Developmental Mechanisms Underlying Risk Behaviors and Their Treatment

描述（由申请人提供）：本申请研究了冲动性在发育（青少年、青少年和成人）、性别、病理学和药物暴露过程中发生变化时所涉及的潜在信号传导机制。本申请的首要目标是：识别与冲动行为相关的功能失调的神经元回路和信号传导机制，并确定新的预防干预方法。我们提出了一个多方面的方法，包括行为和分子分析，以检查在明确的神经通路在啮齿动物的大脑中的男性和女性的神经元功能。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管理这些项目的不同方面。我们建立在我们的新数据上，这些数据表明，大鼠前额叶皮层边缘系统中D1多巴胺受体的升高会增加冲动和其他危险行为。目标1将使用奖励相关冲动性任务和冲动选择（例如，延迟折扣）和冲动动作的运动相关任务（例如，停止信号反应时间任务）。我们将分析前边缘前额叶皮层、基底外侧杏仁核和眶额叶皮层投射的受体，因为它们支配着丘脑核和基底外侧杏仁核。D1和α 2A去甲肾上腺素能受体的差异表达水平被假设为介导这些行为。我们将使用激光显微切割（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进行机制确认，这些病毒载体在给定区域的谷氨酸神经元中选择性过表达这些受体。在目标2中，我们将确定哌甲酯、托莫西汀和胍菲辛在不同年龄和不同性别对冲动性的有效剂量（ED 50）。由于它们对多巴胺和α 2A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。然后将导出的ED 50用于青少年暴露范例，该范例预计可有效预防成年期的冲动行为。在目标3中，将采用生物信息学方法，通过微阵列和微小RNA分析来分析目标1（病毒过度表达）和目标2（预防性干预）的样本，以识别参与冲动行为及其有效干预的会聚信号通路。总之，这些研究将提供信息的发展概况的机制的冲动，因为它是由性别和药物的影响。

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.