Neural Basis of Context Learning in a Rat Model of FASD

描述（由申请人提供）：大鼠出生后4-9天（PD）酒精暴露会导致海马锥体细胞显著减少，此外还会导致依赖海马的任务表现受损。拟议的研究将寻求在这些神经和行为影响之间建立因果关系，特别是在较低水平的酒精暴露下。情境暴露前促进效应（CPFE）为研究新生儿酒精对发育中的海马体的影响提供了理想的准备。在CPFE中，对情境的学习、将情境与休克联系起来以及对行为表达的情境记忆的检索发生在不同的日子里，每一个过程都需要海马体的正常运作。我们之前的研究表明，高剂量的乙醇超过PD4-9会破坏幼年大鼠的CPFE。实验1将通过检查低剂量发育性乙醇暴露大鼠的表现，进一步探讨乙醇在这项任务中引起的缺陷。实验2A将使用免疫组织化学技术，通过检测（未受干扰的）对照大鼠在CPFE范式的三个阶段海马中即时早期基因表达（Fos和Arc蛋白），探索CPFE范式期间情境恐惧条件反射的分子基础。实验2B和实验2C将使用上述实验的行为和免疫组织化学技术，分别检查海马和杏仁核的分子畸变如何可能导致暴露于低剂量和高剂量乙醇超过PD4-9的大鼠CPFE的行为缺陷。

DESCRIPTION (provided by applicant): Alcohol exposure in the rat over postnatal days (PD) 4-9 causes significant decreases in pyramidal cells in the hippocampus, in addition to causing impaired performance on tasks that depend on the hippocampus. The proposed research will seek to establish a causal link between these neural and behavioral effects, particularly at lower levels of alcohol exposure. The context preexposure facilitation effect (CPFE) offers an ideal preparation to examine the effects of neonatal alcohol on the developing hippocampus. In the CPFE, learning about the context, associating the context with shock, and retrieval of the context memory for behavioral expression occurs on separate days, each of which requires the proper functioning of the hippocampus. We have previously shown that a high binge dose of ethanol over PD4-9 disrupts the CPFE in juvenile rats. Experiment 1 will further explore ethanol-induced deficits during this task by examining the performance of rats subjected to lower doses of developmental ethanol exposure. Experiment 2A will use immunohistochemistry techniques to explore the molecular basis of contextual fear conditioning during the CPFE paradigm by examining immediate early gene expression (Fos & Arc protein) in the hippocampus during the three phases of the CPFE paradigm in (undisturbed) control rats. Using the behavioral and immunohistochemical techniques of the preceding experiments, Experiment 2B and 2C will examine how possible molecular aberrations in the hippocampus and the amygdala, respectively, may contribute to the behavioral deficits in the CPFE seen in rats exposed to a low and high dose of ethanol over PD4-9. PUBLIC HEALTH RELEVANCE: Fetal Alcohol Spectrum Disorders (FASD) represent a range of neurobehavioral and structural disorders caused by developmental alcohol exposure, and constitute one of the leading preventable causes of mental retardation. Despite public awareness programs prevalence of FASD remains around 10 per 1,000 births. Animal model research has greatly increased our understanding of how the pattern, level, and developmental period of alcohol exposure influences neurobehavioral outcome; and is helping to identify mechanisms of brain injury and guiding the development of effective treatments for FASD. The research in this proposal addresses an important and continuing challenge for animal model research, which is to demonstrate neurobehavioral effects and mechanisms at lower doses of alcohol exposure that are adverse in humans but often less so in animals.