Genes, Brain, and Behavior in Human Aggression

人类攻击性的基因、大脑和行为

• 批准号: 8135403
• 负责人: Nelly Alia-Klein
• 金额: $ 65.18万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135403
• 关键词: Affective; Aggressive behavior; Alleles; Amygdaloid structure; Anger; Animals; Anterior; Attention; Behavior; Behavioral; Behavioral Paradigm; Brain; Catechol O-Methyltransferase; Cerebellum; Characteristics; Chronic; Clinical; Clorgyline; Code; Cognitive; Color; Complex; Conflict (Psychology); Control Groups; Data; Dimensions; Disease; Emotional; Emotions; Enzymes; Equipment and supply inventories; Event; Functional Magnetic Resonance Imaging; Future; General Population; Genes; Genetic; Genetic Variation; Genotype; Hippocampus (Brain); Human; Individual; Individual Differences; Insula of Reil; Intervention; Investigation; Link; Measures; Medial; Mental disorders; Methaqualone; Minority; Mitochondria; Modeling; Monoamine Oxidase A; Neural Pathways; Neurotransmitters; Norepinephrine; Participant; Pathway interactions; Pattern; Performance; Personality Disorders; Personality Traits; Phenotype; Population; Positron-Emission Tomography; Predisposition; Process; Psychopathology; Public Health; Regulation; Reporting; Research Design; Risk; Role; Serotonin; Social Adjustment; Susceptibility Gene; Symptoms; Testing; Thalamic structure; Variant; Violence; assault; base; blood oxygenation level dependent response; brain behavior; cingulate cortex; cognitive control; executive function; fighting; human subject; in vivo; life history; male; men; monoamine; neural circuit; neurochemistry; outcome forecast; physical assault; public health relevance; radiotracer; response; serotonin transporter; trait

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.

描述（由申请人提供）：对他人的攻击是具有不同遗传认知和情感特征的个体反复实施的一种社会破坏性行为。攻击性行为也与多种精神疾病的症状维度交织在一起，并与不良的社会适应和预后相关。因此，了解与攻击行为相关的基本遗传、神经化学和神经解剖学过程是一个紧迫的公共卫生问题。具有特定行为范式的功能性 MRI (fMRI) 揭示了一种神经功能模式，该模式与易受影响个体的前额皮质控制减少和皮质下对情绪挑战性任务的反应增加一致。这种适应不良模式的背后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) 是一种调节神经递质血清素和去甲肾上腺素的酶，已被证实与攻击行为有关。 MAOA 基因型的低活性等位基因和低脑 MAO A 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，例如儿茶酚-O-甲基转移酶 (COMT) 和血清素转运蛋白 (5-HTT)，以及 MAO A，也被认为是高度攻击行为的研究和治疗中的神经化学标记物。然而，这些遗传和大脑功能变量相互作用在多大程度上导致人类攻击性尚不清楚。因此，我们建议从一般人群中预先选择健康男性，分为攻击性组和非攻击性组，并在这些组中进行比较（1）攻击性反应、愤怒反应性和执行控制（2）使用Stroop在fMRI中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MAO A催化活性和（4）MAOA的敏感性变体， 5-HTT 和 COMT 基因型。我们假设攻击性参与者会使情绪反应的功能神经通路变得敏感，并减少执行控制的通路。这些影响与大脑 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 进行基础人类研究，对复杂且未充分研究的行为中的中间表型进行多层次研究。特别是，在同一人类受试者中整合基因-大脑-行为方法满足了在攻击性研究中弥合不同发现之间的关键需求，有助于揭示人类攻击性行为背后复杂的相互关联机制。研究结果可能提供一个平台，未来可以开展研究，以帮助理解和控制轴一和轴二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行为。攻击性行为也与多种精神疾病的症状维度交织在一起，并导致攻击和其他破坏性后果。因此，了解与攻击行为相关的基本遗传、神经化学和神经解剖学过程是一个公共卫生问题。