A translational approach to understand hippocampal neural circuitry regulating impulsive aggression

理解海马神经回路调节冲动攻击的转化方法

• 批准号: 10395500
• 负责人: Alan Seth Lewis
• 金额: $ 18.54万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395500
• 关键词: Acute; Address; Aggressive behavior; Agonist; Animals; Basic Science; Behavior; Behavioral; Brain Injuries; Childhood; Chronic; Clinical Trials; Community Integration; Complement; Coupled; Criminal Justice; Data; Data Analyses; Development; Disease; Elderly; Emotional; Emotions; Equilibrium; Family; Fiber; Foundations; Future; GTS-21; Goals; Healthcare; Hippocampus (Brain); Hospitalization; Human; Impairment; Imprisonment; Impulsivity; Individual; Institutionalization; Interneurons; Ion Channel Gating; Ligands; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Mood Disorders; Mus; Nature; Neurons; Nicotinic Receptors; Optics; Oral; Outcome; Pathology; Patient Care; Patients; Performance; Pharmacological Treatment; Pharmacology; Phase; Phase II Clinical Trials; Photometry; Placebos; Post-Traumatic Stress Disorders; Psychiatrist; Recording of previous events; Recovery; Regulation; Reporting; Research; Safety; Schizophrenia; Statistical Data Interpretation; Statistical Models; Stimulus; System; Techniques; Testing; Therapeutic Intervention; Time; Training; Translating; Translational Research; Translations; Viral; behavior influence; behavior measurement; behavior test; calcium indicator; career; cell type; cost; dentate gyrus; emotional stimulus; excitatory neuron; experience; experimental study; granule cell; human subject; improved; in vivo; inhibitory neuron; innovation; meetings; mouse model; neural circuit; neurobehavioral; neurocognitive disorder; neuronal circuitry; neuropsychiatric disorder; neuroregulation; non-smoking; novel; novel therapeutic intervention; novel therapeutics; optogenetics; receptor; relating to nervous system; secondary analysis; side effect; skills; small hairpin RNA; societal costs; stem; therapeutically effective; translational approach; translational neuroscience; translational scientist; treatment strategy

PROJECT SUMMARY/ABSTRACT There are few treatments for persistent impulsive aggression in individuals with severe neuropsychiatric disorders, and existing treatments are of limited efficacy yet confer the potential for significant side effects. Aggression contributes to repeat institutionalization and significant costs to healthcare and criminal justice systems. As a neuroscientist and board-certified psychiatrist, this mentored patient-oriented research career development award (K23) will provide training to support Dr. Lewis's goal of becoming an independent translational investigator focused on the development of novel therapeutic approaches informed by the neural circuitry regulating impulsive aggression. To accomplish his career and research goals, Dr. Lewis will receive training in translational neuroscience by acquiring new skills to manipulate neural circuitry in mice and humans, identify effects on behaviors related to impulsive aggression, and rigorously analyze resulting data. Training will be guided by a team of mentors and contributors who are leaders in the basic and translational science of neural circuits underlying behavior relevant to neuropsychiatric disorders as well as in statistical analysis. The research plan is supplemented by coursework at Yale in translational neuroscience and statistical modeling, as well as participation in relevant seminars and national scientific meetings. The proposed experiments build upon preliminary data in mouse models demonstrating that activation of α7 nicotinic receptors in the dentate gyrus (DG) reduces aggressive behavior, while reduction of α7 receptors increases aggressive behavior. Because α7 receptors are highly enriched on local inhibitory interneurons of the DG and their activation enhances DG and hippocampal inhibition, the hypothesis will be tested that hippocampal excitatory-inhibitory (E/I) balance governs the expression of aggressive behavior in mice and humans. In Aim 1, activity of excitatory or inhibitory neurons in the mouse DG will be recorded using fiber photometry and manipulated using optogenetics to determine how DG E/I balance influences aggression onset in real time during resident- intruder tests. In Aim 2, this circuit mechanism will be translated to human subjects with schizophrenia using a pharmacological probe. The α7 partial agonist GTS-21 will be orally administered to enhance hippocampal inhibition, and an Emotional Go/NoGo Task used to determine effects on impulsive responding to negative and neutral valence stimuli. This behavioral task is mediated by prefrontal-temporolimbic circuitry, including the hippocampus, and performance correlates with a history of impulsive aggression in schizophrenia patients. These focused experiments take an innovative translational approach in mice and humans to understand how hippocampal activity influences behavioral measures related to impulsive aggression in neuropsychiatric disorders. Training in contemporary techniques of translational neuroscience, deliberate integration of animal and human paradigms, and data analysis will serve as a critical foundation to support Dr. Lewis's independent translational research career focused on identifying novel therapeutic options for impulsive aggression.

项目总结/摘要 对于患有严重神经精神疾病的个体， 疾病的治疗，现有的治疗方法的疗效有限，但却有可能产生显著的副作用。 攻击性行为导致了反复的机构化，并给医疗保健和刑事司法带来了巨大的成本 系统.作为一名神经科学家和委员会认证的精神病学家， 发展奖（K23）将提供培训，以支持刘易斯博士成为一个独立的目标 翻译研究者专注于开发新的治疗方法，由神经系统提供信息。 控制冲动攻击的回路为了完成他的事业和研究目标，刘易斯博士将获得 通过获得操纵小鼠和人类神经回路的新技能进行转化神经科学培训， 确定与冲动性攻击相关的行为的影响，并严格分析结果数据。培训 将由一个导师和贡献者团队指导，他们是基础科学和转化科学的领导者。 与神经精神疾病相关的行为背后的神经回路以及统计分析。的 研究计划由耶鲁大学的转化神经科学和统计建模课程补充， 以及参加有关的研讨会和国家科学会议。拟议的实验建立 根据小鼠模型的初步数据，表明齿状回中α7烟碱受体的激活 脑回（DG）减少攻击行为，而α7受体减少增加攻击行为。 由于α7受体高度富集在DG的局部抑制性中间神经元上， 增强DG和海马抑制，这一假设将被测试，海马兴奋-抑制 （E/I）平衡支配小鼠和人类中攻击行为的表达。目标1： 将使用纤维光度法记录小鼠DG中的兴奋性或抑制性神经元并进行操作 使用光遗传学来确定DG E/I平衡如何影响住院期间真实的攻击发作， 入侵者测试在目标2中，该回路机制将被翻译为使用一个神经网络的患有精神分裂症的人类受试者。 药理学探针α7部分激动剂GTS-21将口服给药，以增强海马神经元的功能。 抑制，和情绪去/不去任务，用于确定对冲动反应的影响， 中性价刺激。这种行为任务由前额叶-颞叶边缘回路介导，包括 海马体和表现与精神分裂症患者的冲动性攻击史相关。 这些集中的实验在小鼠和人类中采用了创新的转化方法，以了解 海马活动影响神经精神病患者与冲动攻击相关的行为测量 紊乱当代转化神经科学技术培训，动物刻意整合 和人类范式，数据分析将作为一个关键的基础，以支持刘易斯博士的独立 翻译研究生涯的重点是确定新的治疗选择冲动的侵略。