Deciphering gene-environment interactions in pathological reactive aggression

项目概要/摘要 病理性攻击是一种反复出现的破坏性和暴力行为模式，通常出现在 青春期和高峰期在年轻的成年。尽管经济发展造成了巨大的社会经济负担， 由于病理性攻击的影响，现有的治疗方法有限且不足。中的关键问题 病理性攻击的治疗在于其复杂的结构，它反映了不同结构的重叠， 年龄特异性机制;因此，确定共同点和差异的神经发育基础 对于开发更好的疗法至关重要。 为了研究这些神经生物学机制，我们集中在最具特征的基因×环境（G × E） 在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（编码 单胺氧化酶A）和虐待儿童。在上一个资助期内，我们开发了 这种G × E相互作用的第一个动物模型，通过使具有MAOA亚型突变的小鼠品系， 在出生后的第一周就有压力。与未应激和野生型（WT）对照组不同，这些小鼠 发展侵略性遵循两个阶段的过程：第一阶段发生在生命的早期，在发病之前， 攻击性，并反映了前额叶皮层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，在攻击开始之后，其特征是 打斗行为的年龄依赖性升级。 我们的初步数据显示每一次撞击都是由特定的机制维持的。第一次袭击涉及到激活 第二种是基于睾酮及其代谢物的激增。我们 还表明，在我们的模型中的攻击行为反映了多巴胺能神经元的过度激活， 神经传递应对社会挑战。基于这些发现，本研究中提出的研究 应用程序将测试PA的发展是由年龄特异性机制形成的假设 集中于中脑边缘多巴胺能改变 目标1和2中的研究将确定多巴胺能神经传递和不同的攻击性如何影响攻击性。 第一阶段受5-HT 2A受体刺激影响，第二阶段受类固醇影响 阶段目标3中的研究将探索发作期间多巴胺能激活是否可能导致 行为强化，最终促进“攻击成瘾”。总的来说，这项研究将有助于 阐明病理性攻击的神经发育机制，并确定新的潜在靶点， 预防，诊断和治疗这种疾病。

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.