Neural circuitry and synaptic physiology underlying MDMA's prosocial effect

创伤后应激障碍（PTSD）对平民和退伍军人的健康都造成了严重影响。 迫切需要标准治疗的替代方法。典型的创伤后应激障碍治疗，例如长期治疗， 选择性再摄取抑制剂（SSRI）与心理治疗相结合，确实有助于大量的 但它不能治疗大多数PTSD患者。最近，患有难治性创伤后应激障碍的患者 通过一种令人惊讶的治疗方法，MDMA辅助， psychotherapy.娱乐性药物MDMA，也被称为“摇头丸”，曾被用作治疗焦虑症的辅助手段。 在1985年非法化之前就有创伤后应激障碍最近批准的临床试验表明，MDMA辅助 心理治疗对PTSD是安全有效的。MDMA增强了信任感，情感开放， 同情，帮助PTSD患者克服治疗障碍，如极端愤怒，情感麻木， 和极度的焦虑这个项目的目的是定义生物学和神经生理学， MDMA的社会效应通过定义MDMA的亲社会治疗作用的机制，我们可以开始 创造新的治疗方法，利用相同的潜在生物过程。提高社会质量 从自闭症到抑郁症，互动对许多社交能力受损的疾病都有影响。 值得注意的是，初步临床试验中的患者在经历了一次单次治疗后， 精神疗法中的摇头丸剂量此外，MDMA的治疗起效可以在 几分钟和几小时，而不是SSRIs典型的几周和几个月。MDMA的快速起效和持续时间 治疗效果表明，它是一个强大的催化剂，通过治疗行为恢复 突触可塑性;行为的急剧变化反映了神经回路、神经元和神经元水平的可塑性。 突触这个定义明确的时间窗口极大地简化了对潜在神经元的搜索。 其亲社会效应的机制。如果我们能在这个短时间内测量MDMA最突出的治疗方面， 时间尺度，我们可以设计实验，明确测试其机制的要求，使用工具， 非常适合急性测量和干预。 最近对小鼠的社会奖励和互动的研究表明， 大脑中负责奖赏和社会互动的区域。该项目将 系统地评估这些元素中的每一个在MDMA的机制中的作用， 药理学，脑区域特异性药物注射，光遗传学，以及神经元活动的成像， 行为最后，本研究将详细研究MDMA如何产生短-和长- 术语对NAc中突触的影响。

Post-traumatic stress disorder (PTSD) exacts a steep toll on the well being of civilians and veterans alike. Alternatives to standard treatment are urgently needed. Typical PTSD therapy, e.g. long-term treatment with a serotonin-selective reuptake inhibitor (SSRI) coupled with psychotherapy, does help a significant number of patients, but it fails to treat the majority of PTSD sufferers. Recently, patients with treatment-resistant PTSD have achieved dramatic and durable remission of their symptoms with a surprising treatment, MDMA-assisted psychotherapy. The recreational drug MDMA, also known as “ecstasy”, had been used as an aid to treat anxiety and PTSD prior to its illegalization in 1985. Recently approved clinical trials demonstrate that MDMA-assisted psychotherapy is safe and effective for PTSD. MDMA enhances feelings of trust, emotional openness and empathy, helping PTSD patients overcome obstacles to therapy, such as extreme anger, emotional numbing and overwhelming anxiety. This project aims to define the biology and the neurophysiology that create the prosocial effect of MDMA. By defining the mechanism for MDMA's prosocial, therapeutic effect we can begin creating new treatments that harness the same underlying biological processes. Improving the quality of social interaction has implications for many disorders where sociability is impaired, from autism to major depression. Remarkably, patients in preliminary clinical trials have experienced years-long remission of PTSD after a single dose of MDMA in the context of psychotherapy. Further, MDMA's therapeutic onset can be measured in minutes and hours rather than the weeks and months typical of SSRIs. MDMA's rapid onset and lasting therapeutic effect suggest that it is a powerful catalyst for behavioral recovery by means of therapeutic synaptic plasticity; an acute change in behavior reflects plasticity at the level of neural circuits, neurons, and synapses. This well-defined time window dramatically simplifies the search for an underlying neural mechanism of its prosocial effect. If we can measure MDMA's most salient therapeutic aspects on this short time scale, we can design experiments that explicitly test the requirements for its mechanism, using tools ideally suited to acute measurement and intervention. Recent studies of social reward and interaction in mice implicate serotonin and dopamine release in the nucleus accumbens (NAc), a brain area centrally involved in reward and social interaction. This project will systematically evaluate the role of each of these elements in MDMA's mechanism using behavioral pharmacology, brain region-specific drug injection, optogenetics, and imaging of neurons' activity during behavior. Finally this study will carry out a detailed examination of how MDMA produces both short- and long- term effects on synapses in the NAc.