Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice
Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice
复制标题
新生儿七氟醚暴露通过破坏小鼠内侧前额叶皮层的兴奋性神经元诱导冲动行为缺陷
DOI：
10.1038/s41398-020-00884-5
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发表时间：
2020-06-20
影响因子：
6.8
通讯作者：
Hu, Zhiyong
中科院分区：
文献类型：
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作者：
Xie, Linghua;Liu, Yue;Hu, Zhiyong
据报告，七氟烷（尤其是多次暴露）可导致神经发育异常，包括注意力缺陷/多动障碍（ADHD）。本研究旨在探讨在新生期重复暴露七氟烷后成年小鼠的ADHD样冲动性。在存在或不存在3%七氟烷的情况下，将6天大的幼崽暴露于60%氧气中2小时，并连续三天每天给药一次。在第8周进行悬崖回避反应（CAR）以评估冲动性。我们的研究结果表明，重复七氟烷治疗增加了跳跃的次数，缩短了跳跃潜伏期在CAR测试。采用免疫组化法检测内侧前额叶皮质（mPFC）c-Fos和钙调素依赖性蛋白激酶IIα（CaMK II α）的表达。我们发现，mPFC神经元，特别是兴奋性神经元，高度激活，并与冲动行为有关。注射激活病毒（AAV-CaMKIIα-hM 3Dq），观察特异性激活mPFC兴奋性神经元对氯氮平-N-氧化物（clozapine-N-oxide，CNO）刺激下大鼠冲动行为的影响。同样地，在七氟烷组中注射抑制性病毒（AAV-CaMKIIα-hM 4Di）以探索mPFC兴奋性神经元抑制是否降低冲动性。我们的研究结果表明，化学激活的mPFC兴奋性神经元诱导冲动行为，而抑制mPFC兴奋性神经元部分挽救了赤字。这些结果表明，在关键时间重复七氟烷暴露诱导冲动行为伴随着过度激活的mPFC兴奋性神经元在成年阶段。这项工作可能进一步扩展到了解ADHD样冲动行为的麻醉神经毒性。
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. 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. 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 deficit. 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.