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

• 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
• 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

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.

项目总结 3，4-亚甲基二氧基甲基苯丙胺 作为心理治疗辅助的3期临床试验 创伤后应激障碍(PTSD)。已公布的数据显示，MDMA疗法起效快， 培养社会关系、同理心和信任感的能力。然而，MDMA本身可能并不是理想的 治疗，因为众所周知，它有滥用的可能性，并与心血管和神经- 精神毒性。尽管有这些和其他限制，MDMA的明显效果直接表明 增强社交能力和社会奖励敏感性是可行的、潜在有效的治疗策略。在……里面 小鼠模型我们可以使用MDMA作为唯一的探针来理解进化保守的社会行为 具有潜在的治疗相关性。理解MDMA机制的传统方法和 其他精神药物，专注于高亲和力受体相互作用和选定的大脑区域，效果有限。 成功地开发了治疗精神疾病的新疗法。我的实验室已经开发出一种方法来定义 几乎没有关于药理学或大脑区域的假设。这种方法，在老鼠身上， 全脑活动诱发的DU图 用于与MDMA关联的行为。结合社会行为测试和成像可以用来筛选小说 治疗MDMA样谱，并为MDMA的人体成像研究提供可测试的假说。 MDMA释放超生理水平的5-羟色胺(5-HT)和多巴胺(DA)等 神经调节剂和诱发急性社会偏好、社会奖赏学习和非社会性药物奖赏 人类和老鼠。主要释放5-羟色胺(d-芬氟拉明，fen)或多巴胺(d-fenfluramine，fen)的机械相似药物 甲基苯丙胺，冰毒)概括了总的MDMA效应的选择性成分，但都没有诱导 社会奖励学习。在这里，我们建议利用重叠但不同的行为和 独特的亲社会 效果。首先，我们比较了药物/环境下不同组小鼠的脑内Fos表达图谱 符合以下条件的条件 全脑神经活动样行为的研究 效果。其次，我们测试了四个MDMA诱发的表达是否需要识别区域的活性 行为：强烈的社会偏好、毒品渴求、社会回报渴求和社会运作条件反射。我的 初步数据证明了概念的正确性：我们已经发现虹膜背侧核/ 腹屏状核(DEN/VC)在MDMA引起的急性社会偏爱中起着特定的作用。第三，我们详细介绍了 对DEN/VC进行解剖和连接，并测试其活动是否足以驱动亲社会行为。