七氟烷暴露可通过破坏新生小鼠前额叶内侧皮质兴奋性神经元导致冲动性行为缺陷

背景：七氟烷暴露，特别是多次接触，已被报道会导致神经发育异常，包括注意力缺陷/多动障碍（ADHD）。本研究旨在探讨成年小鼠在新生儿期反复暴露于七氟烷后的ADHD样冲动。

方法：我们将6日龄的幼鼠暴露于含或不含3%七氟烷的60%氧气环境中2h，每天一次，连续3天。为评估冲动性，在第8周进行悬崖躲避反应（CAR）。

结果：研究结果显示，在CAR测试中，反复暴露于七氟烷增加了跳跃次数，缩短了跳跃潜伏期。收集皮质组织进行免疫染色，检测内侧前额皮质(mPFC)中c-Fos和钙调蛋白依赖性蛋白激酶II (CaMKII)的表达。我们发现mPFC神经元，特别是兴奋性神经元，高度激活并与冲动行为相关。通过注射活化病毒(AAV-CaMKIIα-hM3Dq)，观察氯氮平- N -氧化物(CNO)对mPFC兴奋性神经元特异性激活对冲动行为的影响。同样，我们在七氟烷组注射抑制性病毒(AAV-CaMKIIα-hM4Di)，以探讨mPFC兴奋性神经元抑制是否降低了冲动性。我们的结果显示，化学遗传激活mPFC兴奋性神经元可诱导冲动行为，而抑制mPFC兴奋性神经元则部分缓解了这一缺陷。

结论：这些结果表明，在成长阶段的关键时期反复暴露于七氟烷在会诱发冲动行为，并伴有mPFC兴奋性神经元的过度激活。这项研究可进一步扩展至理解ADHD类麻醉神经毒性的冲动行为。

文献来源：Xie L, Liu Y, Hu Y, et al. Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice.[J].Transl Psychiatry. 2020 Jun 20;10(1):202. doi: 10.1038/s41398-020-00884-5.

Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice

Abstract

Background：Sevoflurane, in particular multiple exposures, has been reported to cause the abnormal neurological development including attention-deficit/hyperactivity disorder (ADHD). This study is to investigate ADHD-like impulsivity in adult mice after repeated sevoflurane exposures at the neonatal stage.

Method：Six-day-old pups were exposed to 60% oxygen in the presence or absence of 3% sevoflurane for 2 h and the treatment was administrated once daily for three consecutive days. To assess the impulsivity, the cliff avoidance reaction (CAR) was carried out at the 8th week.

Result：Our results showed that repeated sevoflurane treatment increased the number of jumps and shortened the jumping latency in the CAR test. The cortices were harvested for immunostaining to detect c-Fos and calmodulin-dependent protein kinase IIα (CaMKIIα) expression in the medial prefrontal cortex (mPFC). We found that mPFC neurons, especially excitatory neurons, were highly activated and related to impulsive behavior. The activation viruses (AAV-CaMKIIα-hM3Dq) were injected to evaluate the effects of specific activation of mPFC excitatory neurons on impulsive behavior in the presence of clozapine-N-oxide (CNO). Likewise, the inhibitory viruses (AAV-CaMKIIα-hM4Di) were injected in the sevoflurane group to explore whether the mPFC excitatory neuronal inhibition reduced the impulsivity. Our results revealed that chemogenetic activation of mPFC excitatory neurons induced impulsive behavior whereas inhibition of mPFC excitatory neurons partially rescued the defificit.

Conclusion：These results indicate that repeated sevoflurane exposures at the critical time induce impulsive behavior accompanied with overactivation of mPFC excitatory neurons in adult stages. This work may further extend to understand the ADHD-like impulsive behavior of the anesthetic neurotoxicity.