Developmental Origins of Aggressive and Impulsive Behavior

描述(由申请人提供)：大多数神经精神障碍都有发育性起源。这种发育脆弱性通常局限于敏感期，但对受影响的行为、调节因素和潜在机制几乎不了解。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，这是改善神经精神障碍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期，在早期，单胺信号的扰动改变了成年人的行为：出生后早期(P2-P11)，影响焦虑和抑郁相关行为的5-羟色胺敏感期，以及青春期后期(P22-P41)，改变攻击性和行为反应的苯丙胺(AMPH)的DA和5-羟色胺敏感期。在这里，我们将重点研究后者，即青春期(PA)。为此，我们设计了一项研究计划来调查主要的假设，即青春期DAT和5-HTT的阻断对DA系统的成熟具有相反的影响，易于或保护其免受高攻击性和多巴胺功能障碍的影响。我们的应用程序包含三个目标。在Aim1中，我们将更准确地定义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，并将缩小潜在的发育过程和受影响的电路。结果还将有助于将发现转化为跨物种的发现，包括人类。在AIM2中，我们将通过研究DA能神经元在体外和体内的活动来直接评估PA、DAT和5-HTT阻断对DA系统功能的影响。结果将给我们机械地洞察DA系统的哪些元素被改变，使我们能够设计救援和因果关系测试实验。在目标3中，我们将研究在PA、DAT和5-HTT抑制过程中和之后5-HT/DA的相互作用。这些结果将有助于阐明在PA发育过程中，多巴能和5-羟色胺能操作是如何对电路成熟发挥相反作用的，以及它们是否会永久性地改变5-羟色胺/DA-相互作用。我们的研究将影响人们对攻击性和伴有DA功能障碍的神经精神障碍的危险因素的理解。我们的初步数据表明，在PA发育过程中增加DA信号(如兴奋剂的使用)或减少5-HT信号的遗传或环境因素是攻击和DA功能障碍的危险因素。相反，在PA发育过程中减少DA信号或增加5-羟色胺信号(如SSRI)的遗传或环境因素，将降低攻击性和DA功能障碍的风险。再加上我们将提供的机械洞察力，我们的数据可能会改进精神病学的诊断、预防和治疗策略。

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.