A comparison of affective and neuroinflammatory changes in response to unpredictable chronic mild stress and hyperglycemia in male and female mice.


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Diabetes mellitus is a metabolic disorder that affects nearly half a billion people globally. Major Depressive Disorder has twice the prevalence rate in this population. Despite the higher rates of depression among women, most preclinical research in this area has utilized male mice due to their increased susceptibility to developing hyperglycemia. Within this document, two studies were conducted to examine hyperglycemia-induced depressive- and anxiety-like behavior in both male and female C57BL/6J mice, as well as the interaction between hyperglycemia- and stress-induced behavioral changes. I hypothesized that for males, streptozotocin (STZ)-induced hyperglycemia and unpredictable chronic mild stress (UCMS) would independently induce anxiety and depressive-like behaviors, and that they would act additively to exacerbate affective symptoms. I expected similar results in females, but previous literature indicates that female responses would likely be blunted. For males, STZ-induced hyperglycemia was associated with increased depressive-like behavior, increased hippocampal Bdnf and Tnf expression, and elevations in frontal cortex Il1b expression. Our chronic stress protocol produced alterations in anxiety-like behavior and decreased frontal cortex Il1b expression. For females, hyperglycemia was associated affective dysregulation, as observed in forced swim, open field exploration, and marble burying. UCMS did not lead to affective dysregulation on its own. However, it appeared to be the driving factor facilitating the hyperglycemia-associated changes, particularly in the forced swim task. Hyperglycemia-induced neuroinflammation was observed with increased hippocampal Tnf expression. Frontal cortex neuroinflammation only indicated trending effects. Marginal hyperglycemia by stress interactions were noted, such that STZ heightened Tnf and Il1b expression while UCMS drove it back down. Overall, for both sexes the data indicate that stress and hyperglycemia induce different symptom profiles via distinct mechanisms allowing them to exert additive effects, such that UCMS increases the susceptibility to developing affective dysregulation and neuroinflammation.