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

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.

项目概要/摘要病态攻击是一种反复出现的破坏性和暴力行为模式，通常出现在尽管社会负担沉重，但青春期和青年期达到顶峰。病理性攻击的影响，可用的治疗方法是有限且不充分的。治疗病理性攻击行为的关键在于其复杂的结构，这反映了不同结构和特征的重叠。年龄特异性机制；从而确定共同点和差异的神经发育基础这些结构之间的相互作用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，我们重点关注最具特征的基因×环境（G×E）病理性攻击中的相互作用，发生在 MAOA 基因（编码单胺氧化酶 A) 和儿童虐待在我们之前的资助期间，我们开发了这种 G×E 相互作用的第一个动物模型，通过对具有 MAOA 亚等位性突变的小鼠品系进行与未受压力的野生型（WT）对照小鼠不同，这些小鼠在出生后第一周就受到了早期生命压力。攻击性的形成遵循两个阶段的过程：第一阶段发生在生命早期，即攻击性行为发生之前。攻击性，反映了前额皮质及其下游连接的渐进性功能缺陷；相反，第二阶段发生在青春期前后，即攻击行为开始之后，其特点是战斗行为随年龄的增长而升级。我们的初步数据表明，每次打击都是由特定机制维持的，第一次打击涉及激活。血清素 5-HT2A 受体，而第二个是基于睾酮及其代谢物的激增。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基于这些发现，本研究提出了应对社会挑战的神经传递。该应用将检验 PA 的发展是由年龄特异性机制决定的假设集中于中脑边缘多巴胺能的改变。目标 1 和 2 的研究将确定多巴胺能神经传递和不同的攻击行为如何构建体在第一阶段受到 5-HT2A 受体刺激的影响，在第二阶段受到类固醇的影响目标 3 的研究将探讨攻击期间的多巴胺能激活是否可能导致行为强化，最终促进“攻击成瘾” 总而言之，这项研究将有所帮助。阐明病理性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。