靶向表达μ-阿片受体于纹状体直接通路神经元亚群中可恢复阿片类药物奖赏。
Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward.
机构信息
1] Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA. [2] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [3] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [4] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
1] Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA. [2] Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA. [3] David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. [4] Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA.
出版信息
Nat Neurosci. 2014 Feb;17(2):254-61. doi: 10.1038/nn.3622. Epub 2014 Jan 12.
μ-opioid receptors (MORs) are necessary for the analgesic and addictive effects of opioids such as morphine, but the MOR-expressing neuronal populations that mediate the distinct opiate effects remain elusive. Here we devised a new conditional bacterial artificial chromosome rescue strategy to show, in mice, that targeted MOR expression in a subpopulation of striatal direct-pathway neurons enriched in the striosome and nucleus accumbens, in an otherwise MOR-null background, restores opiate reward and opiate-induced striatal dopamine release and partially restores motivation to self administer an opiate. However, these mice lack opiate analgesia or withdrawal. We used Cre-mediated deletion of the rescued MOR transgene to establish that expression of the MOR transgene in the striatum, rather than in extrastriatal sites, is needed for the restoration of opiate reward. Our study demonstrates that a subpopulation of striatal direct-pathway neurons is sufficient to support opiate reward-driven behaviors and provides a new intersectional genetic approach to dissecting neurocircuit-specific gene function in vivo.
μ-阿片受体（MORs）是阿片类药物（如吗啡）产生镇痛和成瘾作用所必需的，但介导这些独特阿片作用的 MOR 表达神经元群体仍然难以捉摸。在这里，我们设计了一种新的条件性细菌人工染色体拯救策略，在小鼠中表明，在纹状体中富含纹状体和伏隔核的直接通路神经元的亚群中靶向表达 MOR，在其他 MOR 缺失的背景下，恢复阿片类药物奖赏和阿片类药物诱导的纹状体多巴胺释放，并部分恢复对阿片类药物的自我给药动机。然而，这些小鼠缺乏阿片类药物镇痛或戒断。我们使用 Cre 介导的拯救的 MOR 转基因的缺失来建立在纹状体中表达 MOR 转基因，而不是在外纹状体部位，是恢复阿片类药物奖赏所必需的。我们的研究表明，纹状体的直接通路神经元的一个亚群足以支持阿片类药物奖赏驱动的行为，并提供了一种新的交叉遗传方法来在体内剖析特定神经回路的基因功能。
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