Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Department of Biology, University of Miami, Coral Gables, FL 33146, USA.
Brain Behav Immun. 2018 Mar;69:556-567. doi: 10.1016/j.bbi.2018.02.003. Epub 2018 Feb 13.
Recovery from major depressive disorder is difficult, particularly in patients who are refractory to antidepressant treatments. To examine factors that regulate recovery, we developed a prolonged learned helplessness depression model in mice. After the induction of learned helplessness, mice were separated into groups that recovered or did not recover within 4 weeks. Comparisons were made between groups in hippocampal proteins, inflammatory cytokines, and blood brain barrier (BBB) permeability. Compared with mice that recovered and control mice, non-recovered mice displaying prolonged learned helplessness had greater hippocampal activation of glycogen synthase kinase-3 (GSK3), higher levels of tumor necrosis factor-α (TNFα), interleukin-17A, and interleukin-23, increased permeability of the blood brain barrier (BBB), and lower levels of the BBB tight junction proteins occludin, ZO1, and claudin-5. Treatment with the GSK3 inhibitor TDZD-8 reduced inflammatory cytokine levels, increased tight junction protein levels, and reversed impaired recovery from learned helplessness, demonstrating that prolonged learned helplessness is reversible and is maintained by abnormally active GSK3. In non-recovered mice with prolonged learned helpless, stimulation of sphingosine 1-phosphate receptors by Fingolimod or administration of the TNFα inhibitor etanercept repaired the BBB and reversed impaired recovery from prolonged learned helplessness. Thus, disrupted BBB integrity mediated in part by TNFα contributes to blocking recovery from prolonged learned helplessness depression-like behavior. Overall, this report describes a new model of prolonged depression-like behavior and demonstrates that stress-induced GSK3 activation contributes to disruption of BBB integrity mediated by inflammation, particularly TNFα, which contributes to impaired recovery from prolonged learned helplessness.
从重度抑郁症中恢复是困难的，尤其是在对抗抑郁治疗有抗药性的患者中。为了研究调节恢复的因素，我们在小鼠中建立了一个延长的习得性无助抑郁模型。在习得性无助的诱导后，将小鼠分为在 4 周内恢复或未恢复的组。在海马蛋白、炎性细胞因子和血脑屏障（BBB）通透性方面对两组进行比较。与恢复的小鼠和对照小鼠相比，表现出延长的习得性无助的未恢复小鼠的海马糖原合酶激酶-3（GSK3）活性更高，肿瘤坏死因子-α（TNFα）、白细胞介素-17A 和白细胞介素-23 水平更高，血脑屏障（BBB）通透性增加，BBB 紧密连接蛋白 occludin、ZO1 和 claudin-5 水平降低。用 GSK3 抑制剂 TDZD-8 治疗可降低炎性细胞因子水平，增加紧密连接蛋白水平，并逆转习得性无助的恢复受损，表明延长的习得性无助是可逆转的，并且由异常活跃的 GSK3 维持。在有延长的习得性无助的未恢复小鼠中，鞘氨醇 1-磷酸受体的刺激用 fingolimod 或 TNFα 抑制剂依那西普治疗可修复 BBB 并逆转习得性无助延长后的恢复受损。因此，部分由 TNFα 介导的 BBB 完整性破坏导致阻断了从延长的习得性无助性抑郁样行为中恢复。总的来说，本报告描述了一种新的延长抑郁样行为模型，并表明应激诱导的 GSK3 激活导致炎症介导的 BBB 完整性破坏，特别是 TNFα，这导致了从延长的习得性无助中恢复受损。
