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

Area of Science:

• Neuroscience
• Endocrinology
• Stress Research

Background:

• Acute stress increases brain allopregnanolone (AP) synthesis, a process catalyzed by 5α-reductase (5αR).
• The distinct roles of 5αR isoenzymes, 5αR1 and 5αR2, in stress response and AP production are not well understood.
• Understanding these roles is critical for deciphering neurosteroid involvement in stress adaptation.

Purpose of the Study:

• To investigate the specific roles of 5αR1 and 5αR2 in the acute stress response.
• To elucidate the contribution of these isoenzymes to allopregnanolone synthesis under stress.
• To identify potential sex differences in 5αR-mediated stress reactivity.

Main Methods:

• Utilized male and female rats, focusing on the medial prefrontal cortex (mPFC).
• Employed techniques including 5αR2 down-regulation, generation of 5αR2 knockout rats, and acute AP administration.
• Applied single-nucleus transcriptomics to analyze cellular responses.

Main Results:

• Acute stress elevated 5αR2 levels in the male rat mPFC, but not 5αR1.
• Reduced 5αR2 in the mPFC diminished stress response in males, with similar sex-specific effects in knockout rats.
• 5αR1 influenced baseline AP synthesis, while 5αR2 was essential for stress-induced AP production.
• 5αR2 facilitated stress-induced protein translation in neurons and glia.

Conclusions:

• 5αR2 plays a critical role in mediating the acute stress response and allopregnanolone production in male rats.
• The findings highlight significant sex differences in the neurosteroid regulation of stress reactivity.
• 5αR2 is identified as a key player in the sex-specific neurobiological adaptations to acute stress.