Zhao Ya-Wei, Pan Yu-Qin, Tang Ming-Ming, Lin Wen-Juan
Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
Front Pharmacol. 2018 May 15;9:511. doi: 10.3389/fphar.2018.00511. eCollection 2018.
Increasing evidence has demonstrated that neuroinflammation contributes to the development of depressive-like behaviors, in both animal models and human patients; however, the brain areas and signaling pathways involved are still elusive. Recent studies have suggested novel roles of the habenula in the onset of depression and other psychiatric disorders; however, there is no evidence for whether the habenula has a function in neuroinflammation-induced depression. Using an animal model of depression, which is induced by the repeated central administration of lipopolysaccharide (LPS), we examined whether cytokine expression and p38 signal activation in the habenula were involved in the depressive-like behaviors. Body weight, saccharin preference test, and tail suspension test were used to measure depressive-like behaviors. Immunohistochemistry, quantitative-polymerase chain reaction (q-PCR), and western blot were used to measure the expression of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and the phosphorylation of p38 in the habenula. The results showed that central LPS administration induced depressive-like behaviors, characterized by anhedonia in the saccharin preference test and increased immobility in the tail suspension test. Central LPS administration also significantly increased the p-p38 level in microglial cells and increased TNF-α expression in the habenula. Treatment with fluoxetine, a widely prescribed antidepressant, or SB203580, a p38-specific inhibitor, reversed the depressive-like behaviors, normalized the alterations in p-p38 and TNF-α levels and increased the levels of the anti-inflammatory cytokine IL-10 in the habenula. The present findings suggest that the habenula is involved in the pathophysiology of behavioral depression induced by neuroinflammation, and the p38 pathway may serve as a novel mechanism-based target for the treatment of inflammation-related depression.
越来越多的证据表明，在动物模型和人类患者中，神经炎症都有助于抑郁样行为的发展；然而，所涉及的脑区和信号通路仍不明确。最近的研究表明，缰核在抑郁症和其他精神疾病的发病中具有新的作用；然而，尚无证据表明缰核在神经炎症诱导的抑郁症中是否发挥作用。我们使用一种由反复中枢注射脂多糖（LPS）诱导的抑郁症动物模型，研究缰核中的细胞因子表达和p38信号激活是否与抑郁样行为有关。采用体重、糖精偏好试验和悬尾试验来测量抑郁样行为。采用免疫组织化学、定量聚合酶链反应（q-PCR）和蛋白质免疫印迹法来检测缰核中肿瘤坏死因子-α（TNF-α）、白细胞介素-10（IL-10）的表达以及p38的磷酸化水平。结果显示，中枢注射LPS可诱导抑郁样行为，表现为糖精偏好试验中的快感缺失和悬尾试验中不动时间增加。中枢注射LPS还显著增加了小胶质细胞中的p-p38水平，并增加了缰核中TNF-α的表达。使用广泛处方的抗抑郁药氟西汀或p38特异性抑制剂SB203580进行治疗，可逆转抑郁样行为，使p-p38和TNF-α水平的改变恢复正常，并增加缰核中抗炎细胞因子IL-10的水平。目前的研究结果表明，缰核参与了神经炎症诱导的行为性抑郁的病理生理过程，p38信号通路可能是治疗炎症相关抑郁症的一种基于新机制的靶点。
