Laboratório de Investigações em Neurodegeneração e Infecção, Hospital Universitário "João de Barros Barreto", Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Pará, Brazil.
Laboratório de Investigações em Neurodegeneração e Infecção, Hospital Universitário "João de Barros Barreto", Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, Pará, Brazil; Laboratório de Microscopia Eletrônica, Instituto Evandro Chagas, Belém, Pará, Brazil.
J Chem Neuroanat. 2021 Jan;111:101875. doi: 10.1016/j.jchemneu.2020.101875. Epub 2020 Oct 27.
Most animal model studies of autism spectrum disorder (ASD) have been performed in males, which may be a reflex of the 3-times higher prevalence in boys than in girls. For this reason, little is known about the mechanisms underlying disease progression in females, and nothing is known about potential associations between microglial changes in the lateral septum (LS) and adult female cognition. Prenatal exposure to valproic acid (VPA) in mice has been widely used as an experimental model of autism-like behaviors associated with cellular changes. However, no study has reported the influence of VPA exposure in utero and its consequences on limbic system-dependent tasks or the microglial response in the LS in adult female mice. We compared the exploratory activity and risk assessment in novel environments of BALB/c control mice to mice exposed in utero to VPA and estimated the total number of microglia in the LS using an optical fractionator. On day 12.5 of pregnancy, females received diluted VPA or saline by gavage. After weaning, VPA exposed or control pups were separately housed in standard laboratory cages. At 5 months of age, all mice underwent behavioral testing and their brain sections were immunolabelled using IBA-1 antibody. In the open field test, VPA group showed a greater distance traveled, which was accompanied by less immobility, less time spent on the periphery and a greater number, crossed lines. Similar findings were found in the elevated plus maze test, where VPA mice traveled greater distances, immobility was significantly higher than that of control and VPA group spent less time on the closed arms of apparatus. Stereological analysis demonstrated higher microglial total number and density in the LS of VPA mice, as the cell count was greater, but the volume was similar. Therefore, we suggest that an increase in microglia in the LS may be part of the cellular changes associated with behavioral dysfunction in the VPA model of ASD.
大多数自闭症谱系障碍（ASD）的动物模型研究都是在雄性动物中进行的，这可能反映了男孩的发病率比女孩高 3 倍。由于这个原因，对于女性疾病进展的机制知之甚少，也不知道外侧隔核（LS）中的小胶质细胞变化与成年女性认知之间的潜在关联。在小鼠中，产前暴露于丙戊酸（VPA）已被广泛用作与细胞变化相关的自闭症样行为的实验模型。然而，没有研究报道过宫内 VPA 暴露及其对边缘系统依赖任务或成年雌性小鼠 LS 中小胶质细胞反应的影响。我们比较了 BALB/c 对照小鼠在新环境中的探索活动和风险评估，以及使用光学分割器估计 LS 中小胶质细胞的总数。在妊娠第 12.5 天，雌性小鼠通过灌胃接受稀释的 VPA 或生理盐水。断乳后，VPA 暴露或对照幼鼠分别饲养在标准实验室笼中。在 5 个月大时，所有小鼠都接受了行为测试，并用 IBA-1 抗体对其脑切片进行免疫标记。在旷场测试中，VPA 组的行进距离更大，同时表现出更少的不动性、更少的时间停留在周边和更多的穿越线。在高架十字迷宫测试中也发现了类似的发现，其中 VPA 小鼠行进的距离更大，不动性显著高于对照组，VPA 组在装置的封闭臂上花费的时间更少。立体学分析表明，VPA 小鼠 LS 中的小胶质细胞总数和密度增加，因为细胞计数更大，但体积相似。因此，我们认为 LS 中小胶质细胞的增加可能是与 ASD 的 VPA 模型中行为功能障碍相关的细胞变化的一部分。
