Prenatal Alcohol Exposure and Neural Representations of Space

项目摘要 胎儿酒精谱系障碍（FASD）是一个主要的公共卫生问题，在美国的发病率为1-5%。 美国和相关的年度成本超过40亿美元。大多数FASD病例属于较少的 严重范围的频谱，其特征是行为和认知缺陷，在没有明显的 颅面或大脑形态的改变。记忆缺陷是影响终生的， 对胎儿期大脑发育的负面影响。目前还没有治疗方法 与FASD相关的记忆缺陷缺乏关于产前酒精暴露（PAE） 改变对记忆至关重要的大脑功能是识别和 开发潜在的治疗方法。在不太严重的FASD大鼠模型中，中度PAE导致空间功能受损 在整个成年期都持续存在的记忆。这项拟议中的研究将测试一个创新和新颖的假设 关于中度PAE对空间记忆影响的神经基础。将细胞置于海马体中 当动物占据一个特定的空间位置时有选择地增加活动。人口法典 由位置单元提供的表示空间“地图”。在健康的动物中，这些空间图往往保持稳定 然而，几个月来，位置细胞的稳定性下降与空间记忆障碍有关。不稳定 因此，空间记忆的神经表征可能代表了空间记忆的系统水平机制。 在PAE之后观察到的记忆障碍。这项拟议的研究将检验PAE的假设， 降低位置细胞稳定性，并且位置细胞稳定性的降低是空间记忆的预测 PAE之后的损伤。在拟议的研究中，成年大鼠在研究期间暴露于中等水平的乙醇， 将在背侧海马中植入电极， 海马定位细胞将在多个阶段进行定量。如果PAE降低了定位细胞的稳定性，那么 这些细胞的空间选择性激发的模式将更可能从会话改变（“重新映射”）到会话。 上网时段我们将研究暴露于酒精的大鼠海马位置细胞的不稳定性是否是预测 在Morris水任务和十字迷宫任务中的空间记忆受损。意义与创新： 这项拟议的研究将是第一项研究来检查PAE对空间神经表征的影响 信息和空间记忆缺陷的关系。该项目将作为未来的基础。 机制和治疗的研究。建立这种模型系统方法的效用是重要的 因为它可以帮助识别潜在的PAE相关空间记忆缺陷的假定机制 在电路，网络，受体和分子水平的分析，这可能有助于识别和评估治疗 战略布局由于在FASD儿童中观察到空间记忆缺陷，因此研究FASD儿童的神经生物学， FASD啮齿动物模型中的空间记忆也具有相当大的翻译意义。

PROJECT SUMMARY Fetal Alcohol Spectrum Disorders (FASD) are a major public health problem with an incidence of 1-5% in the USA and associated annual costs in excess of $4 billion. The majority of FASD cases fall within the less severe range of the spectrum, characterized by behavioral and cognitive deficits in the absence of conspicuous alterations in craniofacial or brain morphology. Memory deficits are among the more profound lifelong, negative effects on exposure to alcohol during prenatal brain development. At present there are no treatments for memory deficits associated with FASD. Lack of knowledge regarding how prenatal alcohol exposure (PAE) alters brain functions critical for memory represents a major barrier to progress on efforts to identify and develop potential treatments. Moderate PAE in rat models of less severe FASD leads to impairments in spatial memory that persist throughout adulthood. The proposed research will test an innovative and novel hypothesis regarding the neural bases of moderate PAE effects on spatial memory. Place cells in the hippocampus increase in activity selectively when an animal occupies a particular spatial location. The population code provided by place cells represents a spatial “map”. In healthy animals these spatial maps tend to remain stable for months, however, reduced stability in place cells has been linked to spatial memory impairments. Instability in the neural representations of spatial memory may, thus, represent a systems level mechanism for spatial memory impairments observed following PAE. The proposed research will test the hypothesis that PAE reduces place cell stability, and that reductions in place cell stability are predictive of spatial memory impairments following PAE. In the proposed studies adult rats exposed to moderate levels of ethanol during gestational developmental will be implanted with electrodes in the dorsal hippocampus and the stability of hippocampal place cells will be quantified over multiple sessions. If PAE reduces place cell stability, then the pattern of spatially-selective firing of these cells will be more likely to change (“remap”) from session to session. We will examine whether instability in hippocampal place cells of rats exposed to alcohol is predictive of impaired spatial memory in the Morris water task and in a plus-maze task. Significance and Innovation : The proposed research will be the first study to examine the effects of PAE on neural representations of spatial information and the relationship to spatial memory deficits. This project will serve as a foundation for future studies on mechanisms and treatments. Establishing the utility of this model systems approach is important because it could facilitate identification of putative mechanisms underlying PAE-related spatial memory deficits at circuit, network, receptor, and molecular levels of analysis, which could help identify and evaluate treatment strategies. Because spatial memory deficits are observed in children with FASD, studying the neurobiology of spatial memory in rodent models of FASD could also hold considerable translational significance.