铝影响认知功能，但机制尚未阐明。L—LTP与长时记忆密切相关。我们前期工作提示，铝损害大鼠长时空间记忆，首次提出海马CA1区L—LTP维持受损是其电生理基础，而后进一步阐明铝干扰cAMP—cPKA—pCREB信号通路是其损害L—LTP维持的关键机制。CREB是长时记忆形成的分子开关。铝对记忆的损害可能与抑制CREB靶基因表达有关。基因表达受多种因素影响，表遗传学模式在调控基因表达和记忆形成中发挥重要作用。MAPK/ERKs信号通路激活程度不仅影响CREB活化状态，而且与表遗传学调控水平密切相关。铝可能通过抑制MAPK/ERKs信号通路尤其阻碍MSK1/2和RSK功能，干扰表遗传学调控模式和CREB活化，抑制CREB靶基因转录而损害长时记忆。本研究拟采用整体动物与离体脑片结合的方法，从表遗传学调控模式、相关信号通路活化程度等不同层面和角度验证上述假设，为寻找有效干预的分子靶点提供依据。

Aluminum (Al) can impact cognitive function. However, the mechanism underlying these adverse effects is not clear. Late phase long—term potentiation(L—LTP) is closely related to long—term memory(LTM).Our previous work has revealed that Al impairs LTM via the impairment of L—LTP maintenance in CA1 area of hippocampus, which is the electrophysiological basis. And then, we further elucidate the key mechanism for L—LTP maintaining damage is the interference of Al by inhibiting cAMP—cPKA—pCREB signaling. CREB is a molecular switch of LTM formation. The memory damage caused by Al may be related to inhibiting the expression of CREB target genes. Gene expression is affected by many factors, epigenetic patterns play an important role in the regulation of gene expression and memory formation. The activation degree of MAPK/ERKs signaling pathways affects not only the activation status of CREB, but also the level of epigenetic regulation. Al may damage LTM with the interference to the pattern of epigenetic regulation, CREB activation, and then restraining the normal transcription of CREB target genes by inhibiting MAPK/ERKs signaling pathway, especially MSK1/2 and RSK. The purpose of this study is to validate the hypothesis mentioned above from the aspect of epigenetic regulation mode, active state of related signaling pathway by experiments in vivo and in vitro. The results of this study will provide scientific basis for searching the molecular target points of effective intervention.