Neonatal Exposure to Sevoflurane Induces Abnormal Social Behaviors and Deficits in Fear Conditioning in Mice

Satomoto, Maiko; Satoh, Yasushi; Terui, Katsuo; Miyao, Hideki; Takishima, Kunio; Ito, Masataka; Imaki, Junko

doi:10.1097/aln.0b013e3181974fa2

Cited by 469 publications

(447 citation statements)

References 31 publications

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“…While others have used a range of 1–4% sevo on P7 rodents (Satomoto et al. 2009; Liang et al. 2010; Feng et al.…”

Section: Discussionmentioning

confidence: 99%

“…Among these behaviors, social interaction impairment associated with neonatal sevo treatment has been reported previously by another group (Satomoto et al. 2009). Using a caged social target in an open field apparatus, the group demonstrated that the no‐sevo–treated control group interacted significantly more with the social target compared to the sevo‐treated group.…”

Section: Discussionmentioning

confidence: 99%

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Early‐life single‐episode sevoflurane exposure impairs social behavior and cognition later in life

et al. 2016

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BackgroundSingle‐episode anesthetic exposure is the most prevalent surgery‐related incidence among young children in the United States. Although numerous studies have used animals to model the effects of neonatal anesthetics on behavioral changes later on in life, our understanding of the functional consequences to the developing brain in a comprehensive and clinically relevant manner is unclear.MethodsThe volatile anesthetic, sevoflurane (sevo) was administered to C57BL6 postnatal day 7 (P7) mice in a 40% oxygen and 60% nitrogen gas mixture. In order to examine the effects of sevo alone on the developing brain in a clinically relevant manner, mice were exposed to an average of 2.38 ± 0.11% sevo for 2 h. No sevo (control) mice were treated in an identical manner without sevo exposure. Mice were examined for cognition and neuropsychiatric‐like behavioral changes at 1–5 months of age.ResultsUsing the active place avoidance (APA) test and the novel object recognition (NOR) test, we demonstrated that P7 sevo‐treated mice showed a deficit in learning and memory both during periadolescence and adulthood. We then employed a battery of neuropsychiatric‐like behavioral tests to examine social interaction, communication, and repetitive behavior. Interestingly, compared to the no‐sevo–treated group, sevo‐treated mice showed significant reductions in the time interacting with a novel mouse (push–crawl and following), time and interaction in a chamber with a novel mouse, and time sniffing a novel social odor.ConclusionsOur study established that single‐episode, 2‐h sevo treatment during early life impairs cognition later on in life. With this approach, we also observed neuropsychiatric‐like behavior changes such as social interaction deficits in the sevo‐treated mice. This study elucidated the effects of a clinically relevant single‐episode sevo application, given during the neonatal period, on neurodevelopmental behavioral changes later on in life.

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“…While others have used a range of 1–4% sevo on P7 rodents (Satomoto et al. 2009; Liang et al. 2010; Feng et al.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Early‐life single‐episode sevoflurane exposure impairs social behavior and cognition later in life

et al. 2016

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“…In addition, several lines of evidence from animal models have suggested that excessive exposure to volatile anesthetics may cause irreversible and long-term behavioral changes resembling autism spectrum disorders (3). In clinical practice, sevoflurane is the most widely used inhaled anesthetics, particularly for cesarean section and surgical procedures in infants and young children (4,5); thus, the present study focused on sevoflurane.…”

Section: Introductionmentioning

confidence: 99%

Sevoflurane exposure in postnatal rats induced long-term cognitive impairment through upregulating caspase-3/cleaved-poly (ADP-ribose) polymerase pathway

