Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Gautier Building room 415, 1011 NW 15th Street, Miami, FL, 33136, USA.
Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Gautier Building room, 4151011 NW 15th Street, Miami, FL, 33136, USA.
J Neuroinflammation. 2020 Aug 22;17(1):246. doi: 10.1186/s12974-020-01922-1.
Major depressive disorder is a widespread mood disorder. One of the most debilitating symptoms patients often experience is cognitive impairment. Recent findings suggest that inflammation is associated with depression and impaired cognition. Pro-inflammatory cytokines are elevated in the blood of depressed patients and impair learning and memory processes, suggesting that an anti-inflammatory approach might be beneficial for both depression and cognition.
We subjected mice to the learned helplessness paradigm and evaluated novel object recognition and spatial memory. Mice were treated with IL-10 intranasally or/and microglia cells were depleted using PLX5622. Statistical differences were tested using ANOVA or t tests.
We first established a mouse model of depression in which learning and memory are impaired. We found that learned helplessness (LH) impairs novel object recognition (NOR) and spatial working memory. LH mice also exhibit reduced hippocampal dendritic spine density and increased microglial activation compared to non-shocked (NS) mice or mice that were subjected to the learned helpless paradigm but did not exhibit learned helplessness (non-learned helpless or NLH). These effects are mediated by microglia, as treatment with PLX5622, which depletes microglia, restores learning and memory and hippocampal dendritic spine density in LH mice. However, PLX5622 also impairs learning and memory and reduces hippocampal dendritic spine density in NLH mice, suggesting that microglia in NLH mice produce molecules that promote learning and memory. We found that microglial interleukin (IL)-10 levels are reduced in LH mice, and IL-10 administration is sufficient to restore NOR, spatial working memory, and hippocampal dendritic spine density in LH mice, and in NLH mice treated with PLX5622 consistent with a pro-cognitive role for IL-10.
Altogether these data demonstrate the critical role of IL-10 in promoting learning and memory after learned helplessness.
重度抑郁症是一种广泛存在的情绪障碍。患者经常经历的最具致残性的症状之一是认知障碍。最近的研究结果表明，炎症与抑郁症和认知障碍有关。抑郁患者血液中的促炎细胞因子升高，并损害学习和记忆过程，这表明抗炎方法可能对抑郁症和认知都有益。
我们让小鼠经历习得性无助范式，并评估新物体识别和空间记忆。我们通过鼻内给予 IL-10 或/和使用 PLX5622 耗尽小胶质细胞来处理小鼠。使用 ANOVA 或 t 检验来测试统计差异。
我们首先建立了一种学习和记忆受损的小鼠抑郁症模型。我们发现习得性无助（LH）会损害新物体识别（NOR）和空间工作记忆。与未受电击（NS）的小鼠或经历过习得性无助但未表现出习得性无助的小鼠（非习得性无助或 NLH）相比，LH 小鼠的海马树突棘密度降低，小胶质细胞激活增加。这些效应是由小胶质细胞介导的，因为用 PLX5622 处理，耗尽小胶质细胞，可以恢复 LH 小鼠的学习和记忆以及海马树突棘密度。然而，PLX5622 也会损害 NLH 小鼠的学习和记忆，并降低其海马树突棘密度，这表明 NLH 小鼠中的小胶质细胞产生了促进学习和记忆的分子。我们发现 LH 小鼠中的小胶质细胞白细胞介素（IL）-10 水平降低，给予 IL-10 足以恢复 LH 小鼠的 NOR、空间工作记忆和海马树突棘密度，以及 NLH 小鼠中用 PLX5622 处理后的 NOR、空间工作记忆和海马树突棘密度，表明 IL-10 具有促进认知的作用。
总之，这些数据表明 IL-10 在习得性无助后促进学习和记忆方面发挥了关键作用。
