Abstract
Inflammation plays an important role in the pathogenesis of depression; however, the underlying mechanisms remain unclear. Apart from the disordered circadian rhythm in animal models and patients with depression, dysfunction of clock genes has been reported to be involved with the progress of inflammation. This study aimed to investigate the role of circadian clock genes, especially brain and muscle ARNT-like 1 (Bmal1), in the linkage between inflammation and depression. Lipopolysaccharide (LPS)-challenged rats and BV2 cells were used in the present study. Four intraperitoneal LPS injections of 0.5 mg/kg were administered once every other day to the rats, and BV2 cells were challenged with LPS for 24 h at the working concentration of 1 mg/L, with or without the suppression of Bmal1 via small interfering RNA. The results showed that LPS could successfully induce depression-like behaviors and an “inflammatory storm” in rats, as indicated by the increased immobility time in the forced swimming test and the decreased saccharin preference index in the saccharin preference test, together with hyperactivity of the hypothalamic–pituitary–adrenal axis, hyperactivation of astrocyte and microglia, and increased peripheral and central abundance of tumor necrosis factor-α, interleukin 6, and C-reactive protein. Moreover, the protein expression levels of brain-derived neurotrophic factor, triggering receptor expressed on myeloid cells 1, Copine6, and Synaptotagmin1 (Syt-1) decreased in the hippocampus and hypothalamus, whereas the expression of triggering receptor expressed on myeloid cells 2 increased. Interestingly, the fluctuation of temperature and serum concentration of melatonin and corticosterone was significantly different between the groups. Furthermore, protein expression levels of the circadian locomotor output cycles kaput, cryptochrome 2, and period 2 was significantly reduced in the hippocampus of LPS-challenged rats, whereas Bmal1 expression was significantly increased in the hippocampus but decreased in the hypothalamus, where it was co-located with neurons, microglia, and astrocytes. Consistently, apart from the reduced cell viability and increased phagocytic ability, LPS-challenged BV2 cells presented a similar trend with the changed protein expression in the hippocampus of the LPS model rats. However, the pathological changes in BV2 cells induced by LPS were reversed after the suppression of Bmal1. These results indicated that LPS could induce depression-like pathological changes, and the underlying mechanism might be partly associated with the imbalanced expression of Bmal1 and its regulated dysfunction of the circadian rhythm.
Graphical Abstract
Conclusions In conclusion, our results indicated that LPS could induce depression-like behaviors and an “inflammatory storm” in vivo, activate microglia in vitro, together with a disruption of synaptic plasticity and circadian rhythm. This mechanism may be involved in the imbalanced expression of Bmal1. Our results can help uncover a novel clock-immunological mechanism of neuroinflammation-induced depression and shed light on the development of new effective pharmacotherapies for depression
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Data Availability
Data will be made available on request.
Abbreviations
- LPS :
-
Lipopolysaccharide
- SD :
-
Sprague–Dawley
- OFT :
-
Open field test
- EPM :
-
Elevated plus maze test
- Y-maze :
-
Y maze test
- FST :
-
Forced swimming test
- SPT :
-
Saccharin preference test
- Real-time RT-PCR :
-
Real-time reverse transcription-polymerase chain
- IL-6 :
-
Interleukin 6
- TNF-α :
-
Tumor necrosis factor-α
- CRP :
-
C-reactive protein
- HPA :
-
Hypothalamic-pituitary-adrenal
- Syt-1 :
-
Synaptotagmin-1
- siRNA :
-
Small interfering RNA
- IF :
-
Immunofluorescence staining
- NMDAR :
-
N-methyl-d-aspartate receptor
- BDNF :
-
Brain-derived neurotrophic factor
- CNS :
-
Central nervous system
- STZ :
-
Streptozotocin
- TREMs :
-
Triggering receptors expressed on myeloid cells
- SCN :
-
Suprachiasmatic nucleus
- MAP2:
-
Microtubule association protein 2
- IBA-1 :
-
Ionized calcium binding adaptor molecule-1
- GFAP :
-
Glial fibrillary acidic protein
- NeuN :
-
Neuron-specific nucleoprotein
- PBS :
-
Phosphate-buffered saline
- RIPA :
-
Radioimmunoprecipitation assay
- CUMS :
-
Chronic unpredictable mild stress
- HE :
-
Hematoxylin and eosin
- CORT :
-
Corticosterone
- AD :
-
Alzheimer's disease
