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: 8837365
• 负责人: Marco Bortolato
• 金额: $ 61万
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837365
• 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; 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; Simulate; 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; public health relevance; 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病症。这一问题造成的破坏性社会经济影响凸显了迫切需要确定有效的预防和治疗战略；不幸的是，由于我们对反应性攻击的病理生理学知之甚少，目前这方面的努力受到阻碍。我们研究的长期目标是阐明攻击行为的神经生物学基础，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不可或缺的工具，但它们的转化和预测有效性往往因无法准确再现人类病理攻击机制而受到损害。得益于之前的 NIH R21 资助，我们开始通过开发第一个小鼠模型来解决这个问题，该模型最能表征病理反应性攻击的遗传和环境脆弱性因素之间的相互作用。这种相互作用涉及： i) 单胺氧化酶 (MAO) A 的低活性，它是血清素 (5HT) 代谢的主要酶； ii) 忽视或虐待儿童。为了模拟这种相互作用，我们培育了一种新的 MAOA 活性低的小鼠品系 (MAOANeo)，并在它们出生后的第一周将它们置于母亲分离状态（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却没有。我们的初步数据表明，MS 使 MAOANeo 小鼠通过年龄特异性过程的相互作用而容易产生攻击性：1）在生命第一周激活 5HT2A 受体； 2）进步，年龄- 整个青春期前额皮质 (PFC) 中 N-甲基-D-天冬氨酸谷氨酸受体 (NMDAR) 的依赖性缺陷； 3）成年期谷氨酸能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 的相互作用会导致 PFC 中 5HT2A 受体过度刺激和年龄依赖性 NMDAR 改变。反过来，这些 PFC 缺陷会通过抑制去抑制而导致攻击行为。 穿过皮层下区域的下游谷氨酸途径。我们将在三个具体目标中检验这一假设：在目标 1 中，我们将确定低 MAO A 活性和 MS 的相互作用如何导致早期 5HT 2A 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，我们将确定在遭受 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技术的独特组合来实现。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，识别这种疾病的新的潜在生物标志物和治疗靶点，并最终减轻其令人震惊的社会经济负担。