母鼠孕晚期七氟醚麻醉对仔鼠听力及认知功能的损害作用

Integrated sensory function forms the necessity for normal cognitive function, hearing loss always companies with cognitive impairment. We have testified that there were learning and memory disability, as well as hearing loss, in offspring mice after sevoflurane exposure as pregnant C57 bl/6 mice in its third gestation trimester (G15). Human epidemic investigations and animal studies have confirmed the toxic effect of anesthesia agent exposure on developing brain. However, the underlying mechanism of anesthesia induced learning and memory impairment in developing brain was still a mistery. They key window of brain development is also applicable for the auditory nervous system. Thus, we speculate that the impaired hearing function, at least, partly involved in anesthesia induced learning and memory function disability. We will focus on: 1. To set up the animal model that anesthesia exposure as developing brain leads to learning and memory impairment, as well as hearing loss in C57bl/6 mice.2. We aim to observe the expression of inflammation factors, oxidation and mitochondrial function, neural apoptosis, growth of neurite of neuron, and development of synapse in the central and peripheral auditory system. The expressions of GABA receptor subunits and NMDA receptors subunits in auditory cortex are also of interest.3. We aim to find out the relation between hearing loss and cognitive dysfunction based on the findings of neurogenesis and synapses development in hippocampus. Through the research, we are trying to confirm that hearing loss is related to anesthesia exposure during brain development and hearing loss is a part of the underlying mechanism that accounts for anesthesia related learning and memory disability.

完整的感知功能是保持正常的认知功能的必要条件，听力损害常伴随认知功能损害。前期研究发现,母鼠孕晚期七氟醚暴露后仔鼠成年期表现为学习记忆功能损害和听力损害。人群调查和动物实验已经证实麻醉药对发育脑的毒作用，但麻醉药导致学习记忆功能损害的具体原因及其作用机制尚不明了。脑发育关键期也是听觉神经系统发育关键期，我们推测麻醉药对听觉神经系统的毒作用参与了麻醉药相关的学习记忆功能损害。本课题拟完成：1,建立母鼠孕晚期七氟醚暴露后仔鼠成年期学习记忆功能损害和听力损害的动物模型；2，从炎症介质、氧化应激和线粒体功能、神经元凋亡和轴突生长、突触发育及听皮层NMDA/GABA受体表达方面观察孕鼠麻醉药暴露对仔鼠中枢和外周听觉神经系统的毒作用；3，根据海马神经再生和突触发育变化探讨听力损害和认知功能损害之间的关系。通过上述研究，力图从听力损害角度阐述发育脑麻醉药暴露致成年期认知功能损害的作用机制。

项目背景：完整的感知功能是保持正常的认知功能的必要条件。前期研究发现,母鼠孕晚期七氟醚暴露后仔鼠成年期表现为学习记忆功能损害和听力损害，但麻醉药导致发育期听觉神经系统损害的机制尚不明了。脑发育关键期也是听觉神经系统发育关键期，故我们拟先阐明七氟醚损害发育期外周听觉神经系统的机制，为从感知功能方面进一步完善发育脑麻醉药暴露致成年期认知功能损害的机制打下基础。.主要内容:1）建立母鼠孕晚期七氟醚暴露后仔鼠成年期听力损害的动物模型；2）从炎症介质、氧化应激和线粒体功能、突触发育方面观察孕鼠麻醉药暴露对仔鼠外周听觉神经系统的毒作用；3）关注喉癌患者术后谵妄的危险因素；4）其他：了解利多卡因对体外肝癌细胞增殖的抑制作用及新型麻醉药艾斯氯胺酮对小鼠听觉脑干反应的影响。.研究结果和关键数据 1）母鼠孕晚期七氟醚暴露可致胎鼠耳蜗炎症介质释放增加，新生鼠耳蜗线粒体肿胀，仔鼠成年期听力损害和认知功能损害。文章已发表。2）母鼠孕晚期七氟醚暴露可导致仔鼠耳蜗突触数量和功能减少及听力损害；耳蜗氧化应激水平增加和自噬功能减退。文章已发表。3)分析喉癌患者术后谵妄的发生率和危险因素(发表病例报导、临床研究、综述各1篇；获医院双优临床项目资助)。4）体外实验研究药利多卡因抑制人肝癌细胞增值的机制。文章已发表。5）艾斯氯胺酮不影响小鼠ABR。文章已投稿。.科学意义：正常的感知功能对于维系正常的认知功能具有重要的意义，感知功能损害的人群多伴有认知功能损害。发育期的神经系统易受外界环境的干扰。我们发现母鼠孕晚期七氟醚暴露可导致仔鼠外周听觉神经系统损害，我们拟进一步从分子水平探讨潜在机制。由于听力损害和认知功能之间的具有密切的关系，通过上述研究一方面找到七氟醚对外周听觉神经系统毒作用的防治靶点，另一方面有助于从感知功能方面进一步完善发育脑麻醉药暴露致成年期认知功能损害的机制。