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 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.

Authors

Institutions

Publication Details

Journal
Science Advances
Published
2025-01-22
DOI
https://doi.org/10.1126/sciadv.adr0563
Citations
5
Primary Topic
Stress Responses and Cortisol
Type
article
Field-Weighted Citation Impact
5.56
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Graziano Pinna, Eleonora Corridori, Caterina Branca, Jesús M. Torres et al.
5 citations
Science Advances
Stress Responses and Cortisol
5.56
article

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

Graziano Pinna, Eleonora Corridori, Caterina Branca, Jesús M. Torres, Gabriele Floris, Philip J. Moos, Giulia Braccagni, Marco Bortolato, Simona Scheggi, Roberto Cadeddu, Luca Spiro Santovito, Sara Salviati, Pilar Sánchez, Esperanza Ortega
article en
5 citations

Abstract

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.

Science AdvancesVol. 11(4)
University of Siena (IT), University of Kansas (US), Universidad de Granada (ES), University of Utah (US), University of Florida (US), University of Illinois Chicago (US), Temple University (US), The University of Texas Health Science Center at Houston (US)
Good health and well-being
Openalex Percentile: Top 4%
Stress Responses and Cortisol
5.56
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.