Hormonal basis of sex differences in anesthetic sensitivity

• 成果类型: Article
• 署名作者: Wasilczuk, Andrzej Z.; Rinehart, Cole; Aggarwal, Adeeti; Stone, Martha E.; Mashour, George A.; Avidan, Michael S.; Kelz, Max B.; Proekt, Alex
• 署名单位: University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Michigan System; University of Michigan; Washington University (WUSTL); University of Pennsylvania
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14721
• DOI: 10.1073/pnas.2312913120
• 发表日期: 2024-01-16
• 关键词: detect intraoperative wakefulness; total intravenous anesthesia; sexually dimorphic nucleus; isolated forearm technique; vigilance test pvt; general-anesthesia; bispectral index; volatile anesthetics; preoptic area; connected consciousness

摘要

General anesthesia-a pharmacologically induced reversible state of unconsciousnes-senables millions of life-saving procedures. Anesthetics induce unconsciousness in part by impinging upon sexually dimorphic and hormonally sensitive hypothalamic circuits regulating sleep and wakefulness. Thus, we hypothesized that anesthetic sensitivity should be sex-dependent and modulated by sex hormones. Using distinct behavioral measures, we show that at identical brain anesthetic concentrations, female mice are more resistant to volatile anesthetics than males. Anesthetic sensitivity is bidirectionally modulated by testosterone. Castration increases anesthetic resistance. Conversely, testosterone administration acutely increases anesthetic sensitivity. Conversion of testosterone to estradiol by aromatase is partially responsible for this effect. In contrast, oophorectomy has no effect. To identify the neuronal circuits underlying sex differences, we performed whole brain c-Fos activity mapping under anesthesia in male and female mice. Consistent with a key role of the hypothalamus, we found fewer active neurons in the ventral hypothalamic sleep-promoting regions in females than in males. In humans, we demonstrate that females regain consciousness and recover cognition faster than males after identical anesthetic exposures. Remarkably, while behavioral and neurocognitive measures in mice and humans point to increased anesthetic resistance in females, cortical activity fails to show sex differences under anesthesia in either species. Cumulatively, we demonstrate that sex differences in anesthetic sensitivity are evolutionarily conserved and not reflected in conventional electroencephalographic-based measures of anesthetic depth. This covert resistance to anesthesia may explain the higher incidence of unintended awareness under general anesthesia in females.