Neural Basis of Spatial Memory Deficits After Prenatal Alcohol Exposure

产前酒精暴露后空间记忆缺陷的神经基础

• 批准号: 10342038
• 负责人: Benjamin J Clark
• 金额: $ 32.89万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-22 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10342038
• 关键词: Action Potentials; Animal Model; Animals; Behavior; Brain; Brain Diseases; Cells; Characteristics; Code; Cognitive; Coupled; Development; Environment; Failure; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Generations; Goals; Hippocampal Formation; Hippocampus (Brain); Human; Impairment; Intervention; Investigation; Learning; Location; Memory; Memory impairment; Monitor; Morphology; Nervous System Physiology; Neurobehavioral Manifestations; Neurobiology; Neurons; Pattern; Play; Population; Pre-Clinical Model; Process; Rattus; Research; Rest; Role; Sleep; Spatial Behavior; System; Testing; Therapeutic Intervention; Translating; Update; alcohol exposure; behavioral phenotyping; dentate gyrus; diagnostic tool; entorhinal cortex; in utero; in vivo; insight; neural circuit; neurobiological mechanism; neurodevelopment; novel; offspring; patient population; personalized diagnostics; programs; relating to nervous system; spatial memory; spatial relationship

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.

项目总结/摘要 胎儿酒精谱系障碍是一组主要的形态学、神经生物学和认知功能障碍。 胎儿在子宫内接触酒精后出现异常。酒精暴露的常见认知表现 在人类神经发育过程中，以及在产前酒精暴露（PAE）的动物模型中， 在空间学习和记忆方面。在中度PAE中，这是最常见和被低估的 PAE的一种形式，空间缺陷的特点是无法准确区分空间位置或 回忆以前学过的空间关系。系统级的神经群体监测 海马结构已经揭示了这个回路在空间记忆产生中的关键作用， 他们后来的回忆。海马放电的良好特征的空间和振荡组织是 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后空间学习和记忆障碍的神经生物学机制。而 中度PAE后空间行为改变的行为表型已经确立，但仍然存在一个关键的 需要确定系统水平的机制，包括神经回路和大脑动力学参与 这样的赤字。一个多层次的理解框架的研究空间障碍是必不可少的， 全面了解PAE对神经系统功能的影响， 制定有针对性的干预措施。本建议的总体目标是确定这些系统一级的 通过监测海马神经元的大集合及其振荡动力学， 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 假设PAE诱导的空间学习和记忆的干扰是由于 不同海马位置编码的表达及其同步化和组织化 在休息和睡眠时海马体的振荡。本R 01的目标代表了向以下目标迈出的关键一步： 我们的长期目标是确定空间学习和记忆缺陷的神经生物学机制， 中度PAE，但也将提供对中度PAE对系统级影响的关键见解， 海马群体活动。海马群体活动与空间位置的关系 学习和记忆在包括人类在内的广泛物种中得到了很好的建立。因此，本提案 有可能提供一个新的科学框架，使新的干预战略， 在临床前模型中开发和测试，但也可以开发用于人类患者群体。