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

Abstract

AbstractAcute 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.