Chronic Stress Exacerbates Hyperglycemia-Induced Affective Symptoms in Male Mice

Abstract

Introduction: Among chronically ill populations, affective disorders remain underdiagnosed and undertreated. A high degree of comorbidity exists between diabetes and affective disorders, particularly depression and anxiety. The mechanisms underlying stress-induced affective dysregulation are likely distinct from those induced by diabetes. A direct comparison between stress- and hyperglycemia-induced affective dysregulation could provide insight into distinct mechanistic targets for depression/anxiety associated with these different conditions.

Methods: To this end, the present study used male C57BL/6J mice to compare the independent and combined behavioral and neuroinflammatory effects of two models: (1) unpredictable chronic mild stress and (2) pharmacologically induced hyperglycemia.

Results: Streptozotocin-induced hyperglycemia was associated with a set of behavioral changes reflective of the neurovegetative symptoms of depression (i.e., reduced open field activity, reduced grooming, increased immobility in the forced swim task, and decreased marble burying), 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.

Discussion: While the combination of chronic stress and hyperglycemia produced limited additive effects, their combination exacerbated total symptom burden. Overall, the data indicate that stress and hyperglycemia induce different symptom profiles via distinct mechanisms.

Keywords: Anxiety; Depression; Hyperglycemia; Neuroinflammation; Streptozotocin; Stress.

Fig. 1.

a A timeline of 7 weeks was applied for this study, in which male C57BL/6J were injected with STZ (50 mg/kg/day) for a 5-day period. Starting 3 weeks after induction of diabetes, mice underwent 2 weeks of UCMS. This was followed by behavioral testing and tissue collection. Created with BioRender.com. b Fasting blood glucose was monitored with the hyperglycemic threshold set at 250 mg/dL; all STZ mice exceeded this threshold post-induction. c Body weight was measured consistently throughout the study, and mice with STZ-induced hyperglycemia had consistently lower body weights compared to buffer mice. Data are graphed as means ± SEM; ***p < 0.001 for the main effect of STZ. n = 12–13 mice per group. UCMS, unpredictable chronic mild stress; STZ, streptozotocin; SEM, standard error of the mean.

Fig. 2.

Effect of STZ administration and UCMS protocol on behaviors measuring affective dysregulation. UCMS mice showed shorter latency to exit the dark arena (a) and more transitions between arenas in the LDA task compared to control mice (b). c STZ mice traveled less distance in the open field task compared to buffer mice. d UCMS mice spent less time in the center of the open field compared to control mice. Data are graphed as means ± SEM; *p < 0.05; **p < 0.01. n = 12–13 mice per group. UCMS, unpredictable chronic mild stress; STZ, streptozotocin; LDA, light/dark aversion; SEM, standard error of the mean.

Fig. 3.

Effect of STZ administration and UCMS protocol on behaviors measuring affective dysregulation. STZ mice showed longer latency to first groom (a) and shorter duration spent grooming in the splash test compared to buffer mice (b). c STZ mice spent longer immobile during FST compared to buffer mice. d STZ mice buried less marbles compared to buffer mice, while UCMS mice buried less marbles compared to control mice. Data are graphed as means ± SEM; *p < 0.05; **p < 0.01, ****p < 0.0001; # indicates significantly different from all other groups. n = 6–7 mice per group for the splash test and n = 12–13 mice per group for FST and marble burying. UCMS, unpredictable chronic mild stress; STZ, streptozotocin; FST, forced swim test; SEM, standard error of the mean.

Fig. 4.

Effect of STZ administration and UCMS protocol on mRNA expression in hippocampus and frontal cortex. a STZ increased hippocampal expression of Tnf and Bdnf compared to buffer mice. b STZ increased frontal cortex expression of Il1b compared to buffer mice while UCMS decreased frontal cortex expression of Il1b compared to control mice. Data are graphed as means ± SEM; *p < 0.05. ^#p < 0.05 stress effect. n = 4–7 mice per group. UCMS, unpredictable chronic mild stress; STZ, streptozotocin; SEM, standard error of the mean.