Deciphering gene-environment interactions in pathological reactive aggression

解读病理性反应性攻击中的基因-环境相互作用

• 批准号: 8921269
• 负责人: Marco Bortolato
• 金额: $ 58.71万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921269
• 关键词: Address; Adolescence; Adolescent; Adult; Affect; Age; Aggressive behavior; Amygdaloid structure; Anger; Animal Model; Area; Behavioral; Biological; Biological Markers; Brain; Child Abuse; Child Abuse and Neglect; Clinical; Complex; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Cues; Data; Development; Diagnosis; Diagnostic tests; Disease; Disinhibition; Economic Burden; Environment; Enzymes; FOS gene; Failure; Functional disorder; Genes; Genetic; Glutamate Receptor; Glutamates; Goals; Grant; Health; Human; Hypothalamic structure; Infusion procedures; Knowledge; Lead; Life; Mediating; Metabolism; Modeling; Molecular Target; Monoamine Oxidase; Monoamine Oxidase A; Mus; N-Methylaspartate; Neurobiology; Neurons; Pathogenesis; Pathway interactions; Prefrontal Cortex; Prevention; Prevention therapy; Process; Proteomics; Receptor Activation; Receptor Signaling; Regimen; Research; Riluzole; Role; ST5 gene; Serotonin; Severities; Signal Pathway; Signal Transduction; Technology; Testing; Translational Research; United States National Institutes of Health; Violence; Wild Type Mouse; activity marker; age related; base; child neglect; economic impact; gene environment interaction; genetic variant; inhibitor/antagonist; innovation; maternal separation; midbrain central gray substance; mouse model; neglect; neurochemistry; novel; novel diagnostics; postnatal; prevent; pup; receptor; receptor binding; response; social; socioeconomics; therapeutic target; tool; translational study; transmission process

DESCRIPTION (provided by applicant): Pathological reactive aggression is a condition characterized by frequent outbursts of impulsive violence and anger. The devastating socio-economic impact of this problem underscores the urgent need to identify effective strategies for its prevention and treatment; unfortunately, current efforts in this direction are thwarted by our poor knowledge of the pathophysiology of reactive aggression. The long-term goal of our research is to elucidate the neurobiological bases of aggression, and identify novel molecular targets for the prevention and therapy of this complex condition. Animal models are indispensable tools to understand the mechanisms of aggression and test novel therapies, but their translational and predictive validity is often compromised by their failure to accurately reproduce the mechanisms of pathological aggression in humans. Thanks to our previous NIH R21 grant, we began to address this problem by developing the first mouse model of the best-characterized interaction of genetic and environmental vulnerability factors for pathological reactive aggression. This interaction involves: i) low activity of monoamine oxidase (MAO) A, the major enzyme for the metabolism of serotonin (5HT); ii) child neglect or abuse. To simulate this interaction, we generated a novel line of mice with low MAOA activity (MAOANeo), and subjected them to maternal separation (MS, simulating child neglect) during the first week of life. Similarly to the clinical scenario, MS induced high levels of aggression in adolescent and adult MAOANeo mice, but not in their wild-type littermates. Our preliminary data suggest that MS predisposes MAOANeo mice to develop aggression through the interplay of age-specific processes: 1) the activation of 5HT2A receptors during the first week of life; 2) progressive, age- dependent deficits of N-methyl-D-aspartate glutamate receptors (NMDARs) in the prefrontal cortex (PFC) throughout adolescence; and 3) the disinhibition of glutamatergic subcortical connections in adulthood. Based on these data, we hypothesize that the interaction of low MAOA activity and MS produces 5HT2A receptor overstimulation and age-dependent NMDAR alterations in the PFC. In turn, these PFC deficits lead to aggression through the disinhibition of downstream glutamate pathways across subcortical regions. We will test this hypothesis in three specific aims: in Aim 1, we will determine how the interaction of low MAO A activity and MS leads to early 5HT 2A receptor overstimulation; in Aim 2, we will examine how early 5HT2A receptor overstimulation leads to age-specific deficits of NMDAR signaling pathways in the PFC; in Aim 3, we will identify the subcortical regions that mediate the role of glutamate in the aggressive responses of MAOANeo mice subjected to MS. These aims will be accomplished with a unique combination of cutting-edge behavioral, neurochemical and proteomic technologies. The results of these translational studies will help us understand the biological bases of reactive aggression, identify new potential biomarkers and therapeutic targets for this condition, and eventually reduce its staggering socio-economic burden.

描述（由申请人提供）：病理反应性攻击是一种以冲动性暴力和愤怒的爆发为特征。该问题的毁灭性社会经济影响强调了迫切需要确定其预防和治疗的有效策略；不幸的是，由于我们对反应性侵略的病理生理学的知识，目前朝着这一方向的努力受到了阻碍。我们研究的长期目标是阐明侵略的神经生物学基础，并确定用于预防和治疗这种复杂条件的新分子靶标。动物模型是必不可少的工具来理解攻击性和测试新疗法的机制，但是它们的翻译和预测有效性通常因其未能准确再现人类病理侵略的机制而受到损害。多亏了我们以前的NIH R21赠款，我们开始通过开发第一个小鼠模型来解决遗传和环境脆弱性因素的最佳特征性相互作用的病理反应性攻击。这种相互作用涉及：i）单胺氧化酶（MAO）A的活性低，这是5-羟色胺代谢的主要酶（5HT）； ii）儿童忽视或虐待。为了模拟这种相互作用，我们在生命的第一周，我们生成了一条具有低MAOA活动（Maoaneo）的新小鼠，并使它们经历了母体分离（MS，MS，模拟儿童忽视）。 与临床方案相似，MS在青少年和成年的Maoaneo小鼠中引起了高水平的攻击性，但在其野生型同窝仔中没有。我们的初步数据表明，MS倾向于通过年龄特定过程的相互作用来发展侵略性：1）在生命的第一周，5HT2A受体的激活； 2）渐进，年龄 - 整个青春期，前额叶皮层（PFC）中N-甲基-D-天冬氨酸谷氨酸受体（NMDAR）的依赖性缺陷； 3）在成年期间对谷氨酸能下皮质下连接的抑制作用。基于这些数据，我们假设低MAOA活性和MS的相互作用会产生5HT2A受体过度刺激和PFC中年龄依赖性的NMDAR改变。反过来，这些PFC缺陷导致侵略 跨皮质区域的下游谷氨酸途径。我们将在三个特定的目的中检验这一假设：在AIM 1中，我们将确定低MAO A活性和MS的相互作用如何导致5HT 2A受体过度刺激；在AIM 2中，我们将检查5HT2A受体过早刺激导致PFC中NMDAR信号通路的年龄特异性缺陷；在AIM 3中，我们将确定介导谷氨酸在经受MS的侵袭性反应中的作用的皮质下区域。这些目标将通过尖端的行为，神经化学和蛋白质组学技术的独特组合来实现。这些翻译研究的结果将有助于我们了解反应性攻击的生物学基础，确定这种情况的新潜在生物标志物和治疗靶标，并最终减少其惊人的社会经济负担。