- STZ :
-
Streptozotocin
- SDS-PAGE :
-
Sodium salt -polyacrylamide gel electrophoresis
- NAc :
-
Nucleus accumbens
- TREM2 :
-
Triggering receptor expressed on myeloid cells 2
- TREM1 :
-
Triggering receptor expressed on myeloid cells 1
- Clock :
-
Circadian locomotor output cycles kaput
- Cry2 :
-
Cryptochrome 2
- Per2 :
-
Period 2
- Bmal1 :
-
Muscle ARNT-like 1
- PVN :
-
Paraventricular nucleus of hypothalamus
- CCK8 :
-
Cell Counting Kit-8
- TLR4 :
-
Toll-like receptor 4
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Funding
This study was provided by the National Natural Science Foundation of China (81870403), Key Research and Development Program of Anhui Province (202004j07020001), Foundation for the Top Talents in University of Anhui Province (gxbjZD2022013), Scientific Research Promotion Plan of Anhui Medical University (2022xkjT009), "Early Contact Research" training program for colleges by School of Pharmacy (2021-YXYZQKY-08), Auhui Medical University (2021-ZQKY-48), and Anhui Province Postgraduate Education Quality Project (2022cxcysj074).
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This study was designed by Qing-Rong Xia and Jin-Fang Ge. Dan-Dan Xu and Zhi-Qi Hou conducted most of the experiments, analyzed the data and wrote the manuscript. Ye-Jun Gao conceived the study and revised the manuscript, Ya-Yun Xu, Jun Liang and Qing-Rong Xia modified the pictures. Ye-Jun Gao, Chen Zhang, Fan Guo, and Dan-Dan Huang assisted in the experiments. All authors read and approved the final manuscript.
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The animal study was reviewed and approved by the Animal Experimentation Ethics Committee of Anhui Medical University (Animal Ethics No.: LLSC20221100).
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Highlights
• Four times intraperitoneal injection of LPS every other day could induce depression-like behaviors in rats and “inflammatory storm”.
• Microglial and its associated neuroinflammation were activated in LPS-challenged rats.
• Bmal1, a rhythmic gene, linking inflammation and depression.
Supplementary Information
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11481_2024_10103_MOESM1_ESM.tif
Supplementary Fig. S1 Effect of LPS injection on the temporal correlation between the production of inflammatory storm and depression-like behavior. A, Correlation between the immobility time in FST and the serum concentrations of TNF-α after the first intraperitoneal injection of LPS; B, Correlation between the immobility time in FST and the serum concentrations of TNF-α after the second intraperitoneal injection of LPS; C, Correlation between the immobility time in FST and the serum concentrations of TNF-α after the third intraperitoneal injection of LPS; D, Correlation between the immobility time in FST and the serum concentrations of TNF-α after the fourth intraperitoneal injection of LPS; E, Correlation between the immobility time in FST and the serum concentrations of IL-6 after the first intraperitoneal injection of LPS; F, Correlation between the immobility time in FST and the serum concentrations of IL-6 after the second intraperitoneal injection of LPS; G, Correlation between the immobility time in FST and the serum concentrations of IL-6 after the third intraperitoneal injection of LPS; H, Correlation between the immobility time in FST and the serum concentrations of IL-6 after the fourth intraperitoneal injection of LPS; I, Correlation between the immobility time in FST and the serum concentrations of CRP after the first intraperitoneal injection of LPS; J, Correlation between the immobility time in FST and the serum concentrations of CRP after the second intraperitoneal injection of LPS; K, Correlation between the immobility time in FST and the serum concentrations of CRP after the third intraperitoneal injection of LPS; L, Correlation between the immobility time in FST and the serum concentrations of CRP after the fourth intraperitoneal injection of LPS. With 8 rats in control group and 12 rats in the model group (TIF 2390 KB)
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Xu, DD., Hou, ZQ., Xu, YY. et al. Potential Role of Bmal1 in Lipopolysaccharide-Induced Depression-Like Behavior and its Associated "Inflammatory Storm". J Neuroimmune Pharmacol 19, 4 (2024). https://doi.org/10.1007/s11481-024-10103-3
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DOI: https://doi.org/10.1007/s11481-024-10103-3