Developmental Origins of Aggressive and Impulsive Behavior

攻击性和冲动行为的发展起源

• 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
• 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

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具有发育起源。这种发育脆弱性通常仅限于敏感时期，但是受影响的行为，调节因素和潜在的机制几乎没有理解。该赠款旨在进一步确定复杂行为的发展轨迹的敏感时期的了解，这是改善神经精神疾病的预防和治疗方法的必要步骤。我们最近确定了2个敏感的发育期，因此单胺信号传导的早期寿命改变了成人的行为：早期的早期（P2-P11）5-HT敏感时期，会影响焦虑和抑郁症相关的行为，以及与抑郁症相关的行为以及后期的杂期（P22-P41）DA-和5-HT和5-HT敏感的周期性抗反应（P22-P41）和5-HT敏感的经历反应抗反应（AM）。在这里，我们将重点关注后者的研究（PA）期。为此，我们设计了一项研究计划，以研究围绕青少年DAT和5-HTT封锁对DA-System的成熟，易于侵略或防止高侵略性和多巴胺功能障碍的成熟的总体假设。我们的应用程序包括三个目标。在AIM1中，我们将更精确地定义PA敏感时期的时间方面，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中的实验，并将缩小受影响的潜在发展过程和电路。结果还将有助于转化包括人类在内的物种之间的发现。在AIM2中，我们将直接评估PA DAT和5-HTT阻滞对DA系统功能的影响，通过研究体外和体内的Daergic神经元活性。结果将为我们提供机械性的影响，使DA系统的要素发生了变化，从而使我们可以设计救援和因果关系测试实验。在AIM 3中，我们将在PA DAT-和5-HTT抑制期间和之后调查5-HT/DA相互作用。结果将揭示出PA发育过程中的Daergic和5个握能操作如何对电路成熟产生相反的影响，以及它们是否永久改变5-HT/DA-DAITACTACTION。我们的研究将影响对患有DA功能障碍的侵略性和神经精神疾病的人类风险因素的理解。我们的初步数据表明，遗传或环境因素会增加DA信号传导（例如兴奋剂使用）或减少PA发育过程中5-HT信号传导作为攻击性和DA功能障碍的风险因素。相反，在PA发育过程中降低DA信号传导或增加5-HT信号传导（例如SSRI）的遗传因素或环境因素将起到减轻攻击性和DA功能障碍的风险。加上我们将提供的机械洞察力，我们的数据可能会改善精神病学的诊断，预防和治疗策略。