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The hippocampus is a key brain area for learning and memory and is one of the regions that is most sensitive to diabetes. However, the pathogenesis of diabetic neuronal lesion is not yet completely understood. We focused on the association of microglia activation and brain lesions in diabetes. In this\u00a0study, we investigated whether and how signal transducer and activator of transcription 3 (STAT3) activation in microglia affects neuronal lesions in diabetic brains. Using a streptozotocin\u2010induced type 1 DM model, we showed enhanced hippocampal neuronal apoptosis that was associated with increased STAT3 activation. We found that hyperglycemia increased the expression of inflammatory cytokines such as interferon\u2010\u03b3 (IFN\u2010\u03b3) and interleukin\u20106, in the diabetic hippocampus. In particular, IFN\u2010\u03b3 induced autocrine activation of microglia, and STAT3 activation is important for this process. We also demonstrated that STAT3 activation in microglia increased tumor necrosis factor\u2010\u03b1\u00a0(TNF\u2010\u03b1) expression; subsequently, TNF\u2010\u03b1 increased neuronal apoptosis by increasing reactive oxygen species (ROS) levels in the neuronal cells. We also took advantage of mice lacking STAT3 in microglia and demonstrated that depletion of microglial STAT3 reduced neuronal apoptosis in the diabetic hippocampus. Taken together, these results suggest that STAT3 activation in microglia plays an important role in hyperglycemia\u2010induced neuronal apoptosis in the diabetic hippocampus and provide a potential therapeutic benefit of STAT3 inhibition in microglia for preventing diabetic neuronal lesions.<\/jats:p>","DOI":"10.1002\/jcp.30373","type":"journal-article","created":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T07:32:21Z","timestamp":1616484741000},"page":"7058-7070","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["STAT3 activation in microglia exacerbates hippocampal neuronal apoptosis in diabetic brains"],"prefix":"10.1002","volume":"236","author":[{"given":"Jang\u2010Hyuk","family":"Yun","sequence":"first","affiliation":[{"name":"Department of Veterinary Pharmacology, College of Veterinary Medicine and Institute of Veterinary Science Kangwon National University  Gangwondo Republic of 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