Genes, Brain, and Behavior in Human Aggression

描述(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人反复犯下。攻击性行为也被编织到多种精神障碍的症状维度中，并与不良的社会适应和预后有关。因此，了解与攻击有关的基本遗传、神经化学和神经解剖学过程是一个紧迫的公共卫生问题。具有特定行为范式的功能磁共振成像(FMRI)显示了一种神经功能模式，与易受伤害个体的前额叶皮质控制减少和皮质下对情绪挑战任务的反应增加一致。在这种不适应模式的背后，是负责调节单胺的基因及其产物。具体地说，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，已被可靠地与攻击有关。MAOA基因的低活性等位基因和脑MAO A活性低被独立地确定为攻击性行为、认知控制不良和情绪调节失调的风险的中间表型。其他单胺调节剂，如儿茶酚-O-甲基转移酶(COMT)和5-羟色胺转运体(5-HTT)，以及MAO A，也被认为是研究和治疗高攻击性行为的神经化学标志物。然而，这些遗传和大脑功能变量相互作用在多大程度上促进了人类的攻击性尚不清楚。因此，我们建议从普通人群中预先选择健康男性，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)行为和神经回路对情绪和认知冲突挑战的反应，(3)使用正电子发射断层扫描(PET)的体内脑MAO A催化活性，以及(4)MAOA、5-HTT和COMT基因的易感变体。我们假设，攻击性参与者将敏化情绪反应的功能神经通路，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携带者的相互作用有关。因此，我们建议使用正电子发射计算机断层扫描和功能磁共振成像进行基础的人体研究，对复杂和未被充分研究的行为中的中间表型进行多水平研究。特别是，在相同的人类受试者中的综合基因-大脑-行为方法满足了在攻击性研究中不同的发现之间架起桥梁的关键需要，有助于揭示人类攻击性行为背后的复杂的相互关联的机制。这些发现可能会为未来的研究提供一个平台，以帮助理解和控制轴心I和II障碍中持续不断的暴力行为。 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性行为。攻击性行为也被编织到多种精神障碍的症状维度中，并导致袭击和其他破坏性后果。因此，了解与攻击有关的基本遗传、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.