新生期接种乙肝疫苗(hepatitis B vaccine,HBV)影响小鼠情绪相关行为及其机制研究

Would neonatal administration of hepatitis B vaccine (HBV) induce autism? Many epidemiological data suggest that neonatal HBV vaccination increases the risk of autism in children, but there is yet no direct experimental evidence. This study will explore such potential influence and its mechanism using mice model of autism (set by imitating maternal infection during pregnancy) as well as normal mice. Significant findings has been obtained by the preliminary study. Neonatal hepatitis B vaccination aggravated the autism-like behavior in mice model and impaired many physical indexes (hippocampal LTP, the levels of neurogenesis and neurotrophins in the hippocampi) in the brain in mice model without significant effect on the autism-like behavior in normal mice. These findings suggest that the risk of autism may be increased by vaccinating the neonates with HBV whose mothers suffered infection during pregnancy. Now, the formal study aims to further investigate such influence and its mechanism by using a combine of the behavior, electrophysiology, histomorphology and molecular biology techniques. We hope to find experimental evidence for the association between neonatal HBV vaccination and autism and find out potential mechanism, whereby basing the further clinical study.

新生儿接种乙肝疫苗（hepatitis B vaccine, HBV）可否诱发自闭症？多数流行病学调查表明新生儿接种HBV增加患自闭症风险，但未见提供确凿实验证据的报道。本项目拟采用自闭症模型小鼠（孕期模拟感染诱发子代自闭症样行为）及正常小鼠，观察新生期接种HBV是否诱发或加重小鼠自闭、焦虑及抑郁样行为，并探索其影响机制。..预实验已发现：新生期接种HBV加重了自闭症小鼠模型的自闭及抑郁样行为，并损害模型鼠多种神经生理指标，如海马LTP、神经发生和神经营养因子表达等；但新生期接种HBV对正常小鼠的行为未见显著影响。提示遭受母体孕期感染的新生儿接种HBV有诱发自闭症的风险。..现欲开展正式研究，综合运用行为学、电生理学、形态学、分子生物学等多种实验技术，深入探索新生期接种HBV对小鼠情绪相关行为的影响特征及机制，获得新生期接种HBV与自闭症发病关系的实验证据，并为进一步临床研究提供实验依据。

新生儿接种乙肝疫苗（hepatitisBvaccine,HBV）可否诱发自闭症？多数流行病学调查表明新生儿接种HBV增加患自闭症风险，但未见提供确凿实验证据的报道。在第一部分研究中，我们采用自闭症模型小鼠（孕期模拟感染诱发子代自闭症样行为），首先证实了新生期接种HBV加重孕期模拟感染诱发的子代小鼠自闭症样行为，并使得孕期模拟感染诱发子代自闭症样行为表现为持久性表型。此后进行了第二部分研究，根据HBV接种后诱导的主要细胞因子是IL-4，且IL-4水平与小鼠的行为学损害呈正相关趋势，因此对新生期接种HBV后小鼠脑内IL-4及其受体的变化进行了深入研究。结果表明，新生期接种HBV后小鼠早期IL-4升高反应引发的脑内IL-4R表达下调是介导脑组织迟发性神经炎症与行为学损害的关键机制。IL-4R下游的分子通路改变涉及STAT6与NF-κB。以上研究结果提供了新生期接种HBV与自闭症发病关系的实验证据，揭示了相应分子机制，为进一步临床研究提供明确的基础实验依据。.此外，本项目经费也有部分用于本人所在课题组的其它课题，参与资助了另外两篇科研论著的发表，分别揭示了：1）孕期口服益生菌减轻母鼠免疫激活诱导的子代小鼠自闭症样行为；2）工诱导脑膜淋巴管增殖有助于老年性痴呆模型小鼠脑内可溶性Aβ的清除。这两项研究均为进一步临床应用研究提供重要的基础实验依据。

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