BALB/c female subjected to valproic acid during gestational period exhibited greater microglial and behavioral changes than male mice: a significant contra intuitive result,International Journal of Developmental Neuroscience

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BALB/c female subjected to valproic acid during gestational period exhibited greater microglial and behavioral changes than male mice: a significant contra intuitive result
International Journal of Developmental Neuroscience ( IF 1.7 ) Pub Date : 2020-11-07 , DOI: 10.1002/jdn.10072
Alinne Lorrany Gomes Dos Santos _{1,

2} , Ellen Rose Leandro Ponce de Leão ₂ , Diego de Almeida Miranda ₂ , Dilza Nazaré Colares de Souza _{1,

2} , Cristovam Wanderley Picanço Diniz _{1,

2} , Daniel Guerreiro Diniz _{1,

2,

3}

Affiliation

Most animal model studies of autism spectrum disorders (ASD) were performed in males. Thus, little is known about the mechanisms underlying disease progression in females. Here we searched for potential influences of sex and environment on gestational valproic acid-induced behavioral abnormalities using hippocampal-dependent tasks, and on number and morphometry of microglia of the molecular layer of the dentate gyrus (Mol-DG). We compared male and females BALB/c control mice with BALB/c mice gestationally exposed to VPA with regards to exploratory activity and risk assessment in novel environments. Pregnant females and males on gestational day 12.5 received VPA in saline (600 mg/kg body weight) or an equal volume of saline by gavage. After weaning, female and male offspring were housed separately either in standard laboratory cages (SE) or enriched cages (EE). At five months of age, these mice underwent behavioral testing and had their brains processed for microglia IBA1 immunolabelling. Compared with control mice, VPA-exposed mice exhibited abnormal behavior in exploring novel environments and assessing risk, and these effects were significantly greater in females than in males and less intense among mice from enriched cages. Three-way ANOVA revealed that environment, sex and valproic acid conditions interacted and altered the behavior results. Microglia number and volume of the Mol-DG were significantly higher in VPA-exposed groups raised in standard cages. The results of counting the intersects of microglia branching on Sholl's circles analyzed with permutational MANOVA, demonstrated that in comparison with males, there was a greater reduction in the number of intersections in females raised in standard cages. These findings suggest that the increased microglia and morphological changes might be associated with behavioral dysfunction in ASD. Moreover, the somatomotor and cognitive stimulation of environmental enrichment started at weaning may be beneficial for reducing behavioral abnormalities and reduction of microglia response in adulthood.

中文翻译：

在妊娠期服用丙戊酸的 BALB/c 雌性小鼠表现出比雄性小鼠更大的小胶质细胞和行为变化：一个显着的反直觉结果

大多数自闭症谱系障碍 (ASD) 的动物模型研究都是在男性中进行的。因此，对女性疾病进展的潜在机制知之甚少。在这里，我们使用海马依赖性任务，以及齿状回分子层 (Mol-DG) 的小胶质细胞的数量和形态测量学，寻找性别和环境对妊娠丙戊酸诱导的行为异常的潜在影响。我们比较了雄性和雌性 BALB/c 对照小鼠与妊娠期暴露于 VPA 的 BALB/c 小鼠在新环境中的探索活动和风险评估。怀孕第 12.5 天的雌性和雄性通过管饲法接受生理盐水中的 VPA（600 毫克/千克体重）或等体积的生理盐水。断奶后，雌性和雄性后代分别饲养在标准实验室笼 (SE) 或富集笼 (EE) 中。在五个月大时，这些小鼠接受了行为测试，并对其大脑进行了小胶质细胞 IBA1 免疫标记处理。与对照小鼠相比，暴露于 VPA 的小鼠在探索新环境和评估风险方面表现出异常行为，这些影响在雌性中明显高于雄性，而在来自富集笼子的小鼠中则不那么强烈。三向方差分析显示环境、性别和丙戊酸条件相互作用并改变了行为结果。在标准笼中饲养的 VPA 暴露组中，Mol-DG 的小胶质细胞数量和体积显着更高。用置换多元方差分析对肖尔圆上小胶质细胞分支的交叉点进行计数的结果，表明与雄性相比，在标准笼子中饲养的雌性的交叉点数量减少更多。这些发现表明，增加的小胶质细胞和形态变化可能与 ASD 的行为功能障碍有关。此外，断奶时开始的环境丰富的躯体运动和认知刺激可能有利于减少成年后的行为异常和小胶质细胞反应。

更新日期：2020-11-07

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