The acute stress response is mediated by prefrontal 5α-reductase 2 in males via allopregnanolone synthesis

Acute stress triggers rapid brain responses, including increased allopregnanolone (AP) synthesis via 5α-reductase (5αR). However, the involvement of this enzyme in stress response remains elusive. Here, we investigated the roles of the two major 5αR isoenzymes in acute stress. Acute stress increased mRNA and protein levels of 5αR2, but not 5αR1, in the medial prefrontal cortex (mPFC) of male, but not female, rats. Targeted mPFC downregulation of 5αR2, but not 5αR1, markedly reduced the responsiveness of males, but not females, to both stressful and arousing stimuli. Similar sex differences were observed in 5αR2 knockout rats. While 5αR1 regulated AP synthesis under baseline conditions, 5αR2 enabled this process in response to acute stress. Single-nucleus transcriptomic analyses revealed that 5αR2 enabled stress-induced protein synthesis in pyramidal neurons and glia of the mPFC. These findings underscore the pivotal role of 5αR2 in shaping sex-related differences in acute stress reactivity.急性应激可触发大脑快速应答，其中包括通过5α-还原酶（5α-reductase, 5αR）增强别孕烷醇酮（allopregnanolone, AP）的合成。不过，该酶在应激反应中的具体作用仍尚不明确。本研究针对两种主要的5αR同工酶在急性应激中的作用展开探究。实验发现，急性应激可提升雄性大鼠内侧前额叶皮层（medial prefrontal cortex, mPFC）中5αR2的mRNA与蛋白表达水平，但对5αR1无显著影响，该效应在雌性大鼠中并未观测到。对大鼠内侧前额叶皮层的5αR2进行靶向下调（而非5αR1），可显著降低雄性大鼠对应激及唤醒刺激的反应性，该效应同样未在雌性大鼠中出现。在5αR2基因敲除大鼠中也观测到了类似的性别差异。5αR1可在基础状态下调控AP的合成，而5αR2则介导急性应激下的AP合成过程。单细胞核转录组分析结果显示，5αR2可介导内侧前额叶皮层锥体神经元与神经胶质细胞中应激诱导的蛋白合成。本研究结果凸显了5αR2在调控急性应激反应性的性别差异中的关键作用。