Opioids and impulsivity: Neuroanatomical examination in a novel animal model

描述（由申请人提供）：冲动，没有适当的事先考虑和/或选择小的，即时的奖励而不是大的，延迟的奖励，是许多精神健康障碍的一个组成部分，包括注意力缺陷多动障碍，药物滥用，双相情感障碍和反社会人格障碍。此外，冲动增加了做出不良健康选择的可能性，并与吸烟和肥胖有关，这是美国死亡的主要原因。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，更好地了解潜在的分子机制是至关重要的。

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.