Gestational exposure to valproic acid (VPA) is known to cause behavioral deficits of sociability, matching similar alterations in human autism spectrum disorder (ASD). Available data are scarce on the neuromorphological changes in VPA-exposed animals. Here, we focused on alterations of the dopaminergic system, which is implicated in motivation and reward, with relevance to social cohesion. Whole brains from 7-day-old mice born to mothers given a single injection of VPA (400 mg/kg b.wt.) on E13.5 were immunostained against tyrosine hydroxylase (TH). They were scanned using the iDISCO method with a laser light-sheet microscope, and the reconstructed images were analyzed in 3D for quantitative morphometry. A marked reduction of mesotelencephalic (MT) axonal fascicles together with a widening of the MT tract were observed in VPA treated mice, while other major brain tracts appeared anatomically intact. We also found a reduction in the abundance of dopaminergic ventral tegmental (VTA) neurons, accompanied by diminished tissue level of DA in ventrobasal telencephalic regions (including the nucleus accumbens (NAc), olfactory tubercle, BST, substantia innominata). Such a reduction of DA was not observed in the non-limbic caudate-putamen. Conversely, the abundance of TH+ cells in the substantia nigra (SN) was increased, presumably due to a compensatory mechanism or to an altered distribution of TH+ neurons occupying the SN and the VTA. The findings suggest that defasciculation of the MT tract and neuronal loss in VTA, followed by diminished dopaminergic input to the ventrobasal telencephalon at a critical time point of embryonic development (E13-E14) may hinder the patterning of certain brain centers underlying decision making and sociability.

中文翻译：

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妊娠期丙戊酸钠暴露会中断中脑多巴胺能神经束的束缚，并选择性降低腹侧被盖区的多巴胺能输出。

妊娠期暴露于丙戊酸（VPA）会导致社交行为缺陷，与人类自闭症谱系障碍（ASD）的类似变化相匹配。现有数据缺乏暴露于VPA的动物的神经形态学变化。在这里，我们集中于多巴胺能系统的改变，这与动机和奖励有关，与社会凝聚力有关。在E13.5上单次注射VPA（400 mg / kg b.wt.）的母亲所生的7日龄小鼠的全脑对酪氨酸羟化酶（TH）进行免疫染色。使用iDISCO方法在激光薄片显微镜下对它们进行扫描，然后对重建的图像进行3D分析以进行定量形态分析。在用VPA治疗的小鼠中，观察到中脑脑（MT）轴突束明显减少，并且MT道变宽，而其他主要的脑束在解剖学上看起来是完整的。我们还发现，多巴胺能腹侧被盖神经（VTA）神经元的数量减少，伴随着脑室基底脑区（包括伏隔核（NAc），嗅结节，BST，无名状实体）DA的组织水平降低。在非边缘的尾状-丘脑中未观察到DA的这种减少。相反，黑质（SN）中TH +细胞的丰度增加，可能是由于补偿机制或占据SN和VTA的TH +神经元分布的改变所致。研究结果表明，MTA的脱束和VTA的神经元丢失，