The hypothalamic steroidogenic pathway mediates susceptibility to inflammation-evoked depression in female mice.
The hypothalamic steroidogenic pathway mediates susceptibility to inflammation-evoked depression in female mice.
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DOI：
10.1186/s12974-023-02976-7
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发表时间：
2023-12-07
影响因子：
9.3
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中科院分区：
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--
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抑郁症在女性中的发生率要高出两到三倍。下丘脑是一个性二态区，与抑郁症的病理生理有关。神经炎症诱导的下丘脑功能障碍是抑郁症相关行为的基础。脂多糖（LPS）诱导的抑郁症小鼠模型已经在许多实验室得到了很好的验证，包括我们自己的实验室，并被广泛用于研究神经炎症和抑郁症之间的关系。然而，抑郁症相关的下丘脑神经炎症的代谢改变的性别特异性差异仍然未知。在这里，我们采用LPS诱导的抑郁症小鼠模型，研究下丘脑代谢的变化，在雄性和雌性小鼠使用代谢组学方法。通过生物信息学分析，我们确认了与所鉴定的代谢物相关的分子途径和生物学过程。此外，我们采用定量实时PCR，酶联免疫吸附试验，蛋白质印迹，和药物干预，以进一步阐明其潜在的机制。与相应的性别匹配对照组相比，在具有抑郁样行为的雄性和雌性小鼠中分别检测到124和61种差异代谢物（DM）。此外，雌性和雄性模型小鼠之间的比较确定了37个DM。我们利用生化聚类和功能富集分析来定义这些DM中的主要代谢变化。超过55%的DM聚集成脂质和类脂质分子，下丘脑存在脂质代谢失衡。此外，类固醇生成途径被证实是一个潜在的性别特异性途径，在下丘脑的雌性抑郁症小鼠。孕烯醇酮是类固醇激素生物合成途径的上游成分，在具有抑郁样表型的雌性小鼠中下调，但在雄性小鼠中不下调，并且与雌性小鼠的抑郁样行为具有相当大的相关性。此外，外源性双烯醇酮输注逆转抑郁症雌性小鼠的抑郁样行为。5α-还原酶I型（SRD 5A 1），一种参与阿替诺龙代谢的类固醇生成中枢酶，在抑郁症雌性小鼠的下丘脑中增加。它的抑制作用增加了下丘脑的双烯醇酮水平，并改善了抑郁症雌性小鼠的抑郁样行为。我们的研究结果表明，在抑郁症的代谢水平上，特别是在下丘脑类固醇代谢方面，存在明显的性二态性，从而确定了具有抑郁样行为的雌性小鼠中潜在的性别特异性途径。在线版本包含补充材料，可通过10.1186/s12974-023-02976-7获得。
Depression is two-to-three times more frequent among women. The hypothalamus, a sexually dimorphic area, has been implicated in the pathophysiology of depression. Neuroinflammation-induced hypothalamic dysfunction underlies behaviors associated with depression. The lipopolysaccharide (LPS)-induced mouse model of depression has been well-validated in numerous laboratories, including our own, and is widely used to investigate the relationship between neuroinflammation and depression. However, the sex-specific differences in metabolic alterations underlying depression-associated hypothalamic neuroinflammation remain unknown. Here, we employed the LPS-induced mouse model of depression to investigate hypothalamic metabolic changes in both male and female mice using a metabolomics approach. Through bioinformatics analysis, we confirmed the molecular pathways and biological processes associated with the identified metabolites. Furthermore, we employed quantitative real-time PCR, enzyme-linked immunosorbent assay, western blotting, and pharmacological interventions to further elucidate the underlying mechanisms. A total of 124 and 61 differential metabolites (DMs) were detected in male and female mice with depressive-like behavior, respectively, compared to their respective sex-matched control groups. Moreover, a comparison between female and male model mice identified 37 DMs. We capitalized on biochemical clustering and functional enrichment analyses to define the major metabolic changes in these DMs. More than 55% of the DMs clustered into lipids and lipid-like molecules, and an imbalance in lipids metabolism was presented in the hypothalamus. Furthermore, steroidogenic pathway was confirmed as a potential sex-specific pathway in the hypothalamus of female mice with depression. Pregnenolone, an upstream component of the steroid hormone biosynthesis pathway, was downregulated in female mice with depressive-like phenotypes but not in males and had considerable relevance to depressive-like behaviors in females. Moreover, exogenous pregnenolone infusion reversed depressive-like behaviors in female mice with depression. The 5α-reductase type I (SRD5A1), a steroidogenic hub enzyme involved in pregnenolone metabolism, was increased in the hypothalamus of female mice with depression. Its inhibition increased hypothalamic pregnenolone levels and ameliorated depressive-like behaviors in female mice with depression. Our study findings demonstrate a marked sexual dimorphism at the metabolic level in depression, particularly in hypothalamic steroidogenic metabolism, identifying a potential sex-specific pathway in female mice with depressive-like behaviors. The online version contains supplementary material available at 10.1186/s12974-023-02976-7.
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