Microglia are essential to masculinization of brain and behavior.
Microglia are essential to masculinization of brain and behavior.
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DOI：
10.1523/jneurosci.1268-12.2013
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发表时间：
2013-02-13
期刊：
影响因子：
--
通讯作者：
McCarthy MM
中科院分区：
文献类型：
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作者：
Lenz KM;Nugent BM;Haliyur R;McCarthy MM
啮齿动物的大脑性别分化是由围产期睾丸雄激素激增引起的。在视前区（POA），由睾酮芳香化的雌二醇上调促炎分子前列腺素E2 （PGE2）的产生，从而产生性别特异性的大脑发育。PGE2在雄性中产生的树突棘密度是雌性的两倍，并使成年交配行为雄性化。一次新生儿剂量的PGE2使POA和行为男性化，同时使用额外前列腺素合成抑制剂治疗可阻止这种男性化，这表明一个正前馈过程导致PGE2持续增加。这种前馈过程的机制尚不清楚。小胶质细胞是大脑中的初级免疫能力细胞，在新生儿时期是活跃的，有助于大脑的正常发育，并产生前列腺素并对其作出反应。我们研究了POA小胶质细胞是否存在性别差异，以及它们是否影响发育中的男性化。新生儿雄性的阿米巴样小胶质细胞数量是雌性的两倍，形态特征更活跃，雌二醇和PGE2均使雌性的小胶质细胞数量和形态男性化。在性别分化的关键时期，小胶质细胞的抑制阻止了小胶质细胞的性别差异、雌二醇诱导的树突棘密度的雄性化和成虫的交配行为。小胶质细胞抑制也阻止了雌二醇诱导的PGE2上调，这表明小胶质细胞在雌二醇上调前列腺素生成的前馈过程中是必不可少的。这些研究表明，在发育过程中，大脑中的免疫细胞与神经系统和内分泌系统相互作用，对大脑和行为的性别分化至关重要。
Brain sexual differentiation in rodents results from the perinatal testicular androgen surge. In the preoptic area (POA), estradiol aromatized from testosterone upregulates the production of the proinflammatory molecule, prostaglandin E2 (PGE2) to produce sex-specific brain development. PGE2 produces a two-fold greater density of dendritic spines in males than in females and masculinizes adult copulatory behavior. One neonatal dose of PGE2 masculinizes the POA and behavior, and simultaneous treatment with an inhibitor of additional prostaglandin synthesis prevents this masculinization, indicating a positive feed-forward process that leads to sustained increases in PGE2. The mechanisms underlying this feed-forward process were unknown. Microglia, the primary immunocompetent cells in the brain, are active neonatally, contribute to normal brain development, and both produce and respond to prostaglandins. We investigated whether there are sex differences in microglia in the POA and whether they influence developmental masculinization. Neonatal males had twice as many ameboid microglia as females and a more activated morphological profile, and both estradiol and PGE2 masculinized microglial number and morphology in females. Microglial inhibition during the critical period for sexual differentiation prevented sex differences in microglia, estradiol-induced masculinization of dendritic spine density, and adult copulatory behavior. Microglial inhibition also prevented the estradiol-induced upregulation of PGE2, indicating that microglia are essential to the feed-forward process through which estradiol upregulates prostaglandin production. These studies demonstrate that immune cells in the brain interact with the nervous and endocrine systems during development, and are crucial for sexual differentiation of brain and behavior.