Mapping Neural Circuit Activity Mediating MDMA's Prosocial Effect

绘制调节 MDMA 亲社会效应的神经回路活动

基本信息

批准号：
10659760
负责人：
Boris Dov Heifets
金额：
$ 56.05万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-02 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659760
关键词：
Acute Affective Affinity Algorithms American Anatomy Area Atlases Axon Behavior Behavioral Biological Assay Biological Markers Brain Brain Mapping Brain region Cardiovascular system Cell Nucleus Cells Chronic Claustral structure Clinical Data Detection Development Dopamine Dorsal Drug usage Elements Empathy FOS gene Feeling Fenfluramine Fostering Genetic Goals Human Image Immediate-Early Genes Label Learning Light Link Maps Mediating Mental disorders Methamphetamine Methods Microscopy Modeling Molecular Mus Neuromodulator Neurons Nucleus Accumbens Operant Conditioning Patients Pharmaceutical Preparations Pharmacology Phase III Clinical Trials Phenotype Post-Traumatic Stress Disorders Process Property Psychotherapy Publishing Recreation Reproducibility Research Research Personnel Resolution Rewards Risk Role Scientist Selective Serotonin Reuptake Inhibitor Serotonin Social Behavior Social Environment Structure Synapses Techniques Testing Therapeutic Tissues Toxic effect Trust Viral abuse liability autism spectrum disorder behavior test brain based conditioned place preference craving drug craving drug reward ecstasy experience human imaging imaging study mouse model neural neural circuit neuroimaging neuromechanism neurophysiology neuropsychiatry novel novel therapeutics optogenetics pharmacologic pre-clinical preference receptor social social anxiety social deficits success

项目摘要

PROJECT SUMMARY 3,4-Methylenedioxymethamphetamine (MDMA) a Phase 3 clinical trials as an adjunct to psychotherapy for Post-Traumatic Stress Disorder (PTSD). Published data show that MDMA therapy has a rapid onset and a ability to foster feelings of social connection, empathy and trust. However, MDMA itself may not be an ideal therapeutic, as it has a well-known potential for abuse and is associated with cardiovascular and neuro- psychiatric toxicity. Despite these and other limitations, the apparent efficacy of MDMA suggests that directly enhancing sociability and social reward sensitivity are feasible, potentially powerful therapeutic strategies. In mouse models we can use MDMA as a unique probe to understand evolutionarily conserved social behaviors with potential therapeutic relevance. Conventional approaches to understanding the mechanism of MDMA and other psychiatric drugs, focusing on high affinity receptor interactions and select brain areas, have had limited success at developing novel therapeutics for psychiatric disease. My lab has developed a way to define with few assumptions about pharmacology or brain areas involved. This method, in mice, maps brain-wide activity evoked du for MDMA-linked behaviors. Combining social behavioral testing and imaging could be used to screen novel therapeutics for MDMA-like profiles and provides testable hypotheses for human imaging studies with MDMA. MDMA releases supraphysiological levels of serotonin (5-HT) and dopamine (DA) among other neuromodulators and evokes acute social preference, social reward learning, and nonsocial drug reward in humans and mice. Mechanistically similar drugs that primarily release 5-HT (d-fenfluramine, FEN) or DA (d- methamphetamine, METH) recapitulate selective components of the total MDMA effect, but neither induces social reward learning. Here, we propose to take advantage of the overlapping yet distinct behavioral and unique prosocial effects. First, we compare brain-wide Fos expression maps between groups of mice under drug/environmental conditions that on brain-wide neural activity -like behavioral effects. Second, we test whether activity in identified regions is required for expression of four MDMA-evoked behaviors: acute social preference, drug craving, social reward craving and social operant conditioning. My preliminary data demonstrates proof-of-concept: we have discovered that the dorsal endopiriform nucleus/ ventral claustrum (DEn/VC) has an obligate role in MDMA-evoked acute social preference. Third, we detail the anatomy and connectivity of the DEn/VC, and test whether its activity can suffice to drive prosocial behaviors.

项目概要 3,4-亚甲二氧基甲基苯丙胺 (MDMA) a 作为心理治疗的辅助疗法的 3 期临床试验创伤后应激障碍（PTSD）。已发表的数据显示，MDMA 疗法起效快，疗效显着。培养社会联系、同理心和信任感的能力。然而，MDMA 本身可能并不是理想的药物治疗性的，因为它具有众所周知的滥用潜力，并且与心血管和神经系统相关精神毒性。尽管存在这些和其他限制，MDMA 的明显功效表明，直接增强社交能力和社会奖励敏感性是可行的、潜在强大的治疗策略。在在小鼠模型中，我们可以使用摇头丸作为独特的探针来了解进化上保守的社会行为具有潜在的治疗相关性。了解 MDMA 机制的传统方法其他精神科药物专注于高亲和力受体相互作用和选择的大脑区域，但效果有限。成功开发精神疾病的新疗法。我的实验室开发了一种方法来定义对所涉及的药理学或大脑区域的假设很少。这种方法在小鼠身上，绘制全脑活动图与 MDMA 相关的行为。结合社会行为测试和成像可用于筛选小说类似 MDMA 的治疗方法，并为 MDMA 的人体成像研究提供可检验的假设。 MDMA 释放超生理水平的血清素 (5-HT) 和多巴胺 (DA) 等神经调节剂并引起强烈的社会偏好、社会奖励学习和非社会药物奖励人类和老鼠。主要释放 5-HT（d-芬氟拉明，FEN）或 DA（d- 甲基苯丙胺 (METH) 概括了总 MDMA 效应的选择性成分，但均不诱导社会奖励学习。在这里，我们建议利用重叠但又不同的行为和独特的亲社会影响。首先，我们比较药物/环境下各组小鼠的全脑 Fos 表达图条件是关于全脑神经活动的行为影响。其次，我们测试了四种 MDMA 诱发的表达是否需要确定区域的活性。行为：强烈的社会偏好、药物渴望、社会奖励渴望和社会操作性条件反射。我的初步数据证明了概念验证：我们发现背侧内皮状核/ 腹侧屏状核 (DEn/VC) 在 MDMA 诱发的急性社会偏好中发挥着重要作用。第三，我们详细介绍了 DEn/VC 的解剖结构和连接性，并测试其活动是否足以驱动亲社会行为。