Neonatal Ethanol-Induced Memory Impairments in Rats

描述（由申请人提供）：本研究的总体目标是扩大酒精相关神经发育障碍（ARND）啮齿动物模型中酒精诱导的记忆障碍的研究。被诊断患有胎儿酒精综合症（FAS）或ARND的个体在各种记忆领域表现出显着缺陷，包括外显记忆、陈述记忆、联想记忆、消退记忆和空间记忆。迄今为止，使用动物模型对记忆障碍的研究几乎完全集中在需要空间学习和空间导航的任务上。本研究计划中概述的实验旨在通过使用没有明显空间成分的任务来扩展对记忆缺陷的研究。我们打算在这项研究中解决四个具体目标。在所有实验中，将在新生期（第4-9天）对动物给予酒精，以模拟妊娠晚期人体暴露。第一个目的是为了进一步探讨短期和长期的非联想记忆缺陷，扩大我们以前的工作，使用习惯化的心率定向反应。这些实验将解决的问题，剂量反应函数，有限的酒精暴露的持续时间，并在方法的变化，以促进非联想学习。第二个目标将使用巴甫洛夫恐惧条件反射程序和测量几个与恐惧相关的条件反射（行为，心率和恐惧增强惊吓）来检查非联想学习和联想学习之间的关系。第三个目标是通过研究酒精引起的痕迹条件反射和背景条件反射的变化来扩展对陈述性和外显记忆障碍的研究。此外，在这些联想任务中获得的条件反射的消退将被评估，以增加我们对酒精对一种执行功能的影响的理解。最后，实现最后一个目标的实验旨在初步检查潜在的行为和药物治疗方法，以改善酒精暴露引起的记忆障碍。行为训练技术的基础是将学习从一种情况转移到另一种情况，而药物治疗将包括在后代的饮食中急性施用胆碱酯酶抑制剂或长期补充胆碱。总的来说，这些研究将通过使用外显空间学习和记忆领域之外的动物模型任务，进一步了解FAS或ARND患者中观察到的记忆障碍。使用行为和药理学策略改善这些认知缺陷的潜力将提供关于受折磨个体的治疗方法的重要信息。

DESCRIPTION (provided by applicant): The overall goal of this research is to expand the investigation of alcohol-induced memory impairments in a rodent model of Alcohol-Related Neurodevelopmental Disorder (ARND). Individuals diagnosed with Fetal Alcohol Syndrome (FAS) or ARND exhibit significant deficits in a variety of memory domains, including explicit, declarative, associative, extinction, and spatial. To date, the study of memory impairments using animal models has focused almost exclusively on tasks that require spatial learning and spatial navigation. The experiments outlined in this research proposal are intended to expand the study of memory deficits by using tasks that have no overt spatial component. We intend to address four specific aims in this research. In all experiments, animals will be administered alcohol during the neonatal period (days 4-9) to model third trimester human exposure. The first aim is intended to further explore short- and long-term nonassociative memory deficits by expanding upon our previous work using habituation of the heart rate orienting response. These experiments will address issues of dose-response functions, limited durations of alcohol exposure, and variations in methodology to promote nonassociative learning. The second aim will examine the relation between nonassociative and associative learning using a Pavlovian fear conditioning procedure and measuring several fear-related conditioned responses (behavior, heart rate, and fear-potentiated startle). The third aim will expand the study of declarative and explicit memory impairments by investigating alcohol-induced changes in trace conditioning and contextual conditioning. In addition, extinction of the conditioned responses acquired in these associative tasks will be evaluated to increase our understanding of alcohol effects on one type of executive function. Finally, the experiments addressing the last aim are geared toward an initial examination of potential behavioral and pharmacological treatments to ameliorate memory impairments resulting from alcohol exposure. The behavioral training techniques are based on transfer of learning from one situation to another, while the pharmacological treatments will include acute administration of cholinesterase inhibitors or chronic choline supplementation to the diet of the offspring. Collectively, these studies will further our understanding of memory impairments observed in humans with FAS or ARND by using tasks with an animal model that fall outside the realm of explicit spatial learning and memory. The potential for amelioration of these cognitive deficits using both behavioral and pharmacological strategies will provide important information regarding treatment approaches for afflicted individuals.