Regulation of Mouse Learning and Mood by the Anti-Inflammatory Cytokine Interleukin-10

TL;DR

This study demonstrates that the anti-inflammatory cytokine IL-10 plays a crucial role in restoring learning and memory deficits in a mouse model of depression induced by learned helplessness, highlighting its potential therapeutic value.

Contribution

It reveals that IL-10 administration can reverse cognitive impairments in depressed mice, emphasizing the cytokine's role in mood and learning regulation.

Findings

IL-10 levels are reduced in learned helplessness mice.

IL-10 administration restores memory and hippocampal spine density.

Microglia are involved in cognitive processes and are modulated by IL-10.

Abstract

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. Utilizing the learned helplessness paradigm, we first established a mouse model of depression in which learning and memory are impaired. We found that learned helplessness (LH) impaired novel object recognition (NOR) and spatial working memory. LH mice also exhibited 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 were mediated by microglia, as treatment with PLX5622, which depletes microglia and macrophages, restored learning and memory and hippocampal dendritic spine density in LH mice. However, PLX5622 also impaired learning and memory and reduced hippocampal dendritic spine density in NLH mice, suggesting that microglia in NLH mice are involved in the production of molecules that promote learning and memory. We found that microglial interleukin (IL)-10 levels were reduced in LH mice and IL-10 administration was 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.