Abstract: Objective To explore the effect of hippocampal microglia activation in neuropathic pain-induced cognitive dysfunction.Methods A neuropathic pain model of mice was established using the spared nerve injury(SNI) model. A total of 36 male C57BL/6 mice were randomly divided into three groups(n=12): a sham-operated(Sham) group, a model(SNI) group and a minocycline(SNI+mino) group. The SNI+mino group was orally administered with minocycline(40 mg/kg) for consecutive 21 days after surgery, while the Sham group and the SNI group were given the same dose of drinking water instead. Then, their mechanical withdrawal threshold was detected one day before surgery and at postoperative 7, 14 and 21 d. Locomotor activity was measured by the open field test, while cognitive function was evaluated by the Y maze test and novel object recognition test at postoperative 21 d. The expression of microglia marker Iba-1, phagocytic activity marker CD68 and synaptic marker PSD95 in hippocampal CA1 region were detected by immunofluorescence staining. The density of dendritic spines of pyramidal neurons in hippocampal CA1 region was detected by Golgi staining.Results Compared with those at one day before operation, no statistical difference was found in mechanical withdrawal threshold between the Sham group and the SNI+mino group at postoperative 7, 14 and 21 d(P>0.05), but remarkable decreases in mechanical withdrawal threshold were see in the SNI group at postoperative 7, 14 and 21 d(P<0.01). Compared with the Sham group, the SNI group showed decreased mechanical withdrawal thresholds at postoperative 7, 14 and 21 d(P<0.01), with a reduced spontaneous alternation rate in the Y maze test(P<0.05) and decreased discrimination index in the novel object recognition test(P<0.05). Compared with the SNI group, the SNI+mino group presented increased mechanical withdrawal thresholds at postoperative 7, 14 and 21 d(P<0.01), with an increased spontaneous alternation rate in the Y maze test(P<0.05) and increased discrimination index in the novel object recognition test(P<0.05). Compared with the Sham group, the number of Iba-1⁺ cells(P<0.05), the area of CD68 in Iba-1⁺ cells(P<0.05), and the engulfment percentage of PSD95 by microglia(P<0.05) increased and the density of pyramidal dendritic spines(P<0.01) decreased in the hippocampal CA1 region of the SNI group. Compared with the SNI group, the number of Iba-1⁺ cells(P<0.05), the area of CD68 in Iba-1⁺ cells(P<0.05), and the engulfment of PSD95 by microglia(P<0.05) decreased and the density of pyramidal dendritic spines(P<0.01) increased in the hippocampal CA1 region in the SNI+mino group.Conclusions Neuropathic pain can activate microglia in the hippocampal CA1 region of mice, increasing synapse engulfment, and eventually lead to cognitive dysfunction, which can be reversed by minocycline.