Genes, Brain, and Behavior in Human Aggression

描述（由申请人提供）：对他人的攻击是一种社会破坏性行为，由具有独特遗传认知和情感特征的个体反复犯下。攻击行为也被编织成多种精神疾病的症状维度，并与不良的社会适应和预后有关。因此，了解与攻击相关的基本遗传、神经化学和神经解剖学过程是一个紧迫的公共卫生问题。功能磁共振成像（fMRI）与选择的行为范式揭示了神经功能模式一致的前额叶皮层控制减少和皮层下反应增加的情绪挑战任务在脆弱个体。这种不适应模式的基础是负责单胺调节的基因及其产物。具体来说，单胺氧化酶A (MAO A)，一种调节神经递质5 -羟色胺和去甲肾上腺素的酶，已经被证实与攻击性有关。MAOA基因型的低活性等位基因和低脑MAOA活性已被独立鉴定为攻击性行为、认知控制不良和情绪失调风险的中间表型。其他单胺调节因子，如儿茶酚- o -甲基转移酶（COMT）和5-羟色胺转运蛋白（5-HTT），以及MAO A，也被认为是研究和治疗高度攻击性行为的神经化学标志物。然而，这些基因和大脑功能变量在多大程度上相互作用，导致人类的侵略行为尚不清楚。因此，我们建议将健康男性从一般人群中预先选择为攻击性和非攻击性组，并比较这些组(1)攻击性反应，愤怒反应和执行控制；(2)使用功能磁共振成像中的Stroop对情绪和认知冲突挑战的行为和神经回路反应；(3)使用正电子发射断层扫描（PET）的体内大脑MAOA催化活性；(4)MAOA， 5-HTT和COMT基因型的易感性变异。我们假设具有攻击性的参与者将具有敏感的情绪反应功能神经通路，并减少潜在的执行控制通路。这些效应将与脑MAO A减少及其与易感基因型携带者的相互作用有关。因此，我们建议使用PET和fMRI进行基本的人体研究，对复杂且未充分研究的行为中的中间表型进行多层次调查。特别是，在同一人类受试者中，整合基因-大脑-行为方法回答了在攻击研究中不同发现之间建立桥梁的关键需求，促进了揭示人类攻击行为背后复杂的相互关联机制。研究结果可能为未来的研究提供一个平台，以帮助理解和控制轴I和II障碍中的持续暴力行为。

DESCRIPTION (provided by applicant): Aggression toward others is a socially destructive behavior repeatedly perpetrated by individuals of distinct genetic cognitive and affective characteristics. Aggressive behavior is also weaved into the symptom dimensions of multiple psychiatric disorders and is associated with poor social adjustment and prognosis. Therefore, understanding the basic genetic, neurochemical and neuroanatomical processes associated with aggression is an urgent public health concern. Functional MRI (fMRI) with select behavioral paradigms have revealed a neurofunctional pattern consistent with reduced prefrontal cortical control and increased subcortical response to emotionally challenging tasks in vulnerable individuals. Underlying this maladaptive pattern are genes and their products responsible for the regulation of monoamines. Specifically, monoamine oxidase A (MAO A), an enzyme regulating the neurotransmitters serotonin and norepinephrine, has been reliably implicated in aggression. The low activity alleles of the MAOA genotype and low brain MAO A activity have been independently identified as intermediate phenotypes of risk for aggressive behavior, poor cognitive control and dysregulated emotion. Other monoamine regulators, such as catechol-O-methyltransferase (COMT) and the serotonin transporter (5-HTT), together with MAO A, are also implicated as neurochemical markers in the study and treatment of highly aggressive behavior. However, the extent to which these genetic and brain function variables interact to contribute to human aggression is not known. Therefore we propose to preselect healthy men from the general population into aggressive versus non-aggressive groups and to compare in these groups (1) aggressive responses, anger reactivity and executive control (2) behavioral and neural circuitry response to emotional and cognitive conflict challenges using Stroop in fMRI (3) in-vivo brain MAO A catalytic activity using positron emission tomography (PET) and (4) susceptibility variants of the MAOA, 5-HTT and COMT genotypes. We hypothesize that aggressive participants will have sensitized functional neural pathways of emotional reactivity and reductions in the pathways underlying executive control. These effects will be associated with reduced brain MAO A and its interaction with the susceptibility genotype carriers. We therefore propose to conduct basic human studies using PET and fMRI, employing a multilevel investigation of intermediate phenotypes in a complex and understudied behavior. In particular, the integrated genes-brain-behavior approach in the same human subjects answers a critical need for bridging between disparate findings in the study of aggression, facilitating the uncovering of the complex interrelated mechanisms that underlie human aggressive behavior. Findings may provide a platform from which future studies can be developed to help understand, and control unremitting violent behavior in Axis I and II disorders. PUBLIC HEALTH RELEVANCE: Aggression toward others is a socially reactive behavior with genetic cognitive and affective characteristics. Aggressive behavior is also weaved into the symptom dimensions of multiple psychiatric disorders and contributes to assault and other damaging consequences. Therefore, understanding the basic genetic, neurochemical and neuroanatomical processes associated with aggression is a public health concern.