Explore in vivo functional connectivity at cellular resolution in drugged brains

项目总结 成瘾是一种慢性复发性大脑疾病，其特征是对被滥用的人强制自我管理 物质，尽管它们有负面后果。在阐明这一问题上取得了重大进展 每种主要药物滥用背后的分子和行为影响。鉴于上瘾是一种疾病 相互连接的大脑网络，检查网络交互对于理解成瘾至关重要- 相关功能障碍。静息状态功能连通性(RsFC)，它衡量不同 人类神经生理事件的fMRI研究，已经提供了洞察力，但缺乏细胞分辨率和 由于无法在人体内进行实验扰动，因此无法进行进一步的因果关系研究。 目前，在动物模型中缺乏网络水平的分析，导致了显著的知识鸿沟 滥用药物的分子作用与其对行为的影响之间的关系。 在这一探索性应用中，我们旨在揭示滥用药物如何在系统水平上改变rsfc。 通过使用全脑钙成像和计算分析对幼虫进行细胞分辨率 斑马鱼。作为脊椎动物遗传模式生物，斑马鱼具有相当大的神经解剖学和 与人类的基因组相似性。斑马鱼幼体，大脑透明，由约100,000个神经元组成(相比之下 ~7500万，人脑中~10亿)，特别适合于单细胞分辨 活体神经环路活动分析。我们已经建立了全脑钙成像和计算 斑马鱼幼体脑内单细胞分辨率rsFC的数据分析平台。我们希望测试一下 无论是单次或多次使用吗啡，都会显著改变rsFC。 影响：如果成功，该项目将建立一个新的范例，以揭示在系统级别和蜂窝 解决方案，成瘾物质如何改变大脑状态。未来的努力可以扩展到所有主要的物质 滥用，这可能会在急性或长期吸毒的患者中显示出不同的功能连接特征 大脑。也有可能使用该平台来检查转基因大脑并进行小型 分子药物筛选。我们将使包括图像采集、处理和计算在内的技术 广泛的研究社区可以使用的算法。 适用于CEBRA：(1)这个项目将开发一个新的平台来检查成瘾者的体内效应 物质的系统水平和细胞分辨率。这些进展对于弥合两国之间的差距至关重要 滥用药物的分子和行为影响。目前，几乎没有先例或初步的 然而，有关这一专题的数据如果得到证实，将对目前采取的办法产生重大影响 了解滥用毒品的原因。(2)该项目将为神经活动开发创新的技术平台 成像，包括图像采集、处理和数据分析的计算算法。这将是 对药物滥用研究和其他领域有很好的适用性。

PROJECT SUMMARY Addiction is a chronic relapsing brain disorder that is characterized by compulsive self-administration of abused substances despite their negative consequences. Significant progress has been made in elucidating the molecules and behavioral effects underlying each major drug of abuse. Given that addiction is a disease of interconnected brain networks, examination of network interactions is critical for understanding addiction- related dysfunctions. Resting-state functional connectivity (rsFC), which measures correlations among distinct neurophysiological events in human fMRI studies, has provided insights, but the lack of cellular resolution and inability to carry out experimental perturbation in humans precludes further cause-effect relationship studies. At present, network level analyses are scarce in animal models, resulting in a significant knowledge gap between molecular actions of drugs of abuse and their effects on behavior. In this exploratory application, we aim to uncover how drugs of abuse alter rsFC at systems levels with cellular resolution, through employing brain-wide calcium imaging and computational analyses in larval zebrafish. As a vertebrate genetic model organism, zebrafish shares considerable neuroanatomical and genomic similarity with humans. Larval zebrafish, with a transparent brain of ~100,000 neurons (as compared to ~75 million in the mouse, and ~1 billion in the human brain), is particularly suitable for single-cell resolution analysis of neural circuit activity in vivo. We have established brain-wide calcium imaging and computational data analysis platforms to characterize rsFC at single-cell resolution in larval zebrafish brain. We wish to to test whether single or repeated exposure to morphine will significantly alter rsFC. Impact: If successful, this project will establish a new paradigm to uncover, at systems level and with cellular resolution, how addictive substances alter brain states. Future efforts can expand to all major substances of abuse, which will potentially reveal distinct functional connectivity signatures in acutely or chronically drugged brains. It is also possible to use the platform to examine genetically modified brains and perform small molecule drug screens. We will make technologies including image acquisition, processing, and computational algorithms available to the broad research community. Suitability for CEBRA: (1) This project will develop a new platform to examine the in vivo effects of addictive substances at systems level and with cellular resolution. Such advances are critical to bridge the gap between molecules and behavioral effects of drugs of abuse. At the moment, there are scant precedents or preliminary data regarding this topic, however, if confirmed, it would have a substantial impact on current approaches to understand drugs of abuse. (2) This project will develop innovative technological platforms for neural activity imaging, including image acquisition, processing, and computational algorithms for data analyses. This will have promising applicability to drug abuse research and beyond.