Neural Basis of Context Learning in a Rat Model of FASD

FASD 大鼠模型情境学习的神经基础

• 批准号: 7912394
• 负责人: Nathen J. Murawski
• 金额: $ 4.09万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912394
• 关键词: Address; Adolescent; Alcohols; Amygdaloid structure; Animal Model; Animals; Awareness; Behavioral; Birth; Brain Injuries; Development; Disease; Dose; Ethanol; Fetal Alcohol Spectrum Disorder; Gene Expression; Hippocampus (Brain); Human; Immediate-Early Genes; Immunohistochemistry; Learning; Link; Memory; Mental Retardation; Modeling; Molecular; Neonatal; Outcome; Pattern; Performance; Phase; Preparation; Prevalence; Proteins; Pyramidal Cells; Rattus; Research; Retrieval; Shock; Techniques; alcohol exposure; base; conditioned fear; effective therapy; neurobehavioral; postnatal; programs; public health relevance; relating to nervous system; research study

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.

描述（由申请方提供）：大鼠在出生后（PD）4-9天内暴露于酒精，除了导致依赖于海马的任务表现受损外，还导致海马锥体细胞显著减少。这项拟议中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。背景暴露前易化效应（CPFE）为研究新生儿酒精对海马发育的影响提供了一个理想的实验条件。在CPFE中，学习情境、将情境与休克联系起来以及检索情境记忆以进行行为表达发生在不同的日子，每一天都需要海马体的正常功能。我们以前已经表明，高剂量的乙醇超过PD 4 -9破坏了幼年大鼠的CPFE。实验1将进一步探讨乙醇诱导的缺陷，在此任务中，通过检查大鼠的性能受到较低剂量的发育乙醇暴露。实验2A将使用免疫组织化学技术，探讨在CPFE范式的分子基础上的上下文恐惧条件反射检查立即早期基因表达（Fos和Arc蛋白）在海马在三个阶段的CPFE范式（未受干扰）控制大鼠。使用上述实验的行为和免疫组织化学技术，实验2B和2C将分别研究海马和杏仁核中可能的分子畸变如何导致暴露于低剂量和高剂量乙醇的大鼠中观察到的CPFE行为缺陷超过PD 4 -9。 公共卫生相关性：胎儿酒精谱系障碍（FASD）代表了一系列由发育性酒精暴露引起的神经行为和结构障碍，并构成了智力迟钝的主要可预防原因之一。尽管开展了提高公众认识的方案，但FASD的患病率仍然保持在每1 000名新生儿中有10人左右。动物模型研究极大地增加了我们对酒精暴露的模式、水平和发育期如何影响神经行为结果的理解;并有助于确定脑损伤的机制，指导FASD有效治疗的发展。该提案中的研究解决了动物模型研究的一个重要和持续的挑战，即证明在较低剂量的酒精暴露下的神经行为效应和机制，这些效应和机制对人类不利，但在动物中往往不那么不利。