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Histone Deacetylase 2-Mediated Epigenetic Regulation is Involved in the Early Isoflurane Exposure-Related Increase in Susceptibility to Anxiety-Like Behaviour Evoked by Chronic Variable Stress in Mice

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Abstract

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.

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Abbreviations

CVS:

Chronic Variable Stress

CNS:

Central Nervous System

OFT:

Open-Field Test

EPM:

Elevated Plus Maze Test

FST:

Forced Swim Test

TST:

Tail Suspension Test

LTP:

Long Term Potentiation

CBP:

cAMP Response Element-Binding Protein (CREB)-Binding Protein

HATs:

Histone Acetyltransferases

HDACs:

Histone Deacetylases

HDACi:

Histone Deacetylases Inhibitor

BDNF:

Brain-Derived Neurotrophic Factor

NaB:

Sodium Butyrate

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Funding

This research was supported by the Natural Science Foundation of Hunan Province, RP China [2018JJ2627].

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Authors and Affiliations

  1. Teaching and Research Section of Clinical Nursing, Xiangya Hospital of Central South University, Xiangya Road, 87#, Changsha City, 410008, Hunan Province, People’s Republic of China

    Luofang Peng

  2. Department of Anaesthesiology and Operating Theatre Services, Xiangya Hospital of Central South University, Xiangya Road, 87#, Changsha City, 410008, Hunan Province, People’s Republic of China

    Luofang Peng, Xian Liu, Yong Yang, Qulian Guo & Tao Zhong

  3. Teaching and Research Section of Anaesthesia and Critical Care Medicine, Xiangya Hospital of Central South University, Changsha City, Hunan Province, People’s Republic of China

    Xian Liu, Yong Yang, Qulian Guo & Tao Zhong

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  1. Luofang Peng
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Contributions

Study design: LP, QG, and TZ. Data collection and analysis: LP and XL. Reagents/materials/analysis tools: XL and YY. Wrote the manuscript: LP and TZ.

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Correspondence to Tao Zhong.

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Peng, L., Liu, X., Yang, Y. et al. Histone Deacetylase 2-Mediated Epigenetic Regulation is Involved in the Early Isoflurane Exposure-Related Increase in Susceptibility to Anxiety-Like Behaviour Evoked by Chronic Variable Stress in Mice. Neurochem Res 46, 2333–2347 (2021). https://doi.org/10.1007/s11064-021-03368-0

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