Brain-wide circuit mapping to delineate therapeutic strategies for amphetamine abuse

项目概要（项目3） MDMA是一种安非他明衍生物，既被称为"致病剂“，也被称为娱乐性药物”迷魂药“， 可能很快就会被批准用于治疗创伤后应激障碍。MDMA的治疗效果与其 培养社会联系和信任感的独特能力。然而，MDMA众所周知的滥用潜力， 以及相关的心血管和神经精神毒性，构成了重大的公共卫生风险。的 MDMA对人类受试者的心理和行为影响与密切相关的 精神兴奋剂，甲基苯丙胺（MA）。而MDMA和MA共享化学和药理学 相似之处在于，MA具有更高的滥用责任，因此，更具破坏性的社会影响。我们 假设MDMA独特的亲社会特性与其相对较低的 滥用潜力更深入地了解MDMA独特的亲社会效应如何减轻滥用 安非他明类化合物可能导致安非他明使用的全新治疗策略 紊乱 我们利用MDMA和MA的对比行为效应来探测大脑范围内的神经模式， 活动对应于这些药物的差异调节自然奖励的敏感性，以及他们的共享 滥用潜力我们提出了一个严格的，系统的筛选过程，以确定和测试新的神经回路 区分MA和MDMA的行为特征。使用简单、可重复的行为分析 在项目4中的平行人体成像实验中，我们识别，验证和表征了这些新电路 分三个步骤。首先，我们使用全脑成像和映射过程来识别候选大脑 神经活动受MDMA、MA或药物行为背景差异调节的区域 互动其次，我们进行功能丧失实验，以确定这些识别的贡献 使用转基因小鼠系，允许特定MA和MDMA诱导的行为的区域集合， 捕获和控制药物激活的集合。第三，我们关注药物诱导的时间结构， 在这些确定的大脑区域内进行整体活动，在项目之间进行合作，以执行详细的 记录体内细胞活动。为现有和新兴的疾病开发有效的、可扩展的疗法 安非他明衍生物滥用障碍需要建立在，并超越， 配体-受体干扰的临床前模型。据我们所知，没有其他研究小组提出或 执行了一种基于电路的方法，该方法利用了并行的鼠-人行为和成像方式， 直接.

PROJECT SUMMARY (Project 3) MDMA, an amphetamine derivative known both as an ‘empathogen’ and the recreational drug ‘ecstasy’, may soon be approved for treating Post-Traumatic Stress Disorder. MDMA’s therapeutic efficacy is linked to its unique ability to foster feelings of social connection and trust. However, MDMA‘s well-known abuse potential, and associated cardiovascular and neuropsychiatric toxicity, present a major public health risk. The psychological and behavioral effects of MDMA in human subjects contrast strongly with the closely related psychostimulant, methamphetamine (MA). While MDMA and MA share chemical and pharmacological similarities, MA has an even higher abuse liability and, accordingly, a more devastating societal impact. We hypothesize that the unique prosocial properties of MDMA are mechanistically linked to its comparatively lower abuse potential. A deeper understanding of how MDMA’s unique prosocial effect mitigates abuse of amphetamine-class compounds may lead to entirely new therapeutic strategies for amphetamine use disorders. We exploit the contrasting behavioral effects of MDMA and MA to probe brain-wide patterns of neural activity corresponding to these drugs’ differential regulation of natural reward sensitivity as well as their shared abuse potential. We propose a rigorous, systematic screening process to identify and test novel neural circuits that differentiate these behavioral properties of MA and MDMA. Using simple, reproducible behavior assays that parallel human imaging experiments in Project 4, we identify, validate and characterize these novel circuits in three broad steps. First, we use a whole-brain imaging and mapping process to identify candidate brain regions where neural activity is differentially regulated by MDMA, MA, or a drug-by-behavioral context interaction. Second, we perform loss-of-function experiments to define the contribution of these identified regional ensembles to specific MA and MDMA-induced behaviors using a transgenic mouse line that allows for capture-and-control of drug-activated ensembles. Third, we focus on the drug-induced temporal structure of ensemble activity within those identified brain regions, collaborating across Projects to perform detailed recordings of cellular activity in vivo. Developing effective, scalable therapies for existing and emerging amphetamine-derivative abuse disorders requires approaches that build upon, and transcend, simple preclinical models of ligand-receptor interference. To our knowledge, no other research group has proposed or executed a circuit-based approach that leverages parallel mouse-human behavior and imaging modalities so directly.