Abstract: Objective To investigate the role of microRNA-134 (miR-134) and cyclic AMP response element binding protein (CREB) in the pathogenesis of post-operative cognitive dysfunction in aged mice. Methods Sixty-eight aged male C57BL/6 mice were randomly divided into four groups: control group (con, underwent sham surgery), isoflurane group (iso, treated by 1.8% isoflurane inhalation anesthesia for 1.5 h), surgery group (sur, underwent abdominal surgery under local anesthesia) and isoflurane+surgery group (iso+sur, underwent abdominal surgery under local anesthesia plus 1.8% isoflurane inhalation anesthesia for 1.5 h). Mice were then sent to Morris Water Maze behavioral test to access their cognition status postoperatively. On day 1, day 3 and day 7 after operation, their hippocampus samples were dissected and sent to detect the expression level of p-ser133-CREB, CREB, brain derived neurotrophic factor (BDNF), postsynaptic density 95 (PSD95) by western blot assay, and relative level of miR-134 by qRTPCR. Results Compared with the control group, mice in surgery group had longer latency time (P＜ 0.05), spent less time in target quadrant (P＜ 0.01) and less frequencies to cross platform (P＜ 0.05). Compared with the surgery group, mice in isoflurane+surgerygroup had shorter latency time (P＜ 0.05), and spent longer time in target quadrant (P＜ 0.05). Compared with the control group, higher level of miR-134, lower ratio of p-CREB/CREB, decreased expression of CREB, BDNF and PSD95 were found in the hippocampus of mice in surgery group (P＜ 0.05，respectively). Whereas compared with the surgery group, lower relative level of miR-134, higher ratio of p-CREB/CREB, increased expression of CREB, BDNF and PSD95 were found in the hippocampus of mice in isoflurane+surgery group (P＜ 0.05，respectively). Conclusion Abdominal surgery can induce early postoperative learning and memory impairment in aged mice. The possible mechanism is that surgery induces the increase of miR-134 expression which inhibits CREB activity, thus leads to the impairment of synaptic plasticity, and eventually causes learning and memory dysfunction. Isoflurane inhalation anesthesia can attenuate this impairment.