Interactions of MAO A with vulnerability factors for aggression

MAO A 与攻击性脆弱因素的相互作用

• 批准号: 8291274
• 负责人: Marco Bortolato
• 金额: $ 6.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291274
• 关键词: Address; Adult; Affect; Aggressive behavior; Allopregnanolone; American; Amygdaloid structure; Androgens; Behavior; Behavioral; Biological Markers; Brain; Brain region; Brunner syndrome; Castration; Characteristics; Child Abuse; Childhood; Chronic; Corpus striatum structure; Data; Development; Diagnosis; Disease; Disease Management; Dopamine; Emotional; Emotional Disturbance; Enzymes; Finasteride; Functional disorder; Gender; Genetic; Gonadal Steroid Hormones; Hormonal; Hypothalamic structure; Individual; Injection of therapeutic agent; Knock-out; Knockout Mice; Knowledge; Lead; Life; Link; Mediating; Mediator of activation protein; Metabolism; Methaqualone; Modeling; Molecular; Molecular Target; Monoamine Oxidase; Monoamine Oxidase A; Mothers; Mus; Neurobiology; Norepinephrine; Orchiectomy; Outcome; Oxidoreductase; Pathway interactions; Patients; Predisposition; Prefrontal Cortex; Prevention; Production; Progesterone; Psychosocial Stress; Puberty; Public Health; Recording of previous events; Regulation; Risk; Role; ST5 gene; Serotonin; Severities; Societies; Staging; Stanolone; Steroids; Stress; System; TNFRSF5 gene; Testing; Testosterone; Therapeutic; Translating; Violence; Wild Type Mouse; anti social; base; biological adaptation to stress; boys; child neglect; economic impact; endophenotype; genetic variant; high risk; inhibitor/antagonist; innovation; male; maternal separation; men; monoamine; mortality; neglect; neurobiological mechanism; neurochemistry; neurosteroids; novel; postnatal; pup; socioeconomics; tool; trait; transmission process

DESCRIPTION (provided by applicant): Pathological aggression has a devastating socio-economic impact, and is a leading mortality in young male Americans. The development of preventative and therapeutic tools for the management of this disorder is greatly limited by our partial understanding of its pathophysiology. The objective of this exploratory R21 proposal is to understand the mechanisms of interaction between the three best-characterized vulnerability factors for pathological aggression: early psychosocial stress; low activity of brain monoamine oxidase (MAO) A, the major enzyme for the degradation of brain serotonin (5-HT), norepinephrine (NE) and dopamine (DA); male gender, in relation to the high levels of androgen testosterone and its metabolites. In fact, recent data show that the high risk to develop post-pubertal aggression in maltreated boys is mainly observed in carriers of genetic variants associated with low MAO A activity. We found that 5-1 reductase (5AR), the enzyme that converts testosterone into its potent androgenic metabolite dihydrotestosterone (DHT), is affected by early stress and MAO-A deficiency; furthermore, its inhibition by finasteride reduces the high aggression of patients and MAO A knockout mice. The leading hypothesis of this proposal is that the interaction of low MAO A activity and early psychosocial stress results in long-term changes in monoamine levels and steroidogenic pathways in the brain. In males, the increase in testosterone levels at puberty interacts with these changes, resulting in imbalances in steroids and monoamines in prefrontal cortex and other key brain regions for emotional regulation. These neurochemical perturbations lead to aggression and antisocial behavior. We will address this hypothesis using male WT, MAO A KO mice and a newly-developed line of MAO A hypomorphic (MAO Aneo) mice, with very low brain MAO A activity. These mice show lower levels of aggression than MAO A KO mice and are an excellent model for carriers of low MAO A- activity genetic variants. In Aim 1, we will study the effects of the interaction between MAO-A genetic variants and early stress in the developmental trajectory of aggression in male mice. To this end, we will subject male MAO Aneo and KO pups (and their WT littermates) to maternal separation (a highly isomorphic model of child neglect) for the first three weeks of postnatal life; aggression-related behaviors before, during and after puberty will be correlated with the levels of MAO A and 5AR, as well as 5-HT, NE, DA, testosterone and their metabolites in key brain regions for the regulation of aggression. In Aim 2, we will study the role of testosterone and 5AR in the aggression of MAO A-deficient mice, by assessing the behavioral and molecular changes induced by castration and finasteride treatment. The proposed project will help establish the neurobiological bases of pathological aggression. The translational application of these findings will be critical to define new biomarkers, endophenotypes and molecular targets for early prevention, diagnosis and treatment of this disorder.

描述（由申请人提供）：病理侵略具有毁灭性的社会经济影响，并且是年轻男性美国人的主要死亡率。我们对其病理生理学的部分理解的限制，用于治疗这种疾病的预防和治疗工具的开发受到了极大的限制。该探索性R21提案的目的是了解三种最佳特征性的脆弱性因素在病理攻击中的相互作用机制：早期的社会心理压力；脑单胺氧化酶（MAO）A活性低，这是脑血清素（5-HT），去甲肾上腺素（NE）和多巴胺（DA）降解的主要酶；男性性别，与高水平的雄激素睾丸激素及其代谢产物有关。实际上，最近的数据表明，在与低MAO A活性相关的遗传变异携带者中，主要观察到在虐待男孩中发展后侵略的高风险。我们发现，将睾丸激素转化为有效的雄激素代谢产物二氢睾丸激素（DHT）的5-1还原酶（5AR）受早期应激和MAO-A缺乏的影响；此外，非那雄胺的抑制作用降低了患者的高攻击性和MAO A基因敲除小鼠。该提议的主要假设是，低MAO A活性和早期社会心理应激的相互作用会导致大脑中单胺水平和类固醇途径的长期变化。在男性中，青春期睾丸激素水平的增加与这些变化相互作用，导致前额叶皮层和其他关键大脑区域的类固醇和单胺的失衡，以进行情绪调节。这些神经化学扰动导致侵略和反社会行为。我们将使用雄性WT，MAO A KO小鼠和新发达的Mao A型肌电（Mao Aneo）小鼠来解决这一假设，其大脑MAO具有非常低的活性。这些小鼠的攻击水平低于MAO A KO小鼠，是低MAO A-A-Attive遗传变异携带者的绝佳模型。在AIM 1中，我们将研究MAO-A遗传变异与早期应力之间相互作用在雄性小鼠侵略性轨迹中的影响。为此，在产后生命的前三周，我们将使男性Mao Aneo和Ko Pup（及其wt同窝仔）（及其wt同窝室）进行母体分离（一种高度同构的儿童忽视模型）；青春期之前，之中和之后与侵略性相关的行为将与MAO A和5AR的水平以及5-HT，NE，DA，DA，睾丸激素及其代谢物在关键大脑区域的调节相关。在AIM 2中，我们将通过评估cast割和非那雄胺治疗引起的行为和分子变化来研究睾丸激素和5AR在MAO A缺陷小鼠侵略中的作用。拟议的项目将有助于建立病理侵略的神经生物学基础。这些发现的翻译应用对于定义新的生物标志物，内表型和分子靶标对于早期预防，诊断和治疗这种疾病至关重要。