Neural circuits of frustration

沮丧的神经回路

• 批准号: 10619573
• 负责人: Neir Eshel
• 金额: $ 19.35万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-08 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619573
• 关键词: Acute; Advisory Committees; Affect; Aggressive behavior; Agitation; Anger; Animals; Behavior; Behavioral Paradigm; Behavioral inhibition; Biological Assay; Bipolar Disorder; Calcium; Diagnostic; Disease; Disparate; Dopamine; Dopamine Receptor; Electrophysiology (science); Environment; Event; Extinction; Fellowship; Female; Fiber; Frustration; Future; Goals; Growth; Head; Human; Image; Impairment; Link; Medicine; Mental disorders; Mentors; Mentorship; Mus; National Institute of Mental Health; Neurobiology; Neuromodulator; Neurons; Neurosciences; Nucleus Accumbens; Outcome; Patients; Phase; Photometry; Positioning Attribute; Post-Traumatic Stress Disorders; Process; Psychiatry; Psychological reinforcement; Publications; Research Domain Criteria; Research Personnel; Rewards; Rodent; Role; Serotonin; Shapes; Signal Transduction; Social Behavior; Symptoms; Technology; Testing; Time; Training; Ventral Tegmental Area; Violence; Viral; Work; autism spectrum disorder; career; career development; clinically relevant; conditioning; dopaminergic neuron; dorsal raphe nucleus; effective therapy; expectation; experimental study; insight; male; motivated behavior; mouse model; neural; neural circuit; neuromechanism; news; optogenetics; prevent; response; reward processing; translational research program; ward

Aggression—acting with the intent to inflict harm—is a universal component of social behavior, and all too often the grim subject of the daily news. One of the most reliable triggers of aggression is frustration, or failing to achieve an expected reward. This state can be adaptive, energizing behaviors to overcome barriers. But it can also lead to anger and violence. In disorders as disparate as PTSD, bipolar disorder, and autism, low frustration tolerance and uncontrolled aggression are among the most prevalent and impairing symptoms in psychiatry. Yet the neurobiology of these behaviors is poorly understood, and current treatment options are grossly inadequate. This proposal aims to define the role of two neuromodulators—dopamine (DA) and serotonin (5HT)—in the neural response to frustrating events. In Aim 1, the candidate will create a mouse model of frustration by combining conditioning tasks with the resident-intruder assay, in which an intruder mouse is added to a resident’s cage to elicit aggression. On test days, the conditioning task will end with an unexpectedly negative outcome, eliciting greater aggression from the resident mouse. In Aim 2, the candidate will use fiber photometry and optogenetics to record and manipulate DA neuron activity and DA release in the nucleus accumbens (NAc) while mice perform the frustration task. DA is a key modulator of motivated behaviors, and has long been considered pro-aggressive. Few studies, however, have recorded DA during frustration or aggression. This experiment will test whether DA release tonically increases with frustration, triggering aggression. In Aim 3, the candidate will use fiber photometry and optogenetics to record and manipulate 5HT neuron activity and 5HT release in the NAc during the frustration task. Unlike DA, 5HT is thought to inhibit behavior, including aggression. But 5HT neurons have not been recorded during aggression. This Aim will test the hypothesis that 5HT release decreases with frustration, and that larger decreases facilitate greater aggression. The proposed studies would be among the first to examine the neural circuit mechanisms of frustration. In the process, the candidate will supplement his background in electrophysiology in head-fixed animals to become proficient in social behaviors and calcium imaging. He will work with an advisory committee comprising world leaders in human (Dr. Emil Coccaro) and rodent (Dr. Klaus Miczek) aggression, frustration (Dr. Ellen Leibenluft), and 5HT (Dr. Liqun Luo), in addition to his primary mentor Dr. Rob Malenka and his career development mentor Dr. Alan Schatzberg. He will take full advantage of the intellectually vibrant environment at Stanford and supplement his technical training with high-quality didactic and professional training via frequent mentor interactions, targeted coursework, and other career and intellectual growth opportunities. By the end of the fellowship, the candidate will be positioned to launch a career as an independent investigator leading a translational research program on the neural basis of aggression and irritability.

攻击性——意图造成伤害的行为——是社会行为的普遍组成部分，而且经常发生 每日新闻的严峻主题攻击性最可靠的触发因素之一是挫败感或未能做到这一点 达到预期的回报。这种状态可以是适应性的，激励行为来克服障碍。但它可以 也会导致愤怒和暴力。在创伤后应激障碍（PTSD）、双相情感障碍和自闭症等不同疾病中，挫败感较低 宽容和不受控制的攻击是精神病学中最普遍和最有害的症状之一。然而 人们对这些行为的神经生物学知之甚少，目前的治疗方案也严重不足。 该提案旨在定义两种神经调节剂——多巴胺 (DA) 和血清素 (5HT)——在 对令人沮丧的事件的神经反应。在目标 1 中，候选人将通过以下方式创建小鼠挫败模型： 将调节任务与常驻入侵者测定相结合，其中将入侵者小鼠添加到 居民的笼子引起攻击。在测试日，调节任务将以意外的负面结果结束 结果，引起驻留小鼠更大的攻击性。在目标 2 中，候选人将使用光纤光度测定法 和光遗传学记录和操纵伏隔核 (NAc) 中的 DA 神经元活动和 DA 释放 当老鼠执行挫折任务时。 DA 是动机行为的关键调节剂，长期以来一直被认为 被认为是激进的。然而，很少有研究记录挫折或攻击期间的 DA。这 实验将测试 DA 释放是否会因挫折而急剧增加，从而引发攻击性。在目标 3 中， 候选人将使用光纤光度测定和光遗传学来记录和操纵 5HT 神经元活动和 5HT 在受挫任务期间在 NAc 中释放。与 DA 不同，5HT 被认为可以抑制行为，包括 侵略。但攻击过程中的 5HT 神经元尚未被记录。该目标将检验以下假设： 5HT 的释放量会随着挫败感而减少，而减少幅度越大，攻击性就会越大。 拟议的研究将是首批研究挫败感的神经回路机制的研究之一。在 在此过程中，候选人将补充他在头部固定动物的电生理学方面的背景，以成为 精通社会行为和钙成像。他将与一个由世界各地组成的咨询委员会合作 人类（Emil Coccaro 博士）和啮齿类动物（Klaus Miczek 博士）的攻击性、挫败感（Ellen 博士）的领导者 Leibenluft）、5HT（罗立群博士），以及他的主要导师 Rob Malenka 博士和他的职业生涯 发展导师 Alan Schatzberg 博士。他将充分利用充满智力活力的环境 在斯坦福大学，并通过高质量的教学和专业培训来补充他的技术培训 频繁的导师互动、有针对性的课程作业以及其他职业和智力发展机会。经过 奖学金结束后，候选人将开始作为独立调查员的职业生涯 领导一项关于攻击性和易怒性神经基础的转化研究项目。