Whole-brain mapping of opiate-sensitive circuits in Drosophila

项目概要： 阿片类药物滥用是一个严重的公共卫生问题。阿片类药物对奖赏记忆有持久的生理影响 神经回路，这有助于对药物的渴望，并改变大脑对其他滥用药物的反应。 然而，这些阿片类药物诱导的变化的分子机制知之甚少。庞大 奖励回路中神经元的数量和异质性，加上它们复杂的连接， 阻碍了对这些持久的分子改变的身份的更深入的理解。一个小而复杂的 大脑和一系列令人印象深刻的神经遗传学工具的体内分析表明，果蝇， 黑腹鼠是发现药物滥用作用新机制的理想模型 在大脑上。值得注意的是，没有任何研究成功地表明果蝇对 尽管一些无脊椎动物物种对阿片类药物治疗表现出强烈的反应，我们的数据表明 果蝇对合成阿片类药物芬太尼表现出强烈的行为反应， 芬太尼在受伤后挥发在这里，我们建议建立果蝇作为一个有效的模型，以了解 寻找芬太尼动机的神经和分子机制。我们的目标是用创新的 神经发生学方法绘制果蝇阿片受体回路对急性伤害性感受和自我伤害性感受的反应 以及它们的突触后连接。这项工作将提供一个大脑范围的表达地图， 单细胞水平的阿片受体，决定了哪些神经元参与奖赏和厌恶， 确定这些电路是如何集成的。

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.