Alcohol-escalated aggression: A role for medial prefrontal cortical interneurons in mice

酒精导致的攻击行为升级：小鼠内侧前额皮质中间神经元的作用

• 批准号: 9329112
• 负责人: Emily L Newman
• 金额: $ 3.76万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2019-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329112
• 关键词: Acute; Address; Aggressive behavior; Alcohol consumption; Alcohols; Area; Automobile Driving; Behavior; Behavioral; Biological; Brain region; Chronic; Clinical; Clozapine; Dependovirus; Diagnosis; Disinhibition; Dose; Enterobacteria phage P1 Cre recombinase; Ethanol; Generations; Genetic; Glutamates; Health; Human; Imprisonment; Individual; Interneurons; Intervention; Investigation; Lead; Light; Link; Medial; Mediating; Mus; Neurons; Opsin; Output; Oxides; Pain; Parvalbumins; Pathologic; Pattern; Phenotype; Physiologic pulse; Physiological; Play; Property; Pyramidal Cells; Rattus; Receptor Activation; Regulation; Role; Signal Transduction; Site; Social Behavior; Social Interaction; Stimulus; Sum; Techniques; Testing; United States; Violence; Viral; Virus Diseases; Water; Wild Type Mouse; Work; alcohol abuse therapy; alcohol consequences; alcohol prevention; base; clinical development; cost; design; designer receptors exclusively activated by designer drugs; excitatory neuron; experimental study; hippocampal pyramidal neuron; insight; male; mouse Cre recombinase; mutant; neurochemistry; nonhuman primate; novel; optogenetics; postsynaptic; psychopharmacologic; recombinase; relating to nervous system; response; social; targeted treatment; tool; tool development; transmission process; vector; violent crime; water treatment

Project summary Alcohol is linked to approximately half of all violent crimes committed in the United States. Severe social and financial ramifications of these acts of violence include chronic health issues, pain and suffering, property damages, repeated arrests, incarceration, and fatalities; financially, the consequences of alcohol-associated violence will cost the US more than $200 billion this year alone. Advancing our understanding of the biological basis for violent outbursts may guide the development of clinical tools for the diagnosis, treatment and prevention of alcohol-associated aggression. According to a frequently cited, yet presently untested hypothesis, alcohol may disrupt medial prefrontal cortical (mPFC) top-down control over subcortical, aggression-promoting brain regions. On a cellular level, alcohol may hinder excitatory inputs onto inhibitory GABAergic interneurons in the mPFC; reduced GABAergic transmission may subsequently disinhibit excitatory corticolimbic projections. To address this hypothesis, chemogenetic or optogenetic tools will be used to target GABAergic interneurons in the mPFC of male mice; analyses of intruder-directed murine aggression will clarify whether reducing inhibitory interneuron activity in the mPFC is sufficient to escalate aggression. Wild- type (wt) and mutant male mice with Cre recombinase (Cre) specifically expressed in fast-spiking parvalbumin- positive interneurons (PV-Cre mice) will be microinfused with an adeno-associated virus (AAV) to drive Cre- dependent expression of inhibitory designer receptors exclusively activated by designer drugs (DREADDs) in the mPFC. After viral infection, PV-Cre mice will be characterized as alcohol-heightened (AHA) or alcohol non- heightened aggressors (ANA) and tested for escalated aggression toward a submissive conspecific upon inhibition of PV+ interneurons with doses of clozapine-N-oxide. The second aim addresses the role of alcohol in the disinhibition of aggression; associated experimental work will test whether alcohol-heightened aggression can be blocked via activation of inhibitory PV+ interneurons in the mPFC. PV-Cre mice and wt controls will be microinfused into the mPFC with an AAV driving Cre-dependent expression of stable stepwise function opsins (SSFOs) in PV+ interneurons. To assess the effects of PVI activation on alcohol- heightened aggression, characterized mice will receive a pulse of blue light for stable depolarization of PVIs via activated SSFOs prior to receiving water or a pro-aggressive dose of alcohol. In sum, experiments guided by aims one and two will test the following hypotheses: 1.) Inhibition of PV+ interneurons in the mPFC is sufficient to escalate aggression and, 2.) Reduced activity by mPFC inhibitory interneurons is required for expression of alcohol-heightened aggression. This work will provide novel insight into the involvement of mPFC microcircuitry in alcohol-heightened aggression and will encourage further investigation into the neurochemical and genetic bases for alcohol-related violence in humans.

项目总结 在美国发生的所有暴力犯罪中，约有一半与酒精有关。严重的社会和 这些暴力行为的经济后果包括慢性健康问题、痛苦和痛苦、财产 损害、反复逮捕、监禁和死亡；在经济上，与酒精有关的后果 仅今年一年，暴力就将给美国造成超过2000亿美元的损失。促进我们对生物学的理解 暴发的基础可以指导临床诊断、治疗和治疗手段的发展 预防与酒精相关的攻击。根据一项经常被引用但目前未经测试的 假设，酒精可能扰乱内侧前额叶皮质(MPFC)对皮质下的自上而下的控制， 促进攻击性的大脑区域。在细胞水平上，酒精可能会阻碍兴奋性传入到抑制性传入 MPFC中的GABA能中间神经元；GABA能传递的减少可能随后抑制兴奋性 皮质边缘投射。为了解决这一假设，将使用化学遗传或光遗传工具来靶向 雄性小鼠mPFC中的GABA能中间神经元；对入侵者引导的小鼠攻击行为的分析将澄清 减少mPFC内抑制性中间神经元活性是否足以升级攻击行为。狂野的- 带有Cre重组酶(Cre)的类型(Wt)和突变型雄性小鼠(Cre)在快速尖峰小白蛋白中特异表达- 阳性中间神经元(PV-Cre小鼠)将被微量输注腺相关病毒(AAV)以驱动Cre- 设计药物(DREADDS)特异性激活的抑制性设计受体在血管内皮细胞的依赖表达 MPFC。在病毒感染后，PV-CRE小鼠的特征将是酒精升高(AHA)或酒精非酒精性 加强侵略者(ANA)，并测试升级的攻击性，以顺从特定的 氯氮平-N-氧化物对PV+中间神经元的抑制作用第二个目标是解决酒精的作用 在解除对攻击的抑制方面；相关的实验工作将测试酒精是否增加 攻击行为可通过激活mPFC中抑制性PV+中间神经元而被阻断。PV-CRE小鼠和 将WT对照基因微量注入mPFC中，携带AAV驱动Cre依赖的稳定表达 PV+中间神经元中的阶梯功能视蛋白(SSFO)。为了评估PVI激活对酒精的影响- 攻击性增强，特征化的小鼠将收到蓝光脉冲，通过 在接受水或具有攻击性的酒精剂量之前激活SSFO。总而言之，实验由 目标一和目标二将检验以下假设：1)MPFC中PV+中间神经元的抑制作用 足以升级侵略和，2.)MPFC抑制中间神经元的活性降低是必需的 以表达酒精强化的攻击性。这项工作将提供对参与的新见解 MPFC微电路在酒精强化的攻击行为中的作用，并将鼓励进一步研究 人类与酒精相关的暴力行为的神经化学和遗传基础。