Prefrontal 5α-reductase 2 mediates male-specific acute stress response

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 5 alpha-reductase (5 alpha R), the role of its two primary isoenzymes, 5 alpha R1 and 5 alpha R2, in stress reactivity remains unclear. Here, we found that acute stress led to increased levels of 5 alpha R2, but not 5 alpha R1, in the medial prefrontal cortex (mPFC) of male, but not female, rats. Down-regulation of 5 alpha R2 in the mPFC significantly reduced stress response in males, and similar sexual dimorphic effects were observed in a novel line of 5 alpha R2 knockout rats. Notably, 5 alpha R1 regulated baseline AP synthesis, whereas 5 alpha R2 enabled AP production under stress. Acute AP administration restored stress response in 5 alpha R2 knockdown rats. Single-nucleus transcriptomics showed that 5 alpha R2 enabled stress-induced protein translation in neurons and glia. These results highlight the crucial role of 5 alpha R2 in mediating sex-specific differences in acute stress reactivity.