Enriched environment alleviates NLRP3 inflammasome mediated neuroinflammation in diabetes complicated with depression rats

Depression is a serious and common complication of diabetes, with a well-established link between the two conditions. Recent studies indicate that activation of the NLRP3 inflammasome in hippocampal microglia plays a key role in the pathogenesis of diabetes complicated with depression (DD). While environmental enrichment (EE) has demonstrated significant anti-neuroinflammatory effects, its potential to alleviate neuroinflammation specifically induced by DD remains unclear. The DD rat model was established using a combination of a high-fat diet, streptozotocin injection, and chronic unpredictable mild stress. The effects of EE on NLRP3 inflammasome activation in the hippocampal microglia of DD rats were examined through a series of behavioral tests (open field test, forced swim test, and elevated plus maze), along with enzyme-linked immunosorbent assays, hematoxylin and eosin staining, TdT-mediated dUTP nick-end labeling staining, Western blot analysis, and immunofluorescence. Compared to the control group, DD rats exhibited impaired glucose metabolism and increased depressive-like behaviors, alongside hippocampal neuronal damage and elevated apoptosis rates. Activation of the NLRP3 inflammasome in hippocampal microglia was observed, with upregulation of the NLRP3 signaling pathway and inhibition of the PI3K/AKT signaling pathway. EE significantly mitigated these effects, reducing hippocampal neuroinflammation and alleviating depressive behaviors in DD rats. Neuroinflammation in the hippocampus is a key mechanism underlying the pathogenesis of DD. This study demonstrated that EE reduces neuroinflammation, likely by inhibiting the activation of the NLRP3 inflammasome in hippocampal microglia.