Electrophysiological Characterization of Sex-Dependent Hypnosis by an Endogenous Neuroactive Steroid Epipregnanolone

TL;DR

This study shows that a natural brain chemical called epipregnanolone causes different levels of sleepiness in male and female mice, with females being more sensitive.

Contribution

The study reveals sex-dependent hypnotic effects of epipregnanolone through electrophysiological analysis in mice.

Findings

Female mice showed increased sensitivity to EpiP-induced loss of righting reflex.

EpiP altered thalamocortical and corticocortical phase synchronization in a sex-dependent manner.

Sex differences were observed in spectral power changes during EpiP-induced hypnosis.

Abstract

Neuroactive steroids (NAS) have long been recognized for their hypnotic and anesthetic properties in both clinical and preclinical settings. While sex differences in NAS sensitivity are acknowledged, the underlying mechanisms remain poorly understood. Here, we examined sex-specific responses to an endogenous NAS epipregnanolone (EpiP) in wild-type mice using behavioral assessment of hypnosis (loss of righting reflex, LORR) and in vivo electrophysiological recordings. Specifically, local field potentials (LFPs) were recorded from the central medial thalamus (CMT) and electroencephalogram (EEG) signals were recorded from the barrel cortex. We found that EpiP-induced LORR exhibited clear sex differences, with females showing increased sensitivity. Spectral power analysis and thalamocortical (TC) and corticocortical (CC) phase synchronization further supported enhanced hypnotic susceptibility in female mice. Our findings reveal characteristic sex-dependent effects of EpiP on the synchronized electrical activity in both thalamus and cortex. These results support renewed exploration of endogenous NAS as clinically relevant anesthetic agents.

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