Early-Life Multiple Sevoflurane Exposures Alleviate Long-term Anxiety-Like Behaviors in Mice via the proBDNF/ERK Pathway
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Early-Life Multiple Sevoflurane Exposures Alleviate Long-term Anxiety-Like Behaviors in Mice via the proBDNF/ERK Pathway Ru-Yi Luo 1,2 & Cong Luo 1,2 & Feng Zhong 1,2 & Wei-Yun Shen 1,2 & Hui Li 1,2 & Yan-Ling Zhang 1,2 & Ru-Ping Dai 1,2 Received: 22 April 2020 / Accepted: 1 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Early-life multiple anesthetics exposure causes neurotoxicity and hence cognitive dysfunction on developing brain. However, the effects of early-life multiple sevoflurane exposures on emotional changes, especially upon stress, are far beyond understood. In young male C57BL6/J mice, the present study showed that 3% sevoflurane inhalation for 2 h in three consecutive days did not influence anxiety-like behaviors as measured by open field test, light dark transition, and elevated plus maze test. In addition, foot shocks stress induced both the short- and long-term anxiety-like behaviors. However, triple sevoflurane exposures ameliorated the long-term anxiety-like behaviors induced by the foot shocks. In parallel, foot shocks stress upregulated the expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and brain-derived neurotrophic factor precursor (proBDNF) in the anterior cingulate cortex (ACC), which were significantly inhibited by triple sevoflurane exposures. Immunofluorescence further indicated that the increased p-ERK was mainly expressed in the proBDNF-positive staining cells. Intra-ACC injection of recombinant proBDNF protein upregulated the p-ERK expression and blocked the anxiolytic effect of sevoflurane exposure on long-term anxiety-like behaviors. Therefore, our study demonstrated that multiple sevoflurane exposures alleviate long-term anxiety-like behaviors upon acute stress in young mice by inhibiting proBDNF-ERK signaling in the ACC. Keywords Sevoflurane . Anxiety-like behaviors . Stress . Anterior cingulate cortex . Phosphorylated extracellular signal-regulated kinase . Brain-derived neurotrophic factor precursor
1. Introduction Millions of children are subjected to general anesthesia every year [1]. The neurotoxic effects of general anesthetics on the developing brain have raised serious concerns due to potentially negative long-term impacts on learning and memory [2]. In 2017, the Food and Drug Administration of the USA warned that repeated or lengthy use of general anesthetics may negatively affect the brain development of children younger than 3 years [3]. In addition to cognitive functions, mood disorders are gaining more attention as they are highly
* Cong Luo [email protected] * Ru-Ping Dai [email protected] 1
Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Central Ren-Min Road No. 139, Changsha 410011, Hunan Province, China
2
Anesthesia Medical Research Center, Central South University, Changsha, China
prevalent in young children worldwide [4]. Notably, clinical studies have reported that anesthetics may negatively impact behavioral disorders in young chil
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