Prefrontal 5α-reductase 2 mediates male-specific acute stress response
Roberto Cadeddu; Giulia Braccagni; Gabriele Floris; Caterina Branca; Eleonora Corridori; Sara Salviati; Pilar Sánchez; Luca Spiro Santovito; Jesus M. Torres; Esperanza Ortega; Graziano Pinna; Philip J. Moos; Simona Scheggi; Marco Bortolato
Science Advances2025
Summary (paraphrased)
Acute stress selectively raises 5α-reductase type 2 — not type 1 — in the medial prefrontal cortex of male rats, and 5αR2 knockdown or knockout blunts the hormonal and behavioral stress response in males only. The authors demonstrate a division of labor: 5αR1 sustains baseline allopregnanolone, while 5αR2 is recruited to boost production under stress; exogenous allopregnanolone rescues the knockdown phenotype. Single-nucleus transcriptomics ties 5αR2 to stress-induced protein translation in neurons and glia. The work reframes the two isoenzymes as functionally distinct rather than redundant in brain.
Why it’s in the systems review
This is among the most PFS-relevant isoenzyme papers in recent years: it shows 5αR2 — finasteride's primary target — is the stress-recruited, male-specific driver of prefrontal allopregnanolone synthesis, while 5αR1 maintains baseline. That division maps directly onto what finasteride does and does not disrupt in brain neurosteroidogenesis, and why effects might be sex-specific and stress-gated. Any causal-pathway model involving 5α-reductase inhibition must reckon with this 2025 result.
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