Neural Basis of Spatial Memory Deficits After Prenatal Alcohol Exposure

项目摘要/摘要 胎儿酒精谱系障碍是一组主要的形态、神经生物学和认知障碍 子代在宫内接触酒精后出现异常。酒精暴露的常见认知表现 在人类神经发育期间，以及在产前酒精暴露(PAE)的动物模型中，存在缺陷 在空间学习和记忆方面。在中等的PAE中，这是最常见和被低估的 空间缺陷是PAE的一种形式，其特点是无法准确区分空间位置或 回想一下以前学过的空间关系。在系统水平上监测神经群体 海马体结构揭示了这个回路在空间记忆和空间记忆的产生中的关键作用 他们随后的召回。海马峰电位的空间和振荡组织具有良好的特征 被认为在这些过程中起着关键作用。我们研究计划的长期目标是确定 中度PAE后空间学习记忆障碍的神经生物学机制。而当 中度PAE良好建立后空间行为改变的行为表型，仍有临界 需要确定系统级别的机制，包括涉及的神经电路和脑动力学 这样的赤字。空间损伤研究的多层次理解框架在 全面了解PAE对神经系统功能的影响以及对 制定有针对性的干预措施。本提案的总体目标是确定这些系统级别 通过监测大的海马神经元集合及其振荡动力学在两者之间的变化 空间学习和记忆以及休息和睡眠的“离线时期”。在两个目标中，我们将测试我们的中央 假说PAE对空间学习和记忆的干扰是脑力衰竭的结果 不同的位置编码在海马区的表达及其同步性和组织性 在休息和睡眠期间，海马体内的振荡。R01的目标是向以下目标迈出关键一步 我们的长期目标是确定空间学习和记忆障碍的神经生物学机制 中等的PAE，但也将提供对中等PAE的系统级别影响的关键洞察 海马区群体活动。海马区群体活动与空间分布的关系 学习和记忆在包括人类在内的各种物种中都得到了很好的确立。因此，这项提议 有可能提供一种新的科学框架，据此新的干预战略可以 在临床前模型中开发和测试，但也可以为人类患者群体开发。

PROJECT SUMMARY/ABSTRACT Fetal Alcohol Spectrum Disorders are a set of major morphological, neurobiological, and cognitive abnormalities in offspring exposed to alcohol in utero. A common cognitive manifestation of alcohol exposure during neural development in humans, and in animal models of prenatal alcohol exposure (PAE), are deficits in spatial learning and memory. In moderate PAE, which accounts for the most common and underestimated form of PAE, spatial deficits are marked by an inability to accurately discriminate between spatial locations or recall previously learned spatial relationships. Systems-level monitoring of neural populations in the hippocampal formation has unraveled a critical role for this circuit in the generation of spatial memories and their subsequent recall. The well-characterized spatial and oscillatory organization of hippocampal spiking is thought to play a critical role in these processes. The long-term goal of our research program is to identify the neurobiological mechanisms of spatial learning and memory impairments after moderate PAE. While the behavioral phenotype of altered spatial behavior after moderate PAE is well established, there is still a critical need to identify the systems-level mechanisms including the neural circuitry and brain dynamics involved in such deficits. A multi-level understanding framework for the study of spatial impairments is essential in developing a complete understanding of the impact of PAE on nervous system function and toward the development of targeted interventions. The overall objective of this proposal is to identify these systems-level alterations by monitoring large ensembles of hippocampal neurons and their oscillatory dynamics during both spatial learning and memory and in “offline periods” of rest and sleep. In two aims, we will test our central hypothesis that PAE induced perturbations to spatial learning and memory are a consequence of a loss in the expression of distinct hippocampal ensemble codes for place and their synchronization and organization within hippocampal oscillations during rest and sleep. The aims of this R01 represent a critical step towards our long-term goal of identifying the neurobiological mechanisms of spatial learning and memory deficits after moderate PAE but will also provide critical insight into the systems-level impact of moderate PAE on hippocampal population activity. The relationship between hippocampal population activity and spatial learning and memory is well established in a wide range of species including humans. Thus, this proposal has the potential to provide a novel scientific framework whereby new strategies for interventions can be developed and tested in preclinical models but can also be developed for human patient populations.