Cadeddu Roberto, Braccagni Giulia, Floris Gabriele, Branca Caterina, Corridori Eleonora, Salviati Sara, Sánchez Pilar, Santovito Luca Spiro, Torres Jesus M, Ortega Esperanza, Pinna Graziano, Moos Philip J, Scheggi Simona, Bortolato Marco
Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Sci Adv. 2025 Jan 24;11(4):eadr0563. doi: 10.1126/sciadv.adr0563. Epub 2025 Jan 22.
A key response to acute stress is the increased brain synthesis of the neurosteroid allopregnanolone (AP). Although the rate-limiting step of this reaction is catalyzed by 5α-reductase (5αR), the role of its two primary isoenzymes, 5αR1 and 5αR2, in stress reactivity remains unclear. Here, we found that acute stress led to increased levels of 5αR2, but not 5αR1, in the medial prefrontal cortex (mPFC) of male, but not female, rats. Down-regulation of 5αR2 in the mPFC significantly reduced stress response in males, and similar sexual dimorphic effects were observed in a novel line of 5αR2 knockout rats. Notably, 5αR1 regulated baseline AP synthesis, whereas 5αR2 enabled AP production under stress. Acute AP administration restored stress response in 5αR2 knockdown rats. Single-nucleus transcriptomics showed that 5αR2 enabled stress-induced protein translation in neurons and glia. These results highlight the crucial role of 5αR2 in mediating sex-specific differences in acute stress reactivity.
对急性应激的一个关键反应是大脑中神经甾体别孕烯醇酮（AP）的合成增加。尽管该反应的限速步骤由5α-还原酶（5αR）催化，但其两种主要同工酶5αR1和5αR2在应激反应性中的作用仍不清楚。在这里，我们发现急性应激导致雄性大鼠（而非雌性大鼠）内侧前额叶皮质（mPFC）中5αR2水平升高，而5αR1水平未升高。mPFC中5αR2的下调显著降低了雄性大鼠的应激反应，并且在新的5αR2基因敲除大鼠品系中也观察到了类似的性别二态性效应。值得注意的是，5αR1调节基线AP合成，而5αR2在应激状态下促进AP生成。急性给予AP可恢复5αR2基因敲低大鼠的应激反应。单核转录组学显示，5αR2在神经元和神经胶质细胞中促进应激诱导的蛋白质翻译。这些结果突出了5αR2在介导急性应激反应性性别特异性差异中的关键作用。
