Abstract
BackgroundMajor 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.MethodsWe 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.ResultsWe 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.ConclusionsAltogether these data demonstrate the critical role of IL-10 in promoting learning and memory after learned helplessness.
Highlights
Depression is a prevalent and debilitating disease that affects ~ 17% of the US population [27] and represents an important economic burden [9]
Microglia are activated after learned helplessness Because stress induces microglial activation [61], we first tested if microglial cells were activated after the induction of learned helplessness
Iba1+ microglial cells in the dentate gyrus displayed an amoeboid morphology as exemplified by a bigger soma area, in mice subjected to the learned helplessness paradigm, whether they exhibited learned helplessness or not, compared to non-shocked mice that had microglia that exhibited a more quiescent, ramified phenotype (Fig. 1 c–e, g)
Summary
Depression is a prevalent and debilitating disease that affects ~ 17% of the US population [27] and represents an important economic burden [9]. Pro-inflammatory cytokines promote depressive-like behaviors in mice [16, 46]. Anti-inflammatory cytokines, such as interleukin (IL)-10, alleviate deleterious effects of cytokines on memory and plasticity [35, 48], blocking for example the detrimental effects of lipopolysaccharide (LPS) or IL-1β on long-term potentiation (LTP) [26, 35, 42], and rescuing learning and memory deficits in inflammation-dependent models of Alzheimer’s disease [25, 29, 30]. 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
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