Ling

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The association of anesthetic exposure in infants or young children with the long-term impairment of neurologic functions has been reported previously; however, the underlying mechanisms remain largely unknown. In order to identify dysregulated gene expression underlying long-term cognitive impairment caused by sevoflurane exposure at the postnatal stage, the present study initially performed behavioral tests on adult Wistar rats, which received 3% sevoflurane at postnatal day 7 (P7) for different time course. Subsequently, transcriptome profiling of hippocampal tissues from experimental and control rats was performed. Significant impairment of the working memory was observed in adult rats with sevoflurane exposure for 4-6 h, when compared with the control rats. The results indicated that a total of 264 genes were aberrantly expressed (51 downregulated and 213 upregulated; fold change >2.0; P<0.05; false discovery rate <0.05) in the hippocampus of experimental adult rats compared with those from control rats. Particularly, the expression of caspase-3 gene (CASP3), encoding caspase-3 protein, presented the most significant upregulation, which was further validated by quantitative polymerase chain reaction and immunohistochemical analysis. Further analysis revealed that CASP3 expression level was negatively correlated with the rats' spatial working memory performance, as indicated by the Y-maze test. The level of cleaved-poly (ADP-ribose) polymerase (PARP), a substrate of caspase-3, was also increased in the hippocampus of experimental adult rats. Thus, the present study revealed that upregulation of caspase-3/cleaved-PARP may be involved in long-term cognitive impairment caused by sevoflurane exposure in infants, which may be useful for the clinical prevention of cognitive impairment.

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“…There are some limitations to the present study. First, the concentration of sevoflurane was 1.9%, ing that rat pups exposed to anesthetics exhibit impaired acquisition of learned memory in adulthood (10,12,23). Here we find that the rats exposed to sevoflurane showed a high percentage of freezing in the contextual fear conditioning test during 4 min.…”

Section: Discussionmentioning

confidence: 63%

“…The first report shows that anesthetics administered to mice on postnatal day (PND) 7 increased neuronal apoptosis throughout the brain and induced working memory disorders in adulthood (10). A subsequent study found that 3% sevoflurane administered to mice at PND 6 for 6 h induced apoptosis in the hippocampus and prefrontal cortex and caused hippocampus-dependent and -independent neurocognitive deficits (23). The spurt of development of the rat nervous system during postnatal week (PNW) 2 corresponds to that between prenatal week 27 and 2 years after birth in humans (1,4,19,22).…”

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confidence: 99%

<b>Influence of neonatal sevoflurane exposure on nerve development-related microRNAs and behavior of </b><b>rats </b>

et al. 2015

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Commonly used anesthetics adversely affect the developing brain, but the mechanisms remain unknown. We previously showed that the expressions of microRNAs (miRNAs) in major organs are affected by anesthetics. Therefore, we used TaqMan low-density array (TLDA) to analyze gene expression in the hippocampus of neonatal rats exposed to sevoflurane and performed behavioral tests after they reached adulthood to evaluate cognitive and memory function. Rat male pups at postnatal day 7 were exposed to 1.9% sevoflurane for 3 h, and the hippocampus-miRNA expression profile on postnatal day 8 was determined. Open field and fear conditioning tests conducted during postnatal weeks 7 and 8 indicated that sevoflurane-exposed rats, but not controls, exhibited anxiety-like disorders. TLDA analysis identified 20 differentially expressed miRNAs, which were not shared between postnatally and maturely sevoflurane-exposed rats. The level of rno-miR-632, which targets brain-derived neurotrophic factor and calcium channel, voltage-dependent, alpha 2/delta subunit 2, increased by 10-fold, indicating that exposure to sevoflurane during early neural development alters hippocampus-miRNA expression and may induce subsequent behavioral disorders.

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Neonatal Exposure to Sevoflurane Induces Abnormal Social Behaviors and Deficits in Fear Conditioning in Mice

Abstract: This study shows that exposure of neonatal mice to inhaled sevoflurane could cause not only learning deficits but also abnormal social behaviors resembling autism spectrum disorder.

Cited by 469 publications

References 31 publications

Early‐life single‐episode sevoflurane exposure impairs social behavior and cognition later in life

Early‐life single‐episode sevoflurane exposure impairs social behavior and cognition later in life

Sevoflurane exposure in postnatal rats induced long-term cognitive impairment through upregulating caspase-3/cleaved-poly (ADP-ribose) polymerase pathway

<b>Influence of neonatal sevoflurane exposure on nerve development-related microRNAs and behavior of </b><b>rats </b>

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