A patch circuit dissection of opioid addiction

阿片类药物成瘾的补丁电路剖析

• 批准号: 10591745
• 负责人: Jason M Tucciarone
• 金额: $ 19.27万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591745
• 关键词: American; Analgesics; Axon; Behavior; Behavioral; Biological Assay; Brain; COVID-19 pandemic; Calcium; Cells; Characteristics; Clinical Research; Consumption; Corpus striatum structure; Depressed mood; Desire for food; Dissection; Dopamine Receptor; Dorsal; Extinction; Fiber; Foundations; Gene Expression; Genetic; Goals; Health; Immediate-Early Genes; Intervention; Intoxication; Island; Knowledge; Label; Maintenance; Measures; Mediator; Monitor; Naloxone; Negative Reinforcements; Negative Valence; Nervous System; Neuroanatomy; Neurobiology; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid Receptor; Optics; Output; Pathologic; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Photometry; Population; Positive Reinforcements; Positive Valence; Pre-Clinical Model; Property; Psychological reinforcement; Public Health; Rabies; Relapse; Rewards; Role; Self Administration; Source; Substance Use Disorder; Techniques; Training; Ventral Striatum; Viral; Virus; Withdrawal; Withdrawal Symptom; Work; addiction; behavioral economic analysis; cell type; combat; conditioned place preference; drug abstinence; drug reward; genetic manipulation; insight; lens; medication-assisted treatment; motivated behavior; mouse genetics; mu opioid receptors; neuroimaging; novel therapeutics; opioid abuse; opioid epidemic; opioid mortality; opioid overdose; opioid use; opioid use disorder; opioid withdrawal; optogenetics; pharmacologic; preclinical study; prodynorphin; receptor expression; recruit; response; striosome

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.

项目概要/摘要 阿片类药物危机仍然是数百万美国人对阿片类药物成瘾的主要健康问题 每年有数千人因阿片类药物而死亡。可悲的现实是，虽然药物辅助疗法非常有效 有效，但复发率仍然很高。需要更多地了解阿片类药物的神经生物学和回路 成瘾以识别新疗法。阿片类药物通过微处的作用发挥其奖励和成瘾作用 阿片受体（MOR）。 MOR 在整个神经系统（包括区域）中广泛表达 与伏隔核等药物奖赏相关。它存在于一种特殊的神经解剖学中 组织被称为“斑块”或“纹状体”，在岛屿网络中具有密集的区域表达 整个背侧纹状体和伏隔核。这些岛屿之外的区域称为矩阵。 这一级别的神经解剖组织的功能相关性是神秘的，它对阿片类药物的影响 使用障碍几乎是完全未知的。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 疾病，它仍然不完整，特别是在腹侧纹状体区域，例如伏隔核。这 “贴片”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 复兴的镜头的可能性，通过它来观察伏隔核的功能组织 动机行为和成瘾。最近，小鼠遗传学的力量揭示了两个不同的种群 直接通路中型多棘神经元位于 MOR 阳性斑块网络内。进一步的工作表明 当一个群体编码正价和正强化时，另一群体编码负价 效价和负强化，挑战直接途径的传统教条。这个提议 重新提交开始定义这些细胞群在阿片类药物滥用的临床前模型中的作用，调查 贴片在阿片类药物价数和戒断、阿片类药物消耗、维持、消除方面的特性 和恢复。输入和输出电路将在细胞核内的每种贴片细胞类型中定义 伏隔核。这项工作将结合阿片类药物自我管理、行为经济分析、病毒 神经解剖技术、光遗传学和化学遗传学操作以及纤维细胞类型神经成像 光度测定。这项工作将是第一个研究阿片类药物使用背景下的 MOR (+) 贴片电路的工作 紊乱。通过职能组织的新视角，可以揭示洞察力，从而带来新的结果 治疗阿片类药物使用障碍对健康和社会造成的破坏性影响的疗法。