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.

项目摘要 3，4-亚甲二氧基甲基苯丙胺（MDMA） a作为心理治疗辅助手段的3期临床试验， 创伤后应激障碍（PTSD）。已发表的数据显示，MDMA治疗起效快， 培养社会联系、同理心和信任感的能力。然而，MDMA本身可能并不是一种理想的药物。 治疗，因为众所周知它有被滥用的可能性，并且与心血管和神经系统有关。 精神毒性尽管有这些和其他限制，MDMA的明显疗效表明， 增强社交能力和社会奖励敏感性是可行的、潜在的强大治疗策略。在 小鼠模型，我们可以使用MDMA作为独特的探针来了解进化保守的社会行为， 具有潜在的治疗意义了解MDMA机制的传统方法， 其他精神病药物，专注于高亲和力受体相互作用和选择大脑区域， 成功开发出治疗精神疾病的新疗法。我的实验室发明了一种方法 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， 地图全脑活动诱发杜 与MDMA相关的行为结合社会行为测试和成像可以用来筛选新的 MDMA样谱的治疗，并提供了可测试的假设，人类成像研究与MDMA。 MDMA释放超生理水平的血清素（5-HT）和多巴胺（DA）等 神经调节剂和唤起急性社会偏好，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MDMA总效应的选择性成分，但两者都没有诱导 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 方面的影响.首先，我们比较了药物/环境条件下小鼠组之间的全脑Fos表达图， 的条件 全脑神经活动--类似于 方面的影响.第二，我们测试了在所鉴定的区域中的活性是否是表达四种MDMA诱导的表达所必需的。 行为：急性社会偏好，药物渴求，社会奖励渴求和社会操作性条件反射。我 初步数据证明了概念的验证：我们已经发现，背侧虹膜状核/ 腹侧屏状核（DEn/VC）在MDMA诱发的急性社会偏好中具有专性作用。第三，我们详细介绍 DEn/VC的解剖和连接，并测试其活动是否足以驱动亲社会行为。