Executive function in a rodent model of FASD

描述(由申请者提供)：胎儿酒精谱系障碍(FASD)是智力和发育障碍的主要原因，一直是全球范围内的一个重大公共卫生问题。FASD的一个重要特征是“执行功能”受损，这是一系列前额皮质依赖的认知过程的总称，如注意力、工作记忆、概念集转移和抑制性学习(Fryer等人，2007；Mattson等人，2011；Rasmussen，2005)。例如，患有FASD的儿童和成人在威斯康星卡片分类任务中受到损害，这是一项众所周知的对人类注意力定势转移和抑制控制的神经心理学评估(Mattson等人，2011年回顾)。这些 关于FASD执行功能的新发现刺激了最近的一些啮齿动物模型研究，表明发育性酒精暴露以前额叶皮质为目标(Hamilton，Whitcher&Klintsova，2010；Otero等人，2012；Smith等人，2012；Whitcher&Klintsova，2008)。然而，在啮齿类动物中寻找这种前额叶靶向的行为相关性却失败了。 使用专门测量前额叶或执行功能的评估(Smith等人，2012年)。为了解决当前知识中的这一差距，这项R03小型研究资助提案试图确定对啮齿动物前额叶执行功能的一项具有良好特征、被广泛接受和高度特异性的测试-注意力定势转移任务(ASST)--是否受到发育性酒精暴露的损害。该提案将PI的经验与成熟的孕晚期相当酒精暴露的啮齿动物模型(例如，Murawski&Stanton，2010；Hamilton等人，2011)和共同PI在注意力集中转移任务方面的经验(Cain，Wasserman，Wathouse&McGaughy，2011；Newman&McGaughy，2011)相结合。该提案使用了以前额叶皮质为目标的酒精暴露情景(Whitcher&Klintsova，2008)。在目标1中，雄性和雌性Long-Evans大鼠将接受5.25g/kg/d酒精插管(Etoh)、假插管(SI)或从出生后4-9天(PD)起保持不受干扰(UD)，然后在成年(PD70-90)进行Asst测试。在目标2中，将通过比较在PD4-9上接受0(SI)、2.75、4和5.25g/kg/天酒精的雄性和雌性大鼠来检验对成体Ast表现的剂量反应效应。ASST范式包括部分-辨别、反转、传统内移和外移-每一个都探测依赖于大鼠不同前额亚区的特定认知过程。如果成功，这些实验将为未来的R01提案奠定基础，该提案将使用注意定势转移来研究FASD啮齿动物模型中与执行功能受损相关的机制和干预措施，FASD啮齿动物模型直接应用于人类疾病。

DESCRIPTION (provided by applicant): Fetal Alcohol Spectrum Disorder (FASD) is a leading cause of intellectual and developmental disabilities that continues to be a significant public health problem worldwide. An important feature of FASD is impairment of "executive function," an umbrella term for a range of prefrontal-cortex-dependent cognitive processes such as attention, working memory, conceptual set shifting, and inhibitory learning (Fryer et al., 2007; Mattson et al., 2011; Rasmussen, 2005). For example, children and adults with FASD are impaired on the Wisconsin Card Sorting Task, a well-known neuropsychological assessment of attentional set shifting and inhibitory control in humans (reviewed in Mattson et al., 2011). These emerging findings on executive function in FASD have stimulated some recent rodent model research showing that developmental alcohol exposure targets the prefrontal cortex (Hamilton, Whitcher & Klintsova, 2010; Otero et al; 2012; Smith et al., 2012; Whitcher & Klintsova, 2008). However, the search for behavioral correlates of this prefrontal targeting in rodents has failed to use assessments that specifically measure prefrontal or executive function (Smith et al., 2012). To address this gap in current knowledge, this R03 Small Research Grant proposal seeks to determine whether a well characterized, widely accepted, and highly specific test of prefrontal executive function in rodents---the attentional set shifting task (ASST)---is impaired by developmental alcohol exposure. The proposal combines the PI's experience with a well-established rodent model of third-trimester equivalent alcohol exposure (e.g., Murawski & Stanton, 2010; Hamilton et al, 2011) with the Co-PI's experience with the attention set shifting task (Cain, Wasserman, Waterhouse & McGaughy, 2011; Newman & McGaughy, 2011). The proposal uses an alcohol exposure scenario that targets prefrontal cortex (Whitcher & Klintsova, 2008). In Aim 1, male and female Long-Evans rats will either receive intubations of 5.25g/kg/day alcohol (EtOH), sham intubation (SI) or will be left undisturbed (UD) from Postnatal Days (PD) 4-9 and then tested on the ASST in adulthood (PD70-90). In Aim 2, dose-response effects on adult ASST performance will be examined by comparing groups of male and female rats receiving 0 (SI), 2.75, 4, and 5.25 g/kg/day of alcohol on PD4-9. The ASST paradigm includes components---Discrimination, Reversal, Intradimensional Shift, and Extradimensional Shift---that each probe specific cognitive processes that depend on different prefrontal subregions in the rat. If successful, these experiments will lay the foundation for a future R01 proposal that will use attentional set shifting to study mechanisms and interventions related to impaired executive function in a rodent model of FASD that has direct translational application to the human disorder.