Genes, Brain, and Behavior in Human Aggression

人类攻击性的基因、大脑和行为

基本信息

批准号：
7993293
负责人：
Nelly Alia-Klein
金额：
$ 66.14万
依托单位：
BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
依托单位国家：
美国
项目类别：
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/7993293
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

项目摘要

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）：对他人的侵略是一种社会破坏性的行为，反复由具有独特的遗传认知和情感特征的个体进行。侵略性行为还编织成多种精神疾病的症状维度，与社会调整和预后不良有关。因此，了解与侵略相关的基本遗传，神经化学和神经解剖过程是紧急的公共健康问题。具有精选行为范式的功能性MRI（fMRI）揭示了一种神经功能模式，与额叶前皮质控制减少以及对弱势群体对情绪挑战性任务的皮层下层反应的增加相一致。这种不良适应模式的基础是基因及其产品负责单胺的调节。具体而言，单胺氧化酶A（MAO A）是调节神经递质5-羟色胺和去甲肾上腺素的酶，已可靠地与侵略有关。 MAOA基因型和低脑MAO A活性的低活性等位基因已被独立鉴定为具有侵略性行为风险，认知控制差和情绪失调的中间表型。其他单胺调节剂，例如Catechol-O-甲基转移酶（COMT）和5-羟色胺转运蛋白（5-HTT），以及MAO A，在研究和治疗高度侵略性行为中也被视为神经化学标记。但是，这些遗传和大脑功能变量在多大程度上相互作用以促进人类侵略。因此，我们建议将一般人口的健康男性与非攻击性群体相比，并在这些群体中进行比较（1）激进的反应，愤怒的反应性和执行控制（2）行为和神经循环的反应对情感和认知冲突的反应， fMRI（3）体内脑MAO中的Stroop使用正电子发射断层扫描（PET）和（4）MAOA，5-HTT和COMT基因型的敏感性变体的催化活性。我们假设积极的参与者将具有情绪反应性的功能神经途径和降低执行途径的途径。这些影响将与脑MAO A的减少以及与易感性基因型载体相互作用有关。因此，我们建议使用PET和fMRI进行基础研究，并在复杂而研究的行为中对中间表型进行了多层次研究。特别是，在同一人类受试者中，综合基因 - 脑 - 行为方法回答了在侵略研究中不同发现之间桥接的关键需求，从而促进了人类侵略行为构成的复杂相互关联的机制。调查结果可能会提供一个平台，可以从该平台开发未来的研究，以帮助理解和控制轴I和II疾病中的不易暴力行为。公共卫生相关性：对他人的侵略是具有遗传认知和情感特征的社会反应性行为。侵略行为还编织成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，了解与侵略相关的基本遗传，神经化学和神经解剖过程是公共卫生的关注点。