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，由具有不同遗传、认知和情感特征的个体反复犯下。攻击性行为也被编入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，了解与攻击性相关的基本遗传、神经化学和神经解剖学过程是一个紧迫的公共卫生问题。功能性磁共振成像（fMRI）与选择的行为范式揭示了一种神经功能模式与减少前额叶皮质控制和增加皮质下反应的情感挑战性的任务在脆弱的个人。这种适应不良模式的基础是负责调节单胺的基因及其产物。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，已经被可靠地牵连到攻击性。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。其他单胺调节剂，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，也涉及作为神经化学标志物在研究和治疗高度攻击性行为。然而，这些遗传和大脑功能变量相互作用对人类攻击性的影响程度尚不清楚。因此，我们建议从普通人群中预选健康男性，分为攻击性和非攻击性两组，并在这些组中比较（1）攻击性反应，愤怒反应和执行控制（2）在fMRI中使用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）的体内脑MAO A催化活性和（4）MAOA、5-HTT和COMT基因型的易感性变体。我们假设攻击性参与者将使情绪反应的功能神经通路变得敏感，并减少执行控制的潜在通路。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和功能磁共振成像进行基础的人类研究，采用多层次的调查中间表型在一个复杂的和未充分研究的行为。特别是，在相同的人类受试者的综合基因-大脑-行为的方法回答了一个关键的需要，在侵略性的研究中不同的发现之间的桥梁，促进揭示复杂的相互关联的机制，人类的侵略行为。研究结果可能提供一个平台，从未来的研究可以开发，以帮助理解和控制轴I和II障碍的不懈暴力行为。 公共卫生相关性：对他人的攻击是一种具有遗传、认知和情感特征的社会反应行为。攻击性行为也被编入多种精神疾病的症状维度，并导致攻击和其他破坏性后果。因此，了解与攻击性相关的基本遗传、神经化学和神经解剖学过程是一个公共卫生问题。

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.