Deciphering gene-environment interactions in pathological reactive aggression

描述(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情况。这一问题的破坏性社会经济影响突出表明，迫切需要确定预防和治疗这一问题的有效战略；不幸的是，目前在这方面的努力因我们对反应性攻击的病理生理学缺乏了解而受挫。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的分子靶点。动物模型是理解攻击机制和测试新疗法不可或缺的工具，但它们的翻译和预测有效性往往因未能准确复制人类病理性攻击机制而受到影响。多亏了我们之前的NIH R21拨款，我们开始解决这个问题，开发了第一个具有最佳特征的遗传和环境脆弱性因素相互作用的病理性反应性攻击的小鼠模型。这种相互作用涉及：1)5-羟色胺(5-羟色胺)代谢的主要酶--单胺氧化酶(MAO)A活性低；2)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MAOA活性低的小鼠品系(MAOANeo)，并在它们出生的第一周让它们接受母系分离(MS，模拟儿童忽视)。 与临床情况类似，MS在青春期和成年MAOANeo小鼠中诱导了高水平的攻击性，但在它们的野生型小鼠中没有。我们的初步数据表明，多发性硬化症通过年龄特异性过程的相互作用使MAOANeo小鼠倾向于发展攻击性：1)5HT2A受体在出生后第一周的激活；2)进行性的，年龄- 青春期前额叶皮质(PFC)中N-甲基-D-天冬氨酸受体(NMDAR)的依赖缺陷；3)成年期谷氨酸能皮质下连接的去抑制。基于这些数据，我们假设低MAOA活性和MS的相互作用在PFC产生5HT2A受体过度刺激和年龄依赖性的NMDAR改变。反过来，这些PFC缺陷通过解除对PFC的抑制而导致攻击性 穿过皮质下区域的谷氨酸下游通路。我们将在三个具体目标中检验这一假说：在目标1中，我们将确定低MAO A活性与MS的相互作用如何导致早期5HT2A受体过度刺激；在目标2中，我们将研究早期5HT2A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，我们将确定在MS引起的MAOANeo小鼠的攻击反应中，介导谷氨酸作用的皮质下区域。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，确定针对这种疾病的新的潜在生物标志物和治疗靶点，并最终减少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.