Developmental Mechanisms Underlying Risk Behaviors and Their Treatment

描述（由申请人提供）：本申请研究冲动性在不同发育阶段（青少年、青少年和成人）、性别、病理和药物暴露中变化的潜在信号机制。本应用程序的总体目标是：确定与冲动行为相关的功能失调的神经元回路和信号机制，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。我们有两个co - pi，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，在大鼠的前额叶皮层，D1多巴胺受体升高会增加冲动和其他危险行为。目的1将利用冲动选择的奖励相关冲动性任务（例如，延迟折扣）和冲动行动的运动相关任务（例如，停止信号反应时间任务）来识别和确认冲动性背后的神经元通路。我们将分析来自前边缘前额叶皮质、基底外侧杏仁核和眶额皮质的受体在支配伏隔核和基底外侧杏仁核时的投射。D1和alpha2A去肾上腺素能受体的差异表达水平被认为介导了这些行为。我们将使用激光显微解剖（LMD）和定量实时PCR进行初步评估，随后通过实验使用病毒载体在给定区域的谷氨酸神经元中选择性地过表达这些受体进行机制确认。在目的2中，我们将确定哌甲酯、托莫西汀和胍非西汀对不同年龄和性别冲动的有效剂量（ed50）。由于它们对多巴胺和alpha2A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独特地激活。衍生的ed50随后将用于青少年暴露范式，预计将有效防止成年后的冲动行为。在aims 3中，来自aims 1（病毒过表达）和aims 2（预防性干预）的样本将使用生物信息学方法进行分析，包括微阵列和microrna分析，以确定涉及冲动行为及其有效干预的趋同信号通路。总之，这些研究将提供关于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.