Depression is a mental disorder with complex gene-environment interactions. Previous studies have shown that the patients with depressive disorders commonly display dysregulations of biological rhythms such as sleep disturbances, and cortisol secretion, which suggests circadian factors play a crucial role in the etiology of depression. Moreover, there is a growing body of evidence supporting neuroinflammation is an important factor involving the pathology of depression. More interestingly, microglia as the main executor of immune function in the central nervous system rhythmically expresses in flammatory factors and circadian clock genes. However, the effects of potential interactions between rhythmicity and neuroinflammation on depression remain unknown.

To address this issue, a research team led by Prof. LIN Wenjuan from Center for Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences has conducted a study to explore whether Per2, a central clock component of circadian output, plays a role in depression by regulating central immune function using a mouse model of depression induced by neuroinflammation. Ten- to twelve- week-old Per2 homozygous mutant (Per2^Brdm1) male mice and age-matched congenic strains of wild type(WT)C57BL/6J control male mice were used to inject lipopolysaccharide (LPS) intracerebroventricularly in a stereotaxic apparatus with a microsyringe attached to a micro infusion pump, and sterile saline treatments as control group.

The results reveal Per2^Brdm1 mice were resilient to neuroinflammation-induced depressive behavior, as shown in figure 1.

Figure1. The WT mice after LPS treatments significantly increased the depressive behaviors as increase of the time spent in the open arms for the elevated plus maze test, and decrease of the immobility time in forced swim test and tail suspension test, but Per2^Brdm1  mice didn’t show those depressive behaviors

 After repeated central LPS injections, chemokines like MCP-1, MIP-1β, and RANTES increased in WT mice but not in Per2^Brdm1 mice in the hippocampus and media PFC. In addition, intracerebroventricular injection of RANTES resulted in depression-like behavior, and Met-RANTES, a RANTES antagonist, could reverse this behavior induced by LPS treatments, as shown in figure2.

Figure2. Different changes of the chemokines and cytokines between WT and Per2^Brdm1 mice after repeated central LPS treatments

 There is no change of Per2 expression in both WT and Per2^Brdm1 mice, while BMAL1 expression decreased only in LPS-treated Per2^Brdm1 mice after repeated central LPS treatments, suggesting that BMAL1 may mediate the effects of Per2 on depressive behaviors induced by neuroinflammation, as shown in figure3.

Figure3 Changes of clock genes expression induce by repeated central LPS treatment in WT and Per2^Brdm1 mice

Circadian transcription factor BMAL1 could bind to the promoter of Rantes, which may be a potential mechanism underlying the resilience of Per2^Brdm1 mice to neuroinflammation-induced depression-like behaviors, as shown in figure4.

 Figure4. Circadian transcription factor BMAL1 bound to promoter of Rantes.

In conclusion, these results uncover a novel clock-immunological mechanism of neuroinflammation-induced depression and promote our understanding of depression, which may facilitate the development of new therapeutic strategy for inflammation-linked depressive disorders.

This work was supported by the National Natural Science Foundation of China (No.91132728, 31741062); and Key Laboratory of Mental Health, Institute of Psychology,
Chinese Academy of Sciences.

This research is now published in The FASEB Journal：

Chen X, Hu Q, Zhang K, et al. The clock-controlled chemokine contributes to neuroinflammation-induced depression. The FASEB Journal. 2020;00:1–10.

Contact:
Ms.Chen LIU
Institute of Psychology
Email: liuc@psych.ac.cn