Supplementary Material for: Chronic Stress Exacerbates Hyperglycemia-Induced Affective Symptoms in Male Mice

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 that 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, increase 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.引言：在慢性病患者群体中，情感障碍仍存在诊断不足与治疗不充分的问题。糖尿病与情感障碍（尤其是抑郁与焦虑）之间存在高度共病现象。应激诱导的情感失调的潜在机制，很可能与糖尿病诱导的情感失调机制存在差异。直接对比应激与高血糖诱导的情感失调，可为明确与这两类不同病症相关的抑郁/焦虑的特异性机制靶点提供研究思路。 方法：为此，本研究以雄性C57BL/6J小鼠为实验对象，对比两种造模方式的独立与联合行为学及神经炎症效应：（1）慢性不可预知温和应激模型；（2）药物诱导高血糖模型。 结果：链脲佐菌素诱导的高血糖与一系列反映抑郁神经植物症状的行为改变相关，具体包括：旷场活动减少、理毛行为减少、强迫游泳实验中不动时间增加以及埋珠行为减少；同时伴随海马体脑源性神经营养因子 (Bdnf) 与肿瘤坏死因子 (Tnf) 表达上调，以及前额叶皮层白细胞介素1β (Il1b) 表达升高。本研究采用的慢性应激造模方案可引发类焦虑行为改变，并使前额叶皮层白细胞介素1β (Il1b) 表达降低。 讨论：尽管慢性应激与高血糖联合造模仅产生有限的叠加效应，但二者联合可加重整体症状负担。总体而言，本研究数据表明，应激与高血糖通过不同的机制诱导出各异的症状表型。