Sex differences in dopamine innervation and microglia are altered by synthetic progestin in neonatal medial prefrontal cortex.
Sex differences in dopamine innervation and microglia are altered by synthetic progestin in neonatal medial prefrontal cortex.
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多巴胺神经支配和小胶质细胞的性别差异被新生儿内侧前额叶皮质中的合成神经胶质蛋白改变。
DOI：
10.1111/jne.12962
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发表时间：
2021-03
影响因子：
3.2
通讯作者：
Wagner CK
中科院分区：
文献类型：
--
作者：
Lolier M;Wagner CK
合成的孕酮17-α-羟孕酮己酸酯（17-OHPC）通常用于有早产史的孕妇，尽管几乎没有疗效证据。17-OHPC给药的时间与胎儿中皮质多巴胺通路的发育一致，但对皮质发育和认知的潜在影响几乎未知。在啮齿动物模型中，暴露于17-OHPC显著增加了内侧前额叶皮质（mPFC）的多巴胺能神经支配，这是一种异常的连接模式，可能是成年期观察到的认知灵活性缺陷的基础。在本研究中，酪氨酸羟化酶（TH）免疫反应性被用来确定是否17-OHPC改变多巴胺能神经支配的mPFC在新生期的突触在男性和女性。虽然TH-免疫反应（−IR）纤维的数量没有差异，但在边缘前区（PL）mPFC深层的TH-IR纤维分布存在性别差异;男性的多巴胺能神经支配模式比女性窄。17-OHPC暴露消除了这些性别特异性模式，使得17-OHPC雌性在PL中的模式比对照雌性窄。在边缘下mPFC（IL），17-OHPC男性有一个更广泛的分布模式的TH-免疫反应性比对照组男性的TH-IR纤维的量没有差异。17-OHPC还造成了性别差异，男性的TH-IR纤维密度低于女性。我们还研究了小胶质细胞，脑巨噬细胞在发育中塑造多巴胺能轴突生长中发挥关键作用，使用表型作为小胶质细胞活性的间接测量。女性有更多的反应性粗壮的小胶质细胞相比，男性在PL，男性有更多的活跃的圆形小胶质细胞比女性在IL。17-OHPC治疗消除了这两个地区的性别差异。这些发现表明，发育暴露于17-OHPC可以发挥差异性的影响，在男性和女性，并可能减少皮质成熟的性别差异。
The synthetic progestin 17-α-hydroxyprogesterone caproate (17-OHPC) is commonly prescribed to pregnant women with a history of preterm delivery, despite little evidence of efficacy. The timing of 17-OHPC administration coincides with fetal mesocortical dopamine pathway development, yet the potential effects on cortical development and cognition are almost unknown. In rodent models, exposure to 17-OHPC significantly increased dopaminergic innervation of the medial prefrontal cortex (mPFC), an aberrant pattern of connectivity that may underlie deficits in cognitive flexibility observed in adulthood. In the present study, tyrosine hydroxylase (TH) immunoreactivity was used to determine whether 17-OHPC altered dopaminergic innervation of the mPFC during a neonatal period of synaptogenesis in males and females. Although there were no differences in the amount of TH-immunoreactive (−IR) fibres, there was a sex difference in TH-IR fibre distribution in deep layers of the prelimbic area (PL) mPFC; males had a narrower pattern of dopaminergic innervation than females. 17-OHPC exposure abolished these sex-specific patterns, such that 17-OHPC females had a narrower pattern in the PL than control females. In the infralimbic mPFC (IL), 17-OHPC males had a broader pattern of distribution of TH-immunoreactivity than control males with no differences in the amount of TH-IR fibres. 17-OHPC also created a sex difference in which males had a lower TH-IR fibre density than females. We also examined microglia, brain macrophages that play a key role in sculpting dopaminergic axon outgrowth in development, using phenotype as an indirect measure of microglial activity. Females had a greater number of reactive stout microglia compared to males in the PL, and males had more active round microglia than females in the IL. 17-OHPC treatment abolished the sex differences in both regions. These findings demonstrate that developmental exposure to 17-OHPC can exert differential effects in males and females and may diminish sex differences in cortical maturation.
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