Opioids and impulsivity: Neuroanatomical examination in a novel animal model

描述(由申请人提供)：冲动，没有适当的预想而采取行动，和/或选择小的，立即的奖励，而不是更大的，延迟的奖励，是许多精神健康障碍的组成部分，包括注意力缺陷多动障碍，药物滥用，以及双相和反社会人格障碍。此外，冲动增加了做出糟糕健康选择的可能性，并与吸烟[1]和肥胖[2]有关，这是美国死亡的主要原因[3]。这些死亡是可以预防的，可以通过改变行为来减少。考虑到冲动行为的广泛负面影响，更好地理解潜在的分子机制是至关重要的。 目前需要更好的动物模型来研究驱动冲动行为的神经回路。目前研究冲动的动物模型主要涉及自然遗传变异的研究(例如，行为任务中的高冲动与低冲动)，以及少数(单)基因突变。神经生物学信息是通过使用损伤研究获得的，考虑到这种方法的相关局限性，以及通过对诱导冲动行为的药物的研究。因为冲动的原因可能是不同的，所以需要在动物模型中测试特定环境先兆因素的重要性。我们认为，孕期喂食高脂肪饲料的母鸡所生的后代代表了一种新的动物模型，在这种模型中，研究冲动的神经生物学具有结构和表面有效性。 过度的妊娠体重增加和母亲肥胖影响了超过一半的美国怀孕，大大增加了婴儿大于胎龄(LGA)的风险。在我们的模型中，母猪在怀孕和哺乳期以高脂肪(HF)饲料喂养，后代出生时为LGA。这些LGA后代表现出更强的冲动。前额叶皮质的基因表达谱揭示了冲动性与µ和阿片受体(MOR和DOR)变化之间的关系。LGA动物PFC内的小胶质细胞激活增加，这可能导致冲动等执行功能缺陷。 本提案的目标是测试在LGA小鼠中驱动冲动的特定分子介体。最重要的策略是使用复杂的操作行为测试来检查阿片类药物和小胶质细胞激活在一种新的冲动模型(LGA小鼠)中的作用。这两个中介是相互联系的，实验不仅将测试对冲动性的直接影响，而且还将测试中介之间的相互作用。在这两个目标中，两个行为任务，即5项选择系列反应时任务(5CSRTT)和延迟折扣(DD)，将被用来确定冲动行为和冲动选择， 分别进行了分析。

DESCRIPTION (provided by applicant):Impulsivity, acting without appropriate forethought and/or choosing small, immediate rewards over a larger, delayed reward, is a component of numerous mental health disorders, including attention-deficit hyperactivity disorder, substance abuse, and bipolar and antisocial personality disorders. Additionally, impulsivity increases the likelihood of making poor health choices, and has been linked to both smoking [1] and obesity [2], which are leading causes of mortality in the US [3]. These are preventable deaths, which could be reduced by changing behavior. Given the broad negative impact of impulsive behavior, a better understanding of the underlying molecular mechanisms is critical. There is currently a need for better animal models in which to study the neural circuitry that drives impulsive behavior. Current animal models to study impulsivity primarily involve the study of natural genetic variation (e.g. high versus low impulsivity in behavioral tasks), as well as a handful of (mono)genic mutations. Neurobiological information has been gained through the use of lesion studies, bearing in mind the associated limitations of this approach, as well as through the study of drugs which induce impulsive behavior. Because the etiologies of impulsivity are likely diverse, work in animal models that test the importance of specific environmental antecedents is needed. We propose that offspring born to dams fed a high fat diet during pregnancy represent a novel animal model in which to study the neurobiology of impulsivity in a model that has construct and face validity. Excessive gestational weight gain and maternal obesity, which affect over half of US pregnancies, significantly increase the risk for a baby to be large for gestational age (LGA). In our model, dams are fed a high fat (HF) diet during pregnancy and lactation, and the offspring are born LGA. These LGA offspring display an increase in impulsivity. Gene expression profiling of the prefrontal cortex reveals a relationship between impulsivity and changes in the µ and - opioid receptors (MOR and DOR). LGA animals have an increase in microglial activation within the PFC, which may contribute to executive function deficits like impulsivity. The goal of the present proposal is to test specific molecular mediators driving impulsivity in LGA mice. The overarching strategy is to use sophisticated operant behavioral testing to examine the role of opioids and microglial activation in a novel model of impulsivity (LGA mice). These two mediators are interconnected and experiments will test not only direct effects on impulsivity, but interactions between the mediators as well. In both aims, two behavioral tasks, the 5 choice serial reaction time task (5CSRTT) and delay discounting (DD), will be used to determine impulsive action and impulsive choice, respectively.