Fedorchak Alexis V, Miller Michael W
Department of Neuroscience and Physiology, SUNY- Upstate Medical University, Syracuse, NY, 13210, US.
Department of Bioengineering, Syracuse University, Syracuse, NY, 13244, USA.
Int J Dev Neurosci. 2019 Dec;79:65-75. doi: 10.1016/j.ijdevneu.2019.10.005. Epub 2019 Nov 6.
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.
胎儿酒精综合征（FAS）是认知功能障碍的主要原因。本研究检验了以下假设：（a）孕期乙醇暴露会导致与海马体相关行为及相关神经发生的缺陷；（b）原肠胚形成期是一个易受影响的时期。怀孕的猕猴每周接受一次乙醇或生理盐水插管，持续3、6或24周。暴露期包括或不包括原肠胚形成期。对后代进行行为测试，包括视觉配对比较（VPC），这是一项与海马体相关的记忆任务，并在其青春期时实施安乐死。对它们的齿状回进行处理，以便通过免疫组织化学鉴定经历细胞周期的细胞（Ki-67和增殖细胞核抗原）、退出细胞周期的细胞（p21）或经历神经元形态发生早期阶段的细胞（Tuj1）。神经行为任务的表现不受乙醇暴露的影响，唯一显著的例外是VPC测试中的表现，暴露于乙醇（包括原肠胚形成期暴露）的猕猴表现较差。解剖学研究表明，在乙醇暴露包括原肠胚形成期的动物中，Ki-67的表达更高，p21阳性细胞与表达Ki-67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，齿状回是孕期乙醇暴露长期后果的一个指标。乙醇对早期神经发生（细胞周期和周期退出）的靶向作用与VPC表现中随时间的退化相关，原肠胚形成期的暴露会导致明显的缺陷。这些变化证明了FAS背后存在胎儿编程模式。
