Developmental Origins of Aggressive and Impulsive Behavior

描述（由申请人提供）：大多数神经精神障碍具有发育起源。这种发育脆弱性通常局限于敏感期，但受影响的行为、调节因素和潜在机制却很少被理解。这项资助旨在进一步加深我们对决定复杂行为发展轨迹的敏感期的认识，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，其中早期单胺信号的扰动会改变成人的行为：出生后早期（P2-P11） 5- ht敏感期会影响焦虑和抑郁相关的行为，而后期（P22-P41） DA和5- ht敏感期会改变安非他明（AMPH）的攻击和行为反应。在这里，我们将重点研究后者，即青少年期（PA）。为此，我们设计了一项研究计划来调查一个总体假设，即青春期前后的DAT和5-HTT阻断对da系统的成熟具有相反的作用，易患或保护免受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，并将缩小潜在的发育过程和受影响的电路。研究结果还将有助于跨物种（包括人类）转化研究结果。在ai2中，我们将通过体外和体内研究da能神经元的活性，直接评估PA DAT-和5- htt -阻断对da系统功能的影响。结果将使我们对da系统的哪些元素被改变的机理有深入的了解，使我们能够设计出救援和因果关系测试实验。在Aim 3中，我们将研究PA - DAT和5- htt抑制期间和之后5-HT/ da的相互作用。研究结果将揭示PA发育过程中的5-羟色胺和5-羟色胺如何对神经回路成熟产生相反的影响，以及它们是否永久性地改变5-羟色胺/ da相互作用。我们的研究将影响人类对攻击和神经精神障碍伴DA功能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，遗传或环境因素增加DA信号（如兴奋剂的使用）或减少5-羟色胺信号是攻击和DA功能障碍的危险因素。相反，遗传或环境因素，在PA发育过程中减少DA信号或增加5-羟色胺信号（如SSRIs），将起到改善攻击和DA功能障碍风险的作用。再加上我们将提供的机制洞察，我们的数据可能会导致精神病学诊断、预防和治疗策略的改进。

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.