu opioid receptor (MOR). The MOR is expressed widely throughout the nervous system including regions associated with drug reward such as the nucleus accumbens. It is present in a peculiar neuroanatomic organization referred to as “patch” or “striosome,” with dense regional expression situated in a network of islands throughout dorsal striatum and nucleus accumbens. The region outside of these islands is referred to as matrix. The functional relevance of this level of neuroanatomic organization is mysterious and its consequence for opioid use disorders is almost completely unknown. While the direct and indirect pathway of striatal organization has revealed critical insights into motivated behavior and pathologic changes associated with substance use disorders, it remains incomplete especially in regions of the ventral striatum such as the nucleus accumbens. The neuroanatomy of “patch” vs “matrix,” and the cell types contained within each compartment, opens the possibility for a revived lens through which to look at the functional organization of the nucleus accumbens in motivated behavior and addiction. Recently, the power of mouse genetics revealed two separate populations of direct pathway medium spiny neurons housed within MOR positive patch networks. Further work has shown that while one population encodes positive valence and positive reinforcement, the other encodes negative valence and negative reinforcement, challenging the traditional dogma of the direct pathway. This proposal resubmission begins to define a role for these cell populations in preclinical models of opioid abuse, investigating the properties of patches in the valence of opioids and withdrawal, opioid consumption, maintenance, extinction and reinstatement. Input and output circuitry will be defined in each patch cell type within the nucleus accumbens. The work will combine opioid self-administration, behavioral economic analysis, viral neuroanatomic techniques, optogenetic and chemogenetic manipulations and cell type neuroimaging with fiber photometry. This work will be among the first to study MOR (+) patch circuits in the context of opioid use disorder. Through this new lens of functional organization, insights can be revealed that could lead to new therapies in treating the devastating health and societal impact of opioid use disorders.