Opioids and impulsivity: Neuroanatomical examination in a novel animal model

描述（由申请人提供）：冲动，没有适当的深谋远虑和/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，双相和反社会人格障碍。此外，冲动增加了做出不良健康选择的可能性，并与吸烟[1]和肥胖[2]有关，这是美国死亡的主要原因[3]。这些都是可以预防的死亡，可以通过改变行为来减少。鉴于冲动行为的广泛负面影响，更好地理解潜在的分子机制至关重要。 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。目前研究冲动性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性与低冲动性），以及少数（单）基因突变。神经生物学信息已通过使用病变研究，铭记这种方法的相关局限性，以及通过药物诱导冲动行为的研究。由于冲动的病因可能是多种多样的，需要在动物模型中测试特定环境前因的重要性。 我们建议，后代出生的母鼠喂养高脂肪饮食在怀孕期间代表了一种新的动物模型，在该模型中，有结构和表面有效性的冲动性的神经生物学研究。 过度的妊娠期体重增加和母亲肥胖，影响了超过一半的美国孕妇，显着增加了婴儿大于胎龄（LGA）的风险。在我们的模型中，母鼠在怀孕和哺乳期间喂食高脂肪（HF）饮食，后代出生时为LGA。这些LGA后代表现出冲动性的增加。前额叶皮层的基因表达谱揭示了冲动与μ和μ阿片受体（莫尔和DOR）变化之间的关系。LGA动物PFC内的小胶质细胞活化增加，这可能导致执行功能缺陷，如冲动。 本提案的目标是测试驱动LGA小鼠冲动的特定分子介质。总体策略是使用复杂的操作性行为测试来检查阿片类药物和小胶质细胞激活在冲动性新模型（LGA小鼠）中的作用。这两种介质是相互关联的，实验不仅将测试对冲动的直接影响，而且还将测试介质之间的相互作用。在这两个目标中，两个行为任务，5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

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.