Executive function in a rodent model of FASD

描述（由申请人提供）：胎儿酒精谱系障碍（FASD）是智力和发育障碍的主要原因，仍然是一个重大的全球公共卫生问题。FASD的一个重要特征是“执行功能”的损害，“执行功能”是一系列前额叶皮层依赖性认知过程的总称，例如注意力、工作记忆、概念集合转移和抑制性学习（Fryer et al.，2007; Mattson等人，2011; Rasmussen，2005）。例如，患有FASD的儿童和成人在威斯康星州卡片分类任务中受损，这是一种对人类注意力转移和抑制控制的众所周知的神经心理学评估（综述于Mattson等人，2011年）。这些 关于FASD中执行功能的新发现刺激了最近的一些啮齿动物模型研究，这些研究表明发育中的酒精暴露靶向前额皮质（汉密尔顿，Whitcher & Klintsova，2010; Oasis等人; 2012; Smith等人，2012; Whitcher & Klintsova，2008）。然而，在啮齿动物中寻找这种前额定位的行为相关性失败了， 使用专门测量前额或执行功能的评估（Smith等人，2012年）。为了解决目前知识的这一差距，这项R 03小额研究资助计划旨在确定啮齿动物前额叶执行功能的一个特征明确、被广泛接受和高度特异性的测试--注意力转移任务（ASST）--是否受到酒精暴露的损害。该提案将PI的经验与成熟的晚期妊娠等效酒精暴露啮齿动物模型（例如，Murawski & Stanton，2010;汉密尔顿et al，2011）与Co-PI在注意力转移任务方面的经验（Cain，Wasserman，Waterhouse & McGaughy，2011;纽曼& McGaughy，2011）。该提案使用了针对前额叶皮层的酒精暴露场景（Whitcher & Klintsova，2008）。在目标1中，雄性和雌性Long-Evans大鼠将接受5.25 g/kg/天酒精（EtOH）插管、假插管（SI）或从出生后第4-9天（PD）不受干扰（UD），然后在成年期（PD 70 -90）接受ASST测试。在目标2中，将通过比较在PD 4 -9接受0（SI）、2.75、4和5.25 g/kg/天酒精的雄性和雌性大鼠组，检查对成年ASST性能的剂量反应效应。ASST范式包括组件-歧视，Reflection，Intradimensional移位和Extradimensional移位-每个探针特定的认知过程，依赖于不同的前额叶子区域的大鼠。如果成功，这些实验将为未来的R 01提案奠定基础，该提案将使用注意力转移来研究与FASD啮齿动物模型中执行功能受损相关的机制和干预措施，该模型可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.