Voluntary wheel running in male mice mitigates select hyperglycemia-induced depressive-like behaviors and modulates BDNF and Tnf in a brain region-specific manner.

Diabetes is associated with an increased risk for depression. Emerging data suggests this effect is partly mediated by hyperglycemia-associated neuroinflammation and decreased BDNF. While exercise reduces depressive symptoms in other models of depression, limited research has investigated the efficacy of voluntary exercise for hyperglycemia-induced depression. Thus, we examined whether chronic voluntary exercise could rescue hyperglycemia-related affective dysfunction, reduce neuroinflammation, and increase BDNF levels in male C57BL/6J mice. Hyperglycemia was induced via administration of 50 mg/kg/day streptozotocin (STZ) over 5 consecutive days. Four weeks post-STZ, mice in the exercise group were provided running wheels in their home cage for approximately 7 weeks. As anticipated, STZ induced depressive-like behavior. Exercise attenuated behavioral deficits in the forced swim and splash test and increased BDNF expression within the brain. However, other depressive-like behaviors (i.e., open field activity, nest building, marble burying, and fear conditioning) and cerebellar Tnf expression failed to respond to exercise. This study provides novel evidence that a subset of hyperglycemia-induced depressive-like behaviors are responsive to voluntary exercise while others remain exercise-resistant. This emphasizes the potential benefit of exercise as a part of a multimodal treatment strategy for hyperglycemia-related depression.