Developmental Origins of Aggressive and Impulsive Behavior

描述（由申请人提供）：大多数神经精神疾病具有发育起源。这种发展的脆弱性往往局限于敏感时期，但受影响的行为，调节因素，和潜在的机制很少被理解。这项资助旨在进一步了解决定复杂行为发展轨迹的敏感时期，这是改善神经精神疾病预防和治疗方法的必要一步。我们最近确定了两个敏感的发展时期，其中早期生活干扰单胺信号改变成年人的行为：出生后早期（P2-P11）5-HT敏感期，影响焦虑和抑郁相关的行为和后期围青春期（P22-P41）DA和5-HT敏感期改变攻击和行为反应安非他明（AMPH）。在这里，我们将重点研究后，围青少年（PA）时期。为此，我们设计了一项研究计划，以调查总体假设，即青少年DAT和5-HTT阻断对DA系统的成熟具有相反的影响，易患或保护免受高攻击性和多巴胺功能障碍。我们的应用程序包括三个目标。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PA 5-HTT-和DAT-抑制影响的行为分析。研究结果将指导Aim 2和Aim 3的实验，并缩小受影响的潜在发育过程和回路。研究结果还将有助于跨物种（包括人类）翻译研究结果。在Aim 2中，我们将通过研究体外和体内DA能神经元活性，直接评估PA DAT和5-HT阻断对DA系统功能的影响。研究结果将使我们对DA系统的哪些元素被改变有深入的了解，从而使我们能够设计出救援和空腔测试实验。在目标3中，我们将研究PA DAT和5-HT抑制期间和之后的5-HT/DA相互作用。结果将揭示DA能和5-HTergic操作在PA发展过程中发挥其相反的影响回路成熟，以及他们是否永久改变5-HT/DA相互作用。我们的研究将影响对攻击性和DA功能障碍的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，增加DA信号（如兴奋剂的使用）或减少5-HT信号在PA的发展作为侵略和DA功能障碍的危险因素。相反，遗传或环境因素，无论是减少DA信号或增加5-HT信号（如SSRIs）在PA的发展，将采取行动，以改善侵略和DA功能障碍的风险。再加上我们将提供的机制见解，我们的数据可能会导致精神病学的诊断，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.