Developmental Mechanisms Underlying Risk Behaviors and Their Treatment

危险行为背后的发展机制及其治疗

基本信息

批准号：
8442936
负责人：
SUSAN L ANDERSEN
金额：
$ 32.02万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8442936
关键词：
Acute Address Adolescence Adolescent Adult Age Agonist Amygdaloid structure Attention deficit hyperactivity disorder Behavior Behavioral Bioinformatics Brain Cells Complex Confocal Microscopy Coupled Data Development Dopamine Dopamine D1 Receptor Dose Drug Exposure Drug effect disorder Effectiveness Excitotoxic lesion Exposure to Female Functional disorder Gene Expression Genes Genetic Engineering Glutamates Goals Impairment Impulsive Behavior Impulsivity Individual Intervention Knowledge Lasers Lead Lentivirus Vector Life Long-Term Effects Mediating Messenger RNA Methylphenidate MicroRNAs Microdissection Microinjections Modification Molecular Motor Neural Pathways Neurons Norepinephrine Nucleus Accumbens Pathological Gambling Pathology Pathway interactions Pharmaceutical Preparations Population Prefrontal Cortex Prevention Prevention approach Rattus Reaction Time Research Rewards Risk Behaviors Rodent Running Sampling Sex Characteristics Signal Pathway Signal Transduction Techniques Testing Therapeutic Time Tissues Tracer Viral Viral Vector Western Blotting Work atomoxetine base discounting effective intervention effective therapy frontal lobe male neural circuit noradrenergic novel novel marker prevent protein expression receptor sex tool

项目摘要

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.

描述（由申请人提供）：本申请研究了冲动性随发育（青少年、青少年和成人）、性别、病理学和药物暴露而变化时涉及的潜在信号机制。该应用程序的总体目标是：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的神经通路内的神经元功能。我们有两名 Co-PI，他们将在 5 年内的不同时间独立且相互依赖地运行这些项目的不同方面。我们的新数据表明，大鼠前边缘前额皮质中 D1 多巴胺受体的升高会增加冲动和其他危险行为。目标 1 将使用与奖励相关的冲动选择任务（例如，延迟贴现）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）来识别和确认冲动背后的神经元通路。我们将分析来自前边缘前额皮质、基底外侧杏仁核和眶额皮质的投射上的受体，因为它们支配伏核和基底外侧杏仁核。推测 D1 和 α2A 去甲肾上腺素受体的差异表达水平可以介导这些行为。我们将使用激光显微切割 (LMD) 和定量实时 PCR 进行初步评估，然后通过实验使用病毒载体进行机械确认，这些病毒载体在给定区域的谷氨酸神经元中选择性过度表达这些受体。在目标 2 中，我们将确定哌醋甲酯、托莫西汀和胍菲辛对不同年龄和不同性别的冲动的有效剂量 (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独特地激活。然后，得出的 ED50 将用于青少年暴露范式，预计该范式可有效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）的样本将采用生物信息学方法进行微阵列和 microRNA 分析，以识别冲动行为及其有效干预所涉及的汇聚信号通路。总之，这些研究将提供有关冲动背后机制的发展概况的信息，因为冲动受到性和药物的影响。