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

Abstract

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.

Quantitative Behavioural Phenotyping to Investigate Anaesthesia-Induced Neurobehavioural Impairment

“…This is broadly in keeping with vertebrate findings, although a few groups have demonstrated behavioural change with single-agent exposure alone (e.g. Lin et al 18 ). It is possible that other C. elegans based screening protocols may be more sensitive to single-agent exposure, though this may not necessarily be an advantage if single-agent exposure does not lead to human impairment (as the best current evidence suggests 17 ).…”

“…Different groups have used, variously, open field tests 18 , fear conditioning tests 19 , assorted tests of spatial awareness, learning and memory 20,21 , and tests which were initially developed to assess depressant behaviour such as the forced swimming test 22 . The lack of standardization limits the power of both individual studies and meta-analyses, and in the absence of a generally accepted behavioural phenotype for AIN, it is difficult to be sure whether the constrained set of behaviours exhibited in these experiments can truly reflect the neuropathological deficit.…”

Neonatal anesthesia exposure impacts brain microRNAs and their associated neurodevelopmental processes

“…Neonatal anesthesia has consistently been associated with neuronal damage such as increased apoptosis, impaired dendritic and axonal branching and altered neurogenesis 21 – 25 . Equally consistent is its association with behavioral changes later on in life, including work from our lab and some human studies that showed decreased social interaction, impaired learning and memory and increased anxiety-like behaviors 22 , 26 , 27 . The current study is a direct follow-up that examines the role of miRNAs in neonatal anesthetic neurotoxicity.…”

“…Since GABA A receptors are ubiquitously expressed throughout the brain, we profiled miRNA expression using whole brain samples. In addition, we also examined the hippocampus based on our understanding of its association with neonatal sevo-associated learning and memory deficits, demonstrated previously by the hippocampus specific, active place avoidance task 26 , 31 .…”

“…All experiments were performed in accordance with relevant guidelines and regulations. At postnatal day 7 (P7), male pups from each litter (ranging from 2–6 pups) were randomly assigned to either the sevo or the no sevo (control) treatment group, while the female pups remained with the dam, as described in our previously established protocol 26 . During a 2-hour treatment period, pups from the sevo group were separated from the dam and exposed to 2.4% sevo in a 40% oxygen (O 2 ) 60% nitrogen (N 2 ) gas mixture (GTS-WELCO, Newark Distribution).…”