Fetal alcohol syndrome (FAS) is a prime cause of cognitive dysfunction. The present study tested the hypotheses (a) that gestational ethanol exposure results in deficits in hippocampal‐related behaviors and associated neurogenesis and (b) that the period of gastrulation is a time of vulnerability. Pregnant macaques were intubated with ethanol or saline once per week for 3, 6, or 24 weeks. Exposures included or omitted the period of gastrulation. Offspring were given behavioral tests including a Visual‐Paired Comparison (VPC), a hippocampal‐associated memory task, and euthanized as adolescents. Their dentate gyri were processed for immunohistochemical identification of cells passing through the cell cycle (Ki‐67 and proliferating cell nuclear antigen), exiting the cell cycle (p21), or passing through early stages of neuronal morphogenesis (Tuj1). Performance in neurobehavioral tasks was unaffected by ethanol exposure, the notable exception being performance in the VPC that was poorer for macaques exposed to ethanol including gastrulation. Anatomical studies show that the expression of Ki‐67 was greater and ratio of p21‐positive cells to the ratio of Ki‐67‐expressing cells was lower in animals in which the ethanol exposure included gastrulation. On the other hand, no ethanol‐induced differences in TuJ1 expression were detected. Thus, the dentate gyrus is a bellwether of long‐term consequences of gestational ethanol exposure. Targeted effects of ethanol on early neural generation (cell cycle and cycle exit) correlate with the timing‐dependent degradation in VPC performance and exposure during gastrulation results in notable deficits. These changes evidence a pattern of fetal programming underlying FAS.

中文翻译：

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偶发性产前乙醇暴露影响猕猴齿状回和视觉识别记忆的出生后神经发生

胎儿酒精综合征 (FAS) 是认知功能障碍的主要原因。本研究检验了假设 (a) 妊娠期乙醇暴露导致海马相关行为和相关神经发生缺陷，以及 (b) 原肠胚形成期是脆弱时期。怀孕的猕猴每周用乙醇或生理盐水插管一次，持续 3、6 或 24 周。暴露包括或省略原肠胚形成期。对后代进行行为测试，包括视觉配对比较 (VPC)、海马相关记忆任务，并在青少年时期实施安乐死。对它们的齿状回进行处理，用于通过细胞周期（Ki-67 和增殖细胞核抗原）、退出细胞周期（p21）或通过神经元形态发生的早期阶段（Tuj1）的细胞的免疫组织化学鉴定。神经行为任务的表现不受乙醇暴露的影响，显着的例外是 VPC 的表现对于暴露于乙醇的猕猴（包括原肠胚形成）来说较差。解剖学研究表明，在乙醇暴露包括原肠胚形成的动物中，Ki-67 的表达更高，p21 阳性细胞与 Ki-67 表达细胞的比例更低。另一方面，未检测到乙醇诱导的 TuJ1 表达差异。因此，齿状回是妊娠期乙醇暴露长期后果的风向标。乙醇对早期神经生成（细胞周期和周期退出）的靶向作用与 VPC 性能的时间依赖性退化和原肠胚形成期间暴露导致显着缺陷相关。