Developmental Origins of Aggressive and Impulsive Behavior

攻击性和冲动行为的发展起源

基本信息

批准号：
8641426
负责人：
Mark Sascha Ansorge
金额：
$ 39.95万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8641426
关键词：
3,4-Dihydroxyphenylacetic Acid Adolescence Adolescent Adolescent Development Adult Affect Aggressive behavior Agonist Amphetamines Animals Anxiety Anxiety Disorders Attention Attention Deficit Disorder Behavior Behavioral Brain Cells Cognitive deficits Complex Corpus striatum structure Data Development Developmental Process Diagnosis Disease Dopamine Drug abuse Electrophysiology (science)Elements Environmental Risk Factor Etiology Functional disorder Genetic Grant Human Impulsive Behavior Impulsivity Knowledge Lead Life Light Mediating Mental Depression Mental disorders Methaqualone Modeling Mus Neurons Ocular Dominance Pathology Phenotype Prevention Prevention strategy Property Psychiatry Psychotic Disorders Receptor Activation Receptor Inhibition Research Risk Risk Factors Serotonin Serotonin Receptor 5-HT2C Short-Term Memory Signal Transduction Slice Suicide System Testing Time Tissues Translating Visual Cortex awake behavior test critical developmental period critical period design improved in vitro activity in vivo insight monoamine neuropsychiatry postnatal psychostimulant public health relevance relating to nervous system research study response sensory system treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Most neuropsychiatric disorders have developmental origins. Such developmental vulnerability is often restricted to sensitive periods, but affected behaviors, modulating factors, and underlying mechanisms are scarcely understood. This grant aims at furthering our knowledge of sensitive periods that determine the developmental trajectory of complex behaviors, which is a necessary step towards improving prevention and treatment approaches for neuropsychiatric disorders. We have recently identified 2 sensitive developmental periods whereupon early-life perturbation of monoamine signaling alters adult behavior: an early postnatal (P2-P11) 5-HT-sensitive period that affects anxiety and depression-related behaviors and a later peri-adolescent (P22-P41) DA- and 5-HT-sensitive period altering aggression and behavioral response amphetamine (AMPH). Here we will focus on the study of the latter, peri-adolescent (PA) period. To that end, we designed a research plan to investigate the overarching hypothesis that peri- adolescent DAT and 5-HTT blockade have opposing effects on the maturation of the DA-system, predisposing or protecting against high aggression and dopamine dysfunction. Our application consists of three aims. In Aim1 we will more precisely define the temporal aspects of the PA sensitive period and broaden the analysis of behaviors impacted by PA 5-HTT- and DAT-inhibition. Results will guide experiments in Aim2 and Aim3 and will narrow down the potential developmental processes and circuits affected. Results will also help to translate findings across species, including humans. In Aim2 we will directly assess the impact of PA DAT- and 5-HTT-blockade on the function of the DA-system by investigating DAergic neuron activity in vitro and in vivo. Results will give us mechanistic insigh into which elements of the DA-system are altered, allowing us to devise rescue and causality-testing experiments. In Aim 3 we will investigate 5-HT/DA-interaction during and after PA DAT- and 5-HTT-inhibition. Results will shed light on how DAergic and 5-HTergic manipulations during PA development exert their opposing effects on circuit maturation and whether they permanently alter 5-HT/DA-interaction. Our research will impact the understanding of human risk factors for aggression and neuropsychiatric disorders with DA dysfunction. Our preliminary data suggest that genetic or environmental factors, which either increase DA signaling (such as stimulant use) or decrease 5-HT signaling during PA development act as risk factors for aggression and DA dysfunction. Conversely, genetic or environmental factors, which either decrease DA signaling or increase 5-HT signaling (such as SSRIs) during PA development, would act to ameliorate risk for aggression and DA dysfunction. Together with the mechanistic insight we will provide, our data could lead to improved diagnosis, prevention and treatment strategies in psychiatry.

描述（由申请人提供）：大多数神经精神疾病都有发育起源。这种发育脆弱性通常仅限于敏感时期，但受影响的行为、调节因素和潜在机制却很少被了解。这笔赠款旨在加深我们对决定复杂行为发展轨迹的敏感期的了解，这是改善神经精神疾病预防和治疗方法的必要步骤。我们最近发现了两个敏感的发育时期，生命早期单胺信号传导的扰动会改变成年行为：出生后早期（P2-P11）5-HT敏感期，影响焦虑和抑郁相关行为，以及后期的青春期前后（P22）。 -P41) DA-和5-HT敏感期改变攻击性和行为反应安非他明(AMPH)。这里我们将重点研究后者，即青春期前后（PA）时期。为此，我们设计了一项研究计划来调查一个总体假设，即青春期 DAT 和 5-HTT 阻断对 DA 系统的成熟具有相反的影响，从而诱发或防止高攻击性和多巴胺功能障碍。我们的应用程序包含三个目标。在目标 1 中，我们将更精确地定义 PA 敏感期的时间方面，并扩大对 PA 5-HTT 和 DAT 抑制影响的行为的分析。结果将指导 Aim2 和 Aim3 的实验，并将缩小受影响的潜在发育过程和回路的范围。结果还将有助于将发现转化为跨物种，包括人类。在 Aim2 中，我们将通过研究体内和体外的 DAergic 神经元活性，直接评估 PA DAT 和 5-HTT 阻断对 DA 系统功能的影响。结果将使我们能够深入了解 DA 系统的哪些元素发生了改变，从而使我们能够设计救援和因果关系测试实验。在目标 3 中，我们将研究 PA DAT 和 5-HTT 抑制期间和之后的 5-HT/DA 相互作用。结果将揭示 PA 发育过程中 DAergic 和 5-HTergic 操作如何对回路成熟产生相反的影响，以及它们是否永久改变 5-HT/DA 相互作用。我们的研究将影响对人类攻击性和 DA 功能障碍神经精神疾病危险因素的理解。我们的初步数据表明，在 PA 发育过程中增加 DA 信号传导（例如兴奋剂的使用）或减少 5-HT 信号传导的遗传或环境因素是攻击性和 DA 功能障碍的危险因素。相反，在 PA 发育过程中，遗传或环境因素会减少 DA 信号传导或增加 5-HT 信号传导（例如 SSRI），从而减轻攻击性和 DA 功能障碍的风险。加上我们将提供的机制见解，我们的数据可以改善精神病学的诊断、预防和治疗策略。