Whole-brain mapping of opiate-sensitive circuits in Drosophila

项目总结： 阿片类药物滥用是一个严重的公共卫生问题。鸦片类药物对奖赏记忆有持久的生理影响 电路，这有助于对药物的渴望，并改变大脑对其他药物滥用的反应。 然而，对阿片类药物诱导的这些变化背后的分子机制知之甚少。纯净的 奖励回路中神经元的数量和异质性，再加上它们复杂的连接性，已经 阻碍了对这些持久的分子变化的身份的更深层次的理解。一台虽小但复杂的 大脑和一系列令人印象深刻的神经遗传学工具用于活体分析表明，果蝇，果蝇 黑素胃泌素是发现药物滥用影响的新机制的理想模型 在大脑上。值得注意的是，没有研究成功地表明果蝇在行为上对 鸦片类药物，尽管一些无脊椎动物物种对鸦片类药物治疗表现出强烈的反应。我们的数据显示 果蝇对合成阿片剂芬太尼表现出强烈的行为反应，并会自我管理 受伤后挥发的芬太尼。在这里，我们建议建立果蝇作为一个有效的模型来理解 寻求芬太尼的动机背后的神经和分子机制。我们的目标是用创新的 用神经遗传学方法定位果蝇对急性伤害性感觉和自我伤害反应的阿片受体回路 以及它们的突触后连接。这项工作将提供一个全脑范围的表达地图 在单细胞水平上，阿片受体定义了这些神经元中哪些参与奖赏和厌恶，以及 确定这些电路的集成方式。

PROJECT SUMMARY: Opioid abuse is a serious public health issue. Opiates have lasting physiological effects on reward memory circuitry, which contributes to cravings for the drug and changes the brain's response to other drugs of abuse. However, little is known of the molecular mechanisms underlying these opioid-induced changes. The sheer number and heterogeneity of neurons within reward circuits, combined with their elaborate connectivity, has prevented a deeper understanding of the identity of these lasting molecular alterations. A small but sophisticated brain and impressive array of neurogenetic tools for in vivo analysis have shown the fruit fly, Drosophila melanogaster to be an ideal model for discovery of novel mechanisms underlying the effects of drugs of abuse on the brain. Remarkably, no work has successfully shown that Drosophila are behaviorally responsive to opiates, despite several invertebrate species showing robust responses to opiate treatment. Our data suggest that Drosophila show acute behavioral responses to the synthetic opiate fentanyl, and will self-administer volatilized fentanyl after injury. Here we propose to establish Drosophila as an effective model to understand the neural and molecular mechanisms underlying the motivation to seek fentanyl. Our goal is to use an innovative neurogenetic approach to map Drosophila opioid receptor circuits responsive to acute nociception and to self- administration, and their post-synaptic connections. This work will provide a brain-wide map of expression of opioid receptors at a single cell level, define which of these neurons are involved in reward and aversion, and determine how these circuits are integrated.