Deciphering gene-environment interactions in pathological reactive aggression

描述（由申请人提供）：病理性反应性攻击是一种以频繁爆发冲动暴力和愤怒为特征的疾病。这一问题的破坏性社会经济影响突出表明，迫切需要确定有效的预防和治疗战略;不幸的是，我们对反应性攻击的病理生理学知之甚少，阻碍了目前在这方面的努力。我们研究的长期目标是阐明攻击性的神经生物学基础，并确定预防和治疗这种复杂疾病的新分子靶点。动物模型是理解攻击机制和测试新疗法的不可或缺的工具，但它们的翻译和预测有效性往往受到无法准确再现人类病理性攻击机制的影响。由于我们之前的NIH R21资助，我们开始通过开发第一个遗传和环境脆弱性因素相互作用的病理反应性攻击的最佳特征的小鼠模型来解决这个问题。这种互动包括：i）单胺氧化酶（MAO）A（5-羟色胺（5-HT）代谢的主要酶）活性低; ii）忽视或虐待儿童。为了模拟这种相互作用，我们产生了一种新的低MAOA活性的小鼠品系（MAOANeo），并在生命的第一周内将它们进行母体分离（MS，模拟儿童忽视）。 与临床情况类似，MS在青少年和成年MAOANeo小鼠中诱导了高水平的攻击性，但在其野生型同窝小鼠中没有。我们的初步数据表明，MS通过年龄特异性过程的相互作用使MAOANeo小鼠易于发展攻击性：1）在生命的第一周内激活5 HT 2A受体; 2）进行性，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）成年期大脑皮层下连接的去抑制。基于这些数据，我们假设低MAOA活性和MS的相互作用产生PFC中5 HT 2A受体过度刺激和年龄依赖性NMDAR改变。 在皮层下的谷氨酸通路下游。我们将从三个方面来验证这一假设：第一，我们将确定低MAO A活性和MS的相互作用如何导致早期5 HT 2A受体过度刺激;第二，我们将研究早期5 HT 2A受体过度刺激如何导致PFC中NMDAR信号通路的年龄特异性缺陷;在目标3中，我们将鉴定在经受MS的MAOANeo小鼠的攻击性反应中介导谷氨酸作用的皮层下区域。这些目标将通过尖端行为，神经化学和蛋白质组学技术。这些转化研究的结果将帮助我们了解反应性攻击的生物学基础，确定这种疾病的新的潜在生物标志物和治疗靶点，并最终减轻其惊人的社会经济负担。

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.