丰富环境对新生小鼠七氟醚多次麻醉后认知功能障碍相关的细胞改变的逆转作用

There are more and more humane epidemic investigations indicating that the risk of develpoing a learning and memory disability was sinificantly increased for pediatrics exposed to multiple exposures of surgery and anesthesia. Animal studies confirmed there were induced apoptosis in brain，inhibition of neurogenesis and learning deficit after anesthetic exposure as neonates.The underlying mechanism of anesthesia induced learning and memory impairment in developing brain was still a mistery. Some treatment strategy should be found to reverse degeneration of central neural system after anesthesia exposures.The structure and function of brain ungergoes a dynamic course of being mature since born and environment enrichment playes an important role in brain plasticity.We have testified that enriched environment could attenuate anesthesia-induced learning and memory impairment in neonatal mice in our preliminary work. Based on the findings in our preliminary work, we will focus on: 1.Whether enriched environment would attenuate neuro-apoptosis and promote hippocampal neurogenesis.2. Whether enriched environment would influnce axonal and dendritic development of pyramidal cells in CA1. 3.Whether enriched environment would influence hippocampal synapses plasticity. Through the research, on the one hand,we are trying to confirm the mechnism of of environmental enrichment on learning and learning ability on molecular as well as cellular level. On the other hand,we are tying to provide theoretically based strategy to prevent potential learning and memory disability caused by anesthetics in pediatrics.

越来越多的人类流行病学调查显示婴幼儿期多次手术和麻醉暴露是学习记忆能力受损的重要因素。动物实验研究证实麻醉药导致新生动物神经细胞凋亡增加、神经再生受抑和成年期认知功能障碍。然而，目前麻醉药导致学习记忆功能损害的机制尚不明了。如何积极有效地治疗麻醉药导致的中枢退行性变成为关注的焦点。出生后脑的结构功能经历一个不断发育和成熟过程，丰富环境（Environmental Enrichment, EE）在脑的可塑性中扮演重要角色。本课题组前期工作证实了丰富环境可以逆转新生小鼠三次七氟醚麻醉后成年期学习记忆功能受损。本课题拟完成：1.观察EE对海马齿状回神经细胞凋亡、神经细胞再生的影响；2.观察CA1区锥体细胞轴突、树突发育情况；3.检测EE对海马突触可塑性的影响。通过上述研究，力图阐明EE改善新生小鼠多次麻醉后成年期学习记忆能力受损的作用机制,为婴幼儿麻醉后潜在的学习记忆能力受损的防治提供理论基础。

项目背景：麻醉药对发育脑的神经毒作用与暴露时间窗、暴露次数和暴露时间有关。普遍认为孕早晚期和出生后2-3岁是人类对麻醉药易感时间窗。临床调查和动物研究证实发育脑多次麻醉暴露会导致成年期学习和记忆功能损害，主要细胞学变化包括：凋亡增加，中枢炎症介质增加，神经元增殖受抑，突触发育受损等。我们以往的研究证实新生鼠七氟醚多次暴露导致中枢神经元凋亡增加、炎症介质释放增加和成年期认知功能损害。但是丰富环境可以改善七氟醚麻醉小鼠的认知功能损害，所以我们拟研究丰富环境改善七氟醚相关脑毒作用的机制。.主要内容:1）观察丰富环境对七氟醚麻醉后新生小鼠的中枢细胞学改变；2）丰富环境改善七氟醚中枢毒作用的潜在信号通路如过氧化物酶体增生物激活受体γ（PPAR-γ)；3）探索麻醉药中枢毒作用的其他机制如对胚胎干细胞和听觉神经系统的影响。.研究结果和关键数据 1）丰富环境可能通过 PPAR-γ途径改善七氟醚麻醉小鼠的神经再生和认知功能。相关文章已发表；2）孕早期异氟醚暴露可损害胚胎干细胞自我修复功能，视磺酸受体是异氟醚作用靶点。而抗氧化剂维生素A 可以改善异氟醚对胚胎干细胞的损害作用。相关文章已发表；3) 母鼠孕晚期七氟醚暴露可导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。七氟醚损害听力的潜在机制以及听力损害和认知功能之间的关系正在研究中。项目负责人就这一研究方向获得了国家自然基金委面上项目资助。.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。首先，脑发育关键期也是听觉系统发育的关键期。我们已发现母鼠孕晚期七氟醚暴露可导致仔鼠听力损害和认知功能损害。我们拟进一步确认听力损害和认知功能之间的因果关系，从而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。其次，丰富环境是否通过增强感知功能（如听力）来改善认知功能也是潜在的研究方向。