Developmental Mechanisms Underlying Risk Behaviors and Their Treatment

描述(由申请人提供)：这项申请检查了冲动的潜在信号机制，因为它随着发育(青少年、青少年和成人)、性别、病理和药物暴露的变化而变化。这项应用的首要目标是：识别与冲动行为相关的功能失调的神经元回路(S)和信号机制，并确定新的干预预防方法。我们提出了一种多方面的方法，包括行为和分子分析，以检查雄性和雌性啮齿动物大脑中明确定义的神经通路中的神经元功能。我们有两名协理，他们将在5年内的不同时间独立和相互依赖地运行这些项目的不同方面。我们的新数据表明，大鼠前额叶皮质D1多巴胺受体的升高会增加冲动和其他危险行为。目标1将使用与奖励相关的冲动选择任务(例如，延迟折扣)和与运动相关的冲动行动任务(例如，停止信号反应时间任务)来识别和确认潜在的冲动的神经元通路。我们将分析支配伏隔核和基底外侧杏仁核的前额叶皮质、杏仁基底外侧核和眼眶额叶皮质的受体投射。假设去甲肾上腺素能受体D1和α2A型受体的差异表达水平介导了这些行为。我们将使用激光显微切割(LMD)和定量实时聚合酶链式反应(PCR)进行初步评估，然后通过实验使用选择性地在给定区域的谷氨酸神经元中过度表达这些受体的病毒载体进行机械确认。在目标2中，我们将确定不同年龄和性别的哌甲酸甲酯、托莫西汀和鸟苷类药物对冲动性的有效剂量(ED50)。由于它们对多巴胺和α2a受体的选择性不同，我们预计不同的信号通路将在不同的年龄被唯一地激活。然后，衍生出的ED50将被用于青少年接触范例，预计将有效地防止成年后的冲动行为。在目标3中，来自目标1(病毒过度表达)和目标2(预防性干预)的样本将用生物信息学方法结合微阵列和microRNAs分析，以确定参与冲动行为的汇聚信号通路及其有效干预。总之，这些研究将提供有关冲动的潜在机制的发展概况的信息，因为它受到性别和药物的影响。

DESCRIPTION (provided by applicant): This application examines the underlying signaling mechanisms that are involved in impulsivity as it changes across development (juvenile, adolescent, and adult), sex, pathology, and drug exposure. The overarching goal of this application is to: To identify dysfunctional neuronal circuit(s) and signaling mechanisms associated with impulsive behaviors and identify novel prevention approaches for intervention. We propose a multi-faceted approach that encompasses behavioral and molecular analyses to examine neuronal function within well-defined neural pathways in the rodent brain of both males and females. We have two Co-PIs, who will be running different aspects of these projects indepdently and interdependently at various times within the 5 year period. We build on our new data that show that elevated D1 dopamine receptors in the prelimbic prefrontal cortex of the rat increase impulsivity and other risky behaviors. Aim 1 will identify and confirm neuronal pathways underlying impulsivity using both a reward-associated impulsivity task of impulsive choice (e.g., delayed discounting) and a motor-related task of impulsive action (e.g., the stop signal reaction time task). We will analyze receptors on projections from the prelimbic prefrontal cortex, the basolateral amygdala, and the orbital frontal cortex as they innervate the nucleus accumbens and the basolateral amygdala. Differential expression levels of D1 and alpha2A noradrenergic receptors are hypothesized to mediate these behaviors. We will use laser microdissection (LMD) and quantitative, real-time PCR for this initial assessment, followed by mechanistic confirmation with experimental use of viral vectors that selectively over-express these receptors in glutamate neurons in a given region. In Aim 2, we will determine effective doses (ED50s) of methylphenidate, atomoxetine, and guanficine on impulsivity at different ages and across sex. Due to their different selectivity for dopamine and alpha2A receptors, we expect that different signaling pathways will be uniquely activated at different ages. The derived ED50s will then be used in a juvenile exposure paradigm that is predicted to effectively prevent impulsive behaviors in adulthood. In Aim 3, samples from Aim 1 (viral over-expression) and Aim 2 (preventative interventions) will be analyzed with a bioinformatics approach with microarray and microRNAs analyses to identify convergent signaling pathways involved in impulsive behaviors and its effective intervention. Together, these studies will provide information on the developmental profile of the mechanisms underlying impulsivity as it is influenced by sex and medication.