Estrogen Receptor-A in Medial Preoptic Area Contributes to Sex Difference of Mice in Response to Sevoflurane Anesthesia

Yunyun Zhang,Xinxin Zhang,Dan Wang,Sa Wang,Jiajia Wang,Zhen Zhang,Huiming Li,Tingting Tong,Qianzi Yang,Hailong Dong

doi:10.1007/s12264-022-00825-w

Yunyun Zhang, Xinxin Zhang + Show 8 more

Open Access

https://doi.org/10.1007/s12264-022-00825-w

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Abstract

A growing number of studies have identified sex differences in response to general anesthesia; however, the underlying neural mechanisms are unclear. The medial preoptic area (MPA), an important sexually dimorphic structure and a critical hub for regulating consciousness transition, is enriched with estrogen receptor alpha (ERα), particularly in neuronal clusters that participate in regulating sleep. We found that male mice were more sensitive to sevoflurane. Pharmacological inhibition of ERα in the MPA abolished the sex differences in sevoflurane anesthesia, in particular by extending the induction time and facilitating emergence in males but not in females. Suppression of ERα in vitro inhibited GABAergic and glutamatergic neurons of the MPA in males but not in females. Furthermore, ERα knockdown in GABAergic neurons of the male MPA was sufficient to eliminate sex differences during sevoflurane anesthesia. Collectively, MPA ERα positively regulates the activity of MPA GABAergic neurons in males but not in females, which contributes to the sex difference of mice in sevoflurane anesthesia.

Highlights

General anesthesia, with the features of unconsciousness, analgesia, amnesia, and immobility, has been widely used in surgery for more than 170 years
We found that female mice took longer to lose the righting reflex than male mice (398.9 ± 46.8 s vs 313.3 ± 26.5 s, P = 0.0002, n = 9 per group; Fig. 1B), and less time to emerge from anesthesia after sevoflurane exposure ceased (196.7 ± 33.9 s vs 245 ± 38.2 s, P = 0.0119, n = 9 per group; Fig. 1B)
The above results suggest that sevoflurane anesthesia has a sex-dependent effect in mice, and males are more sensitive to sevoflurane than females

Summary

Introduction

With the features of unconsciousness, analgesia, amnesia, and immobility, has been widely used in surgery for more than 170 years. Accumulating evidence has shown that unconsciousness induced by general anesthetics shares the neural pathway with sleep [1], and many sleep-related nuclei and networks have been reported to be involved in anesthesia [2,3,4]. In both basic and clinical research, females have been primarily excluded for a long time because of the confounding variables of breeding, pregnancy, and hormonal fluctuations that are characteristic of this sex.

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