Whole-brain mapping of opiate-sensitive circuits in Drosophila

果蝇阿片敏感回路的全脑图谱

基本信息

批准号：
9765603
负责人：
Karla R. Kaun
金额：
$ 20.31万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765603
关键词：
Acute Affect Allatostatin Automobile Driving Behavior Behavioral Binding Biological Brain Brain Mapping CRISPR/Cas technology Cells Complex Data Drosophila genus Drosophila melanogaster Equilibrium Fentanyl Genes Goals Heterogeneity Injury Invertebrates Learning Mammals Maps Mediating Memory Modeling Molecular Molecular Target Motivation Neuronal Plasticity Neurons Nociception Opiate Addiction Opioid Opioid Receptor Orthologous Gene Outcome Pharmaceutical Preparations Physiological Proteins Public Health Regulation Resolution Rewards Role Self Administration Structure Synapses System Testing Transgenic Organisms United States Dept. of Health and Human Services Work behavioral response clinical effect drug craving drug of abuse effective therapy experience fly genetic approach hedonic in vivo innovation mu opioid receptors neurogenetics neuroregulation nociceptive response novel opioid abuse opioid epidemic opioid use optogenetics postsynaptic postsynaptic neurons prevent receptor receptor binding relating to nervous system response synthetic opioid tool

项目摘要

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.

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具有持久的生理作用电路，它会导致对药物的渴望并改变大脑对其他滥用药物的反应。然而，人们对这些阿片类药物引起的变化背后的分子机制知之甚少。纯粹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分子改变的身份的更深入的了解。一个小而复杂的大脑和用于体内分析的一系列令人印象深刻的神经遗传学工具已经表明果蝇，果蝇黑腹果蝇是发现滥用药物影响的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以下行为有反应阿片类药物，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芬太尼表现出急性行为反应，并且会自行给药受伤后挥发的芬太尼。在这里，我们建议建立果蝇作为理解果蝇的有效模型寻求芬太尼动机背后的神经和分子机制。我们的目标是使用创新的神经遗传学方法绘制果蝇阿片受体回路对急性伤害感受和自我感觉的反应管理及其突触后连接。这项工作将提供全脑表达图单细胞水平的阿片受体，定义哪些神经元参与奖赏和厌恶，以及确定如何集成这些电路。