Interactions of MAO A with vulnerability factors for aggression

描述(申请人提供)：病理性攻击具有破坏性的社会经济影响，是美国年轻男性死亡的主要原因。这种疾病的预防和治疗工具的开发受到我们对其病理生理学的部分了解的极大限制。这一探索性R21建议的目的是了解病理性攻击的三个最具特征的易感性因素之间的相互作用机制：早期心理社会应激；低活性的脑单胺氧化酶(MAO)A，大脑5-羟色胺(5-HT)、去甲肾上腺素(NE)和多巴胺(DA)的主要降解酶；男性，与高水平的雄激素睾酮及其代谢物有关。事实上，最近的数据显示，受虐待的男孩在青春期后发生攻击性行为的高风险主要发生在与MAO A活性低相关的基因变异携带者中。我们发现，5-1还原酶(5AR)是将睾酮转化为其强大的雄激素代谢物二氢睾酮(DHT)的酶，受到早期应激和MAO-A缺乏的影响；此外，非那雄胺对其的抑制降低了患者和MAO A基因敲除小鼠的高攻击性。这一建议的主要假设是，低MAO A活性和早期心理社会应激的相互作用会导致大脑中单胺水平和类固醇合成途径的长期变化。在男性中，青春期睾酮水平的增加与这些变化相互作用，导致前额叶皮质和其他大脑情绪调节关键区域的类固醇和单胺失衡。这些神经化学干扰会导致攻击性和反社会行为。我们将使用雄性WT、MAO A KO小鼠和一种新开发的MAO A亚型(MAO Aneo)小鼠来解决这一假设，这些小鼠的大脑MAO A活性非常低。这些小鼠表现出比MAO A KO小鼠更低的攻击性水平，是携带低MAO A活性基因变体的优秀模型。在目标1中，我们将研究MAO-A基因变异与早期应激在雄性小鼠攻击行为发育轨迹中的相互作用。为此，我们将在出生后的前三周让雄性MAO Aneo和KO幼崽(及其WT后代)接受母系分离(一种高度同构的儿童忽视模型)；青春期前、青春期期间和青春期后与攻击相关的行为将与大脑关键区域的MAO A和5AR水平以及5-羟色胺、去甲肾上腺素、多巴胺、睾酮及其代谢物相关，以调节攻击行为。在目标2中，我们将通过评估去势和非那雄胺治疗引起的行为和分子变化，研究睾酮和5AR在MAO A缺陷小鼠攻击行为中的作用。拟议的项目将有助于建立病理性攻击的神经生物学基础。这些发现的翻译应用对于确定新的生物标记物、内表型和分子靶点对于早期预防、诊断和治疗这种疾病至关重要。

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.