Consequences of prenatal ethanol exposure and maternal stress on offspring

描述(由申请者提供)：这项资助建议旨在促进申请者在酒精研究领域的培训和研究技能，特别是胎儿酒精谱系障碍(FASD)。这项提议的培训部分将与研究计划的大部分内容相吻合，因为申请者将第一次学习许多技术，并培养她与同事有效地交流她的研究和发现的能力。这项研究计划植根于医学知识，即据报道，产前适度酒精暴露会导致儿童时期的行为和认知缺陷，并持续到成年。与患有FASD的儿童的行为缺陷类似，产前暴露于母亲压力下的儿童被证明存在学习困难。这些干扰背后的分子、细胞和生化过程还没有被很好地理解。申请者已经开发并表征了一个将适度自愿产前酒精暴露与产前捕食者气味暴露相结合的模型，作为她论文研究项目的目标1。在这个模型中产生的后代将用于评估双重产前侮辱对学习的组合影响，以及与齿状回突触可塑性相关的活动依赖变化的测量，这包括项目目标2和3。有人假设，怀孕期间的母体应激将加剧学习障碍，并减少齿状回突触可塑性的活动依赖性变化，如中度产前酒精暴露所见。为了评估双重暴露的子代的认知能力和突触可塑性标志物的变化，除了建立模型系统的第一个特定目标外，还制定了两个特定目标。AIM 2旨在评估暴露组的认知缺陷，将使用最近开发的一项新的两次试验跟踪条件任务来评估冻结行为作为海马区敏感学习的一种衡量标准。预计，双重产前暴露将导致比产前酒精或单独的产前压力更大的认知缺陷。目的3旨在评估突触可塑性标志物的变化。申请者将学习荧光原位杂交技术，以检测齿状回ARC mRNA表达的变化，以及学习放射性配基结合技术，用于检测学习激活后齿状回AMPA受体表达的变化。我们预计，在同时暴露于产前酒精和产前应激的动物中，诱发的ARC mRNA和AMPA受体的表达水平将比单独暴露于产前酒精或产前应激的动物更低。该项目的最终结果将导致一个新的特征，并加强对产前酒精和产前应激暴露的啮齿动物所观察到的行为和生化变化的了解。

DESCRIPTION (provided by applicant): This grant proposal is targeted at furthering the training and research skills of the applicant in the field of alcohol research, specifically Fetal Alcohol Spectrum Disorders (FASDs). The training portion of this proposal will coincide with the majority of the research plan in that the applicant will be learning many of the techniques for the first time, as well as fostering her abilities to effectively communicate her research and findings to her colleagues. The research plan is rooted in the medical knowledge that moderate ethanol exposure prenatally has been reported to cause behavioral and cognitive deficits in childhood that persist into adulthood. Similar to the behavioral deficits seen in children with a FASD diagnosis, children prenatally exposed to maternal stress have been shown to suffer from learning challenges. The molecular, cellular, and biochemical processes which underlie these disturbances is not well understood. The applicant has developed and characterized a model of combined moderate voluntary prenatal ethanol exposure with a prenatal predator scent exposure as Aim 1 of her dissertation research project. The offspring generated in this model will be used in assessments of the combinatorial effects of dual prenatal insults on learning, as well as measures of activity-dependent changes associated with synaptic plasticity in the dentate gyrus, which comprise Aims 2 and 3 of the project. It is hypothesized that maternal stress during pregnancy will potentiate the learning deficits and diminished activity- dependent changes in synaptic plasticity in the dentate gyrus as seen in moderate prenatal alcohol exposure. In order to assess cognitive abilities and alterations in markers of synaptic plasticity in the dual exposed offspring, two specific aims have been developed in addition to the first specific aim of establishing the model system. Aim 2, targeted at assessing cognitive deficits in the exposure groups, will use a recently developed, novel Two Trial Trace Conditioning task to assess freezing behavior as a measure of hippocampal sensitive learning. It is expected that the dual prenatal exposure will result in larger cognitive deficits than either the prenatal alcohol or the prenatal stress alone. Aim 3 is targeted at evaluating changes in markers of synaptic plasticity. The applicant will learn fluorescence in situ hybridization techniques to detect changes in ARC mRNA expression in the dentate gyrus, as well as learn radioligand binding techniques used to detect changes in AMPA receptor expression in the dentate gyrus following learning activation. We expect that the levels of evoked ARC mRNA and AMPA receptor expression will be more reduced in animals exposed to both prenatal alcohol and prenatal stress than animals exposed to either prenatal alcohol or prenatal stress alone. The culmination of this project will result in a novel characterization and an enhanced understanding of the behavioral and biochemical alterations observed in prenatal ethanol and prenatal stress exposed rodents.