孤养与束缚应激致脑缺血小鼠抑郁样行为的性别差异

目的研究孤养与束缚应激对小鼠脑缺血损伤后抑郁样行为的影响及性别差异。方法将2～3月龄C57BL/6j雌、雄小鼠随机分为正常对照组（Ctrl组）、脑缺血再灌注组（IR组）以及脑缺血再灌注加孤养与束缚组（IRS组）。通过线栓法阻塞小鼠右侧大脑中动脉,制备局灶性脑缺血再灌注损伤模型;孤养小鼠每天给予2 h束缚,连续刺激4周。期间,每周记录小鼠的体重变化。4周后,通过检测小鼠的糖水偏爱率和行为学（旷场测试和强迫游泳实验）,比较小鼠的抑郁样行为;此外,检测小鼠外周血血清中的肿瘤坏死因子-α、白细胞介素-1β以及皮质酮和促肾上腺皮质激素水平。结果与Ctrl组相比,刺激1周后,IRS组雌、雄小鼠体重均显著减轻（P<0.05）,雌性小鼠的体重至刺激4周后仍显著减轻。与Ctrl组和IR组相比,IRS组雌、雄小鼠在刺激4周后均出现糖水偏爱率的显著降低;在旷场试验中,仅雌性小鼠表现为在活动中心区域的距离减少、停留时间缩短、穿梭次数减少及运动速度增快,而雄性小鼠无显著变化;强迫游泳试验中,仅雌性小鼠的不动时间显著延长,而雄性小鼠变化不显著。与Ctrl组相比,IR组和IRS组雄性小鼠外周血清中炎症因子肿瘤坏死因子-α和白细胞介素-1β均显著升高,而雌性小鼠无显著变化。此外,与Ctrl组和IR组相比,IRS组雄性小鼠仅外周血清中皮质酮显著增高,而雌性小鼠皮质酮和促肾上腺皮质激素均显著增高。结论连续4周的孤养与束缚应激致脑缺血小鼠发生抑郁样行为,并且雌性小鼠更加易感;炎症和下丘脑-垂体-肾上腺轴的反应差异参与性别差异的调节。

Differences in depression-like behaviors of mice with cerebral ischemia-induced by isolated housing and restraint stresses between genders

Objective To study the sex-different influence of isolated housing and restraint stresses on depression-like behaviors in mice with cerebral ischemia. Methods In this study, two-three months female and male C57BL/6j mice were randomly divided into 3 groups, the control group (Group Ctrl), cerebral ischemia and reperfusion group (Group IR), and cerebral ischemia and reperfusion plus isolation and restraint stresses group (Group IRS). The focal cerebral ischemia and reperfusion model was established by occluding the right middle cerebral artery. The isolated housing mice were restrained for 2 hours per day for four weeks. During the period, the changes in body weight were weekly recorded. After four-week stresses, their depressive-like behaviors were observed by comparing sucrose preference rate and behavioral tests, including open field test and forced swim test. Furthermore, serum inflammatory cytokines, including tumor necrosis factorα(TNF-α) and interleukin 1β(IL-1β), and hormones including corticosterone (CORT) and adrenocorticotropic hormone (ACTH), were assessed. Results Compared with Group Ctrl, the body weight of both female and male IRS group was significantly reduced after one-week stresses (P<0.05), and the weight of female mice was still significantly reduced after four-week stresses. Compared to Group Ctrl and IR, the sucrose preference rate was significantly reduced in both male and female IRS mice. In the open field test, only Group IRS female mice were significantly reduced in the walking distance, time and entries, and increased in velocity in the center area; but there′s no difference in the males. In the forced swim test, female mice in Group also displayed significant extension of immobility time, but there′s no difference in the males. By comparison with Group Ctrl, both the male mice in Group IR and IRS showed significantly increases in TNF-α and IL-1β, while no significant change was revealed in the females. In addition, compared with Group Ctrl and IR, male mice in Group IRS showed significant increase in CORT in serum, while the female mice in Group IRS showed significant increase in CORT and ACTH. ConclusionsFour-week isolated housing and restraint stresses result in depression-like behaviors in mice with cerebral ischemia, and the females are more susceptible. Moreover, disturbances in inflammation and hypothalamic-pituitary-adrenal axis might contribute to the sex-difference.