Objective Diabetic cognitive dysfunction (DCD), usually accompanied with chronically elevated glucocorticoids and hippocampal astrocytic alterations, is one of the most serious complications in patients with type 1 diabetes.However, the role for chronically elevated glucocorticoids and hippocampal astrocytic activations in DCD remains to be elucidated, and it is not clear whether astrocytic N-myc downstream-regulated gene 2 (NDRG2, involved in cell differentiation and development) is participated in DCD.The present study is to explore the potential role of elevated glucocorticoids, astrocytes and NDRG2 for DCD.Methods Three months after streptozotocin (STZ)-induced type 1 diabetes onset, rats received 9-day administration of glucocorticoids receptor (GR) antagonist, RU486, at doses of 10, 25 or 40 mg/kg.The cognitive function was detected by Morris water maze, serum corticosterone was investigated by radio immuno assay, and the alterations of glial fibrillary acidic protein (GFAP, a key indicator of astrocytic reactivity) and NDRG2 in hippocampus were revealed by immunohistochemistry staining, real-time PCR and Western blot.Results Three months after diabetes onset: (1) Diabetic rats develop remarkable cognitive impairments and elevated serum corticosterone level; (2) Diabetic rats show significant down-regulation of GFAP and NDRG2 in hippocampus; (3) Nine-day administration with RU486 at dose of 25 mg/kg ameliorates DCD and reverses the expression of hippocampal GFAP and NDRG2 simultaneously.Conclusion Glucocorticoids-GR system is crucial for DCD, astrocytic reactivity and NDRG2 are involved in these processes.