Deciphering gene-environment interactions in pathological reactive aggression

解读病理性反应性攻击中的基因-环境相互作用

基本信息

批准号：
10460716
负责人：
Marco Bortolato
金额：
$ 62.65万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-05 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10460716
关键词：
Adolescence Adult Age Aggressive behavior Alleles Animal Model Area Behavior Behavioral Biological Brain Castration Child Child Abuse and Neglect Chronic Complex Cues Data Development Diagnosis Dopamine Dopaminergic Cell Enzymes Exposure to Female Funding Genes Glutamates Goals Growth HTR2A gene Heterogeneity Hypersensitivity Impairment Impulsivity Individual Knock-out Lead Life Male Adolescents Measures Methaqualone Modeling Monoamine Oxidase A Mus Mutation Neurobiology Neuronal Plasticity Nucleus Accumbens Output Pathologic Pathway interactions Pattern Phenotype Plasma Prefrontal Cortex Prevention Process Psychological reinforcement Puberty Pyramidal Cells Recurrence Regimen Research Rewards Risk ST5 gene Self Administration Serotonin Serotonin Receptor 5-HT2A Sex Differences Shapes Stanolone Steroids Stimulus Stress Structure Testing Testosterone Therapeutic Time Ursidae Family Ventral Tegmental Area Violence addiction age related androgenic base conditioned place preference early life stress fighting gene environment interaction male mesolimbic system mouse model mutant neurobiological mechanism neurophysiology neurotransmission postnatal prevent pup response social socioeconomics stem transcriptomics transmission process young adult

Adolescence Adult Age Aggressive behavior Alleles Animal Model Area Behavior Behavioral Biological Brain Castration Child Child Abuse and Neglect Chronic Complex Cues Data Development Diagnosis Dopamine Dopaminergic Cell Enzymes Exposure to Female Funding Genes Glutamates Goals Growth HTR2A gene Heterogeneity Hypersensitivity Impairment Impulsivity Individual Knock-out Lead Life Male Adolescents Measures Methaqualone Modeling Monoamine Oxidase A Mus Mutation Neurobiology Neuronal Plasticity Nucleus Accumbens Output Pathologic Pathway interactions Pattern Phenotype Plasma Prefrontal Cortex Prevention Process Psychological reinforcement Puberty Pyramidal Cells Recurrence Regimen Research Rewards Risk ST5 gene Self Administration Serotonin Serotonin Receptor 5-HT2A Sex Differences Shapes Stanolone Steroids Stimulus Stress Structure Testing Testosterone Therapeutic Time Ursidae Family Ventral Tegmental Area Violence addiction age related androgenic base conditioned place preference early life stress fighting gene environment interaction male mesolimbic system mouse model mutant neurobiological mechanism neurophysiology neurotransmission postnatal prevent pup response social socioeconomics stem transcriptomics transmission process young adult

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项目摘要

PROJECT SUMMARY/ABSTRACT Pathological aggression is a recurrent pattern of disruptive and violent behavior, which typically emerges in adolescence and peaks in young adulthood. Despite the significant socioeconomic burden imposed by the repercussions of pathological aggression, available treatments are limited and inadequate. A key problem in treating pathological aggression lies in its complex structure, which reflects the overlap of distinct constructs and age-specific mechanisms; thus, identifying the neurodevelopmental bases of the commonalities and differences between these constructs is critical to developing better therapies. To study these neurobiological mechanisms, we focused on the best-characterized gene × environment (G×E) interaction in pathological aggression, occurring between low-activity alleles of the MAOA gene (encoding the enzyme monoamine oxidase A) and child maltreatment. During our previous funding period, we developed the first animal model of this G×E interaction, by subjecting a line of mice with a MAOA hypomorphic mutation to early-life stress during the first week of life. Unlike their unstressed and wild type (WT) controls, these mice develop aggression following a two-stage process: the first stage occurs in early life, before the onset of aggression, and reflects progressive functional deficits of the prefrontal cortex and its downstream connectivity; conversely, the second stage occurs around puberty, after the onset of aggression, and is characterized by an age-dependent escalation of fighting behavior. Our preliminary data show that each hit is sustained by a specific mechanism. The first hit involves the activation of serotonin 5-HT2A receptors, while the second is based on an upsurge of testosterone and its metabolites. We also showed that the attacking behavior in our model reflects the hyperactivation of dopaminergic neurotransmission in response to social challenges. Based on these findings, the studies proposed in this application will test the hypothesis that the development of PA is shaped by age-specific mechanisms converging on mesolimbic dopaminergic alterations. The studies in Aims 1 and 2 will determine how dopaminergic neurotransmission and different aggression constructs are influenced by 5-HT2A receptor stimulation during the first stage and steroids during the second stage. The studies in Aim 3 will explore whether the dopaminergic activation during attacks may lead to behavioral reinforcement, ultimately promoting “aggression addiction”. Taken together, this research will help elucidate the neurodevelopmental mechanisms of pathological aggression, and identify new potential targets for the prevention, diagnosis, and treatment of this condition.

项目摘要/摘要病理侵略性是一种反复出现的破坏性和暴力行为的模式，通常出现青少年和成年时期的峰值。尽管有重要的社会经济伯恩尼病理侵略性，可用治疗的影响是有限且不足的。一个关键问题处理病理侵略在于其复杂的结构，这反映了不同构造和特定年龄的机制；因此，识别共同点和差异的神经发育基础这些结构之间对于开发更好的疗法至关重要。为了研究这些神经生物学机制，我们专注于特征最佳的基因×环境（G×e）病理攻击中的相互作用，发生在MAOA基因的低活性等位基因之间（编码酶单胺氧化物A）和儿童虐待。在以前的资金期间，我们开发了通过将具有MAOA肌电突变的小鼠线降为生命第一周的早期压力。这些老鼠与他们的无重理和野生型（WT）控件不同遵循两个阶段的过程：第一阶段发生在早期生命之前，在积极反映前额叶皮层及其下游连通性的渐进功能缺陷；相反，第二阶段发生在青春期，侵略性发作之后，其特征是战斗行为依赖年龄的升级。我们的初步数据表明，每个命中均由特定机制持续。第一个命中涉及激活 5-羟色胺5-HT2A受体的含量，而第二种是基于睾丸激素及其代谢产物的膨胀。我们还表明我们模型中的攻击行为反映了多巴胺能的过度激活神经传递应对社会挑战。基于这些发现，这项研究提出了应用将检验以下假设，即PA的发展是由年龄特异性机制塑造的融合中唇多巴胺能改变。目标1和2中的研究将决定多巴胺能神经传递和不同的侵略构建体受到第一阶段5-HT2A受体刺激的影响，第二阶段的类固醇在第二阶段的影响阶段。 AIM 3中的研究将探讨攻击过程中多巴胺能激活是否可能导致行为加强，最终促进“侵略成瘾”。综上所述，这项研究将有所帮助阐明病理攻击的神经发育机制，并确定新的潜在目标这种情况的预防，诊断和治疗。