Neural circuits of frustration

沮丧的神经回路

• 批准号: 10186830
• 负责人: Neir Eshel
• 金额: $ 19.27万
• 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/10186830
• 关键词: Acute; Advisory Committees; Affect; Aggressive behavior; Agitation; Anger; Animals; Behavior; Behavioral Paradigm; Behavioral inhibition; Biological Assay; Bipolar Disorder; Calcium; Disease; Dopamine; Dopamine Receptor; Electrophysiology (science); Environment; Event; Extinction (Psychology); Fellowship; Female; Fiber; Frustration; Future; Goals; Growth; Head; Human; Image; Impairment; Lead; Link; Masks; 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 circuit; neuromechanism; news; optogenetics; prevent; relating to nervous system; 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--是社会行为的一个普遍组成部分，而且经常发生 每日新闻的严峻主题。最可靠的攻击性诱因之一是挫折感，或未能做到 获得预期的回报。这种状态可以是适应性的、充满活力的行为，以克服障碍。但它可以 也会导致愤怒和暴力。在创伤后应激障碍、双相情感障碍和自闭症等不同的疾病中，低挫折感 容忍和不受控制的攻击性是精神病学中最普遍和最有害的症状之一。还没有 对这些行为的神经生物学了解甚少，目前的治疗方案严重不足。 这项提议旨在确定两种神经调节剂--多巴胺(DA)和5-羟色胺(5-HT)--在 对令人沮丧的事件的神经反应。在目标1中，应试者将通过以下方式创建一个受挫的老鼠模型 将条件反射任务与常驻入侵者测试相结合，在该测试中，将入侵者老鼠添加到 居民的笼子，以引起攻击性。在考试日，条件反射任务将以出人意料的否定结束 结果，引起了常驻老鼠更大的攻击性。在目标2中，候选人将使用光纤光度法 和光遗传学来记录和操纵伏核(NAC)中DA神经元的活动和DA的释放 而老鼠则执行受挫任务。DA是动机行为的关键调节器，长期以来一直是 被认为是支持攻击性的。然而，很少有研究记录到DA在受挫或攻击时的情况。这 实验将测试DA释放是否在受挫时音调增加，从而引发攻击性。在目标3中， 考生将使用纤维光度学和光遗传学来记录和操纵5HT神经元的活动和5HT 在受挫任务期间在NAC释放。与DA不同，5-羟色胺被认为可以抑制行为，包括 攻击性。但在攻击过程中没有记录到5-羟色胺神经元。这一目标将检验这一假设 5-羟色胺的释放随着挫折感的减少而减少，而更大的减少有助于更大的攻击性。 这项拟议的研究将是第一批研究挫折的神经回路机制的研究之一。在 在这个过程中，候选人将补充他在头部固定动物方面的电生理学背景，成为 精通社交行为和钙质成像。他将与一个咨询委员会合作，该委员会由世界 人类(埃米尔·科卡罗博士)和啮齿动物(克劳斯·米切克博士)攻击性、挫折感(埃伦博士) Leibenluft)和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 发展导师艾伦·沙茨伯格博士。他将充分利用充满智力活力的环境 在斯坦福大学学习，并通过以下途径补充他的技术培训：高质量的教学和专业培训 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增长机会。通过 奖学金结束后，候选人将成为一名独立调查员。 领导一个关于攻击性和易怒的神经基础的翻译研究项目。