Increasing studies report that prolonged or multiple anaesthetic exposures early in life are associated with detrimental effects on brain function. Although studies have evaluated the detrimental effects on neurocognitive function, few have focused on long-term neuropsychiatric effects. In the present study, C57BL/6 mice received either three neonatal isoflurane exposures or control exposure. Starting on postnatal day 45, the mice were either exposed or not to a chronic variable stress (CVS) paradigm, and CVS-related neuropsychiatric performance was evaluated using a series of behavioural tests. The expression levels of histone 3 lysine 9 acetylation (acetyl-H3K9), brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein-binding protein, and histone deacetylases 1–4 in the amygdala were measured by immunoblotting or immunohistochemistry analysis. In mice with neonatal isoflurane exposure, the effects of sodium butyrate (NaB), a commonly used HDAC inhibitor, were examined on CVS-related behavioural and molecular alterations. The results showed that repeated neonatal isoflurane exposure did not affect innate depression-like and anxiety-like behaviours under non-stress conditions but facilitated the CVS-induced anxiety-like behavioural phenotype. Increased HDAC2 expression in the amygdala was associated with an increase in the CVS-induced repression of acetyl-H3K9 and BDNF expression and an enhanced CVS-evoked anxiety-like behavioural phenotype in mice neonatal isoflurane exposure. NaB significantly decreased the CVS-induced anxiety level by elevating acetyl-H3K9 and BDNF expression. These results suggested that early anaesthesia exposure facilitated chronic stress-induced neuropsychiatric outcomes, and the HDAC2-related epigenetic dysregulation of BDNF gene expression is involved in the underlying mechanism.

越来越多的研究表明，生命早期长期或多次接触麻醉剂会对大脑功能产生有害影响。尽管研究评估了对神经认知功能的有害影响，但很少有人关注长期的神经精神影响。在本研究中，C57BL/6 小鼠接受了三种新生异氟醚暴露或对照暴露。从出生后第 45 天开始，小鼠要么暴露于慢性可变应激 (CVS) 模式，要么不暴露于慢性可变应激 (CVS) 范式，并使用一系列行为测试评估 CVS 相关的神经精神表现。通过免疫印迹或免疫组织化学分析测量杏仁核中组蛋白3赖氨酸9乙酰化（乙酰-H3K9）、脑源性神经营养因子（BDNF）、cAMP反应元件结合蛋白结合蛋白和组蛋白脱乙酰酶1-4的表达水平。在新生期接触异氟醚的小鼠中，研究了常用 HDAC 抑制剂丁酸钠 (NaB) 对 CVS 相关行为和分子改变的影响。结果表明，新生儿反复接触异氟醚不会影响非应激条件下先天的抑郁样和焦虑样行为，但会促进 CVS 诱导的焦虑样行为表型。杏仁核中 HDAC2 表达的增加与 CVS 诱导的乙酰基 H3K9 和 BDNF 表达抑制的增加以及新生异氟烷暴露小鼠中 CVS 诱发的焦虑样行为表型的增强有关。 NaB 通过提高乙酰基-H3K9 和 BDNF 的表达，显着降低 CVS 诱导的焦虑水平。 这些结果表明，早期麻醉暴露促进了慢性应激诱导的神经精神结局，而 HDAC2 相关的 BDNF 基因表达的表观遗传失调参与了潜在的机制。