Neural circuits of frustration

沮丧的神经回路

• 批准号: 10039801
• 负责人: Neir Eshel
• 金额: $ 19.23万
• 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/10039801
• 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--是社会行为的普遍组成部分，而且经常发生 每日新闻的严肃话题其中一个最可靠的触发侵略是挫折，或未能 获得预期的奖励。这种状态可以是适应性的，激励行为，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完全不同的疾病中， 容忍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 这些行为的神经生物学知之甚少，目前的治疗方案严重不足。 该建议旨在确定两种神经调节剂-多巴胺（DA）和5-羟色胺（5-HT）-在脑内的作用。 神经对挫折的反应在目标1中，候选人将通过以下方式创建一个沮丧的小鼠模型： 将条件反射任务与居民-入侵者测定相结合，其中将入侵者小鼠添加到 居民的笼子来引发攻击在测试日，条件反射任务将以一个意想不到的负面结果结束。 结果，引起更大的侵略从居民的鼠标。在目标2中，候选人将使用光纤测光 和光遗传学来记录和操纵多巴胺神经元的活动和多巴胺释放在延髓核（NAc） 而小鼠则执行挫折任务。DA是动机行为的关键调节器，长期以来一直是 被认为是亲侵略者然而，很少有研究记录了沮丧或侵略期间的DA。这 实验将测试多巴胺的释放是否会随着沮丧而增加，从而引发攻击性。在目标3中， 候选人将使用纤维光度学和光遗传学来记录和操纵5 HT神经元活动和5 HT 在挫折任务期间在NAc中释放。与DA不同，5 HT被认为抑制行为，包括 侵略但在攻击行为中未记录到5 HT神经元。本目标将检验以下假设： 5 HT释放减少挫折，更大的减少促进更大的侵略性。 这项研究将是第一批研究挫折感神经回路机制的研究。在 在这个过程中，候选人将补充他在头部固定动物电生理学方面的背景， 精通社交行为和钙成像他将与一个咨询委员会， 人类（埃米尔·科卡罗博士）和啮齿动物（克劳斯·米切克博士）的攻击性、挫折感（埃伦博士 Leibenluft）和5 HT（利群罗博士），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，并补充他的技术培训与高质量的教学和专业培训，通过 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成长机会。通过 研究金结束时，候选人将被定位为独立调查员的职业生涯 领导一个关于攻击性和易怒的神经基础的转化研究项目。