Deciphering gene-environment interactions in pathological reactive aggression

项目摘要/摘要 病理性攻击是一种反复出现的破坏性和暴力行为，通常出现在 青春期和成年期高峰期。尽管美国政府施加了沉重的社会经济负担 在病理性攻击的影响下，现有的治疗方法是有限和不充分的。的一个关键问题 病理性攻击的治疗在于其复杂的结构，它反映了不同的结构和 特定年龄的机制；因此，确定共性和差异的神经发育基础 这些结构之间的关系对于开发更好的治疗方法至关重要。 为了研究这些神经生物学机制，我们重点研究了特征最好的基因×环境(G×E) 病理性攻击中的相互作用，发生在MAOA基因的低活性等位基因之间(编码 单胺氧化酶A)和虐待儿童。在我们之前的融资期间，我们开发了 第一个这种G×E相互作用的动物模型，通过使一系列带有MAOA亚型突变的小鼠 在生命的第一周，生命早期的压力。与非应激和野生型(WT)对照组不同，这些小鼠 在两个阶段之后发展攻击性：第一阶段发生在生命的早期，在 攻击性，反映了前额叶皮质及其下游连接的进行性功能缺陷； 相反，第二阶段发生在青春期前后，在攻击性开始之后，特征是 年龄相关的战斗行为升级。 我们的初步数据显示，每一次打击都有特定的机制支撑。第一次命中涉及到激活 而第二种是基于睾酮及其代谢物的激增。我们 我们模型中的攻击行为也反映了多巴胺能神经元的过度激活 应对社会挑战的神经传递。基于这些发现，本报告中提出的研究 应用程序将检验PA的发展是由特定年龄的机制塑造的假设 聚集在中脑边缘的多巴胺能改变。 目标1和目标2中的研究将确定多巴胺能神经传递和不同的攻击 结构在第一阶段受到5-HT2A受体刺激的影响，在第二阶段受到类固醇的影响 舞台。AIM 3中的研究将探索发作过程中的多巴胺能激活是否会导致 行为强化，最终促进“攻击性成瘾”。综上所述，这项研究将有所帮助 阐明病理性攻击的神经发育机制，并确定新的潜在靶点 这种情况的预防、诊断和治疗。

PROJECT SUMMARY/ABSTRACT Pathological aggression is a recurrent pattern of disruptive and violent behavior, which typically emerges in adolescence and peaks in young adulthood. Despite the significant socioeconomic burden imposed by the repercussions of pathological aggression, available treatments are limited and inadequate. A key problem in treating pathological aggression lies in its complex structure, which reflects the overlap of distinct constructs and age-specific mechanisms; thus, identifying the neurodevelopmental bases of the commonalities and differences between these constructs is critical to developing better therapies. To study these neurobiological mechanisms, we focused on the best-characterized gene × environment (G×E) interaction in pathological aggression, occurring between low-activity alleles of the MAOA gene (encoding the enzyme monoamine oxidase A) and child maltreatment. During our previous funding period, we developed the first animal model of this G×E interaction, by subjecting a line of mice with a MAOA hypomorphic mutation to early-life stress during the first week of life. Unlike their unstressed and wild type (WT) controls, these mice develop aggression following a two-stage process: the first stage occurs in early life, before the onset of aggression, and reflects progressive functional deficits of the prefrontal cortex and its downstream connectivity; conversely, the second stage occurs around puberty, after the onset of aggression, and is characterized by an age-dependent escalation of fighting behavior. Our preliminary data show that each hit is sustained by a specific mechanism. The first hit involves the activation of serotonin 5-HT2A receptors, while the second is based on an upsurge of testosterone and its metabolites. We also showed that the attacking behavior in our model reflects the hyperactivation of dopaminergic neurotransmission in response to social challenges. Based on these findings, the studies proposed in this application will test the hypothesis that the development of PA is shaped by age-specific mechanisms converging on mesolimbic dopaminergic alterations. The studies in Aims 1 and 2 will determine how dopaminergic neurotransmission and different aggression constructs are influenced by 5-HT2A receptor stimulation during the first stage and steroids during the second stage. The studies in Aim 3 will explore whether the dopaminergic activation during attacks may lead to behavioral reinforcement, ultimately promoting “aggression addiction”. Taken together, this research will help elucidate the neurodevelopmental mechanisms of pathological aggression, and identify new potential targets for the prevention, diagnosis, and treatment of this condition.