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.

据报道，七氟醚，特别是多次接触，会导致神经系统发育异常，包括注意力缺陷/多动障碍 (ADHD)。本研究旨在调查成年小鼠在新生儿期反复接触七氟醚后的 ADHD 样冲动。六天大的幼崽在存在或不存在 3% 七氟醚的情况下暴露于 60% 的氧气中 2 小时，每天进行一次治疗，连续三天。为了评估冲动性，在第 8 周进行了悬崖回避反应 (CAR)。我们的结果表明，在 CAR 测试中，重复七氟醚治疗增加了跳跃次数并缩短了跳跃潜伏期。收获皮质进行免疫染色，以检测内侧前额叶皮层 (mPFC) 中 c-Fos 和钙调蛋白依赖性蛋白激酶 IIα (CaMKIIα) 的表达。我们发现 mPFC 神经元，尤其是兴奋性神经元，被高度激活并与冲动行为有关。注射激活病毒 (AAV-CaMKIIα-hM3Dq) 以评估在氯氮平-N-氧化物 (CNO) 存在下 mPFC 兴奋性神经元的特异性激活对冲动行为的影响。同样，将抑制性病毒（AAV-CaMKIIα-hM4Di）注射到七氟醚组，以探索 mPFC 兴奋性神经元抑制是否降低了冲动性。我们的研究结果表明，mPFC 兴奋性神经元的化学遗传学激活诱导冲动行为，而 mPFC 兴奋性神经元的抑制部分挽救了这种缺陷。这些结果表明，在关键时间重复暴露于七氟醚会诱发冲动行为，并伴有成人阶段 mPFC 兴奋性神经元的过度激活。这项工作可能会进一步扩展以了解麻醉神经毒性的 ADHD 样冲动行为。