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A Chronic Immobilization Stress Protocol for Inducing Depression-Like Behavior in Mice
Published on: May 15, 2019
Antidepressive properties of microglial stimulation in a mouse model of depression induced by chronic unpredictable
Zixuan Cai1, Ting Ye1, Xing Xu1
1Department of Pharmacy, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu Province, China.
Abstract:
The decrease of microglia in the hippocampus is a novel mechanism for depression onset. Reversal of this decrease can ameliorate stress-induced depression-like behaviors in rodents. However, the property of this therapeutic strategy remains unclear. We addressed this issue by designing a series of behavioral experiments. Results showed that a single lipopolysaccharide (LPS) injection at the dose of 75 and 100 μg/kg, but not at 30 or 50 μg/kg, produced obvious antidepressant effects in chronic unpredictable stress (CUS) mice at 5 h after the drug administration. In the time-dependent experiment, a single LPS injection (100 μg/kg) ameliorated the CUS-induced depression-like behaviors in mice at 5 and 8 h, but not at 3 h, after the drug administration. The antidepressant effect of a single LPS injection persisted at least 10 days and disappeared at 14 days after the drug administration. 14 days after the first injection, a second LPS injection (100 μg/kg) still produced antidepressant effects in chronically-stressed mice who re-displayed depression-like behaviors at 5 h after the drug administration. The antidepressant effect of LPS appears to be dependent on microglia, as at 5 h after LPS administration (100 μg/kg), the CUS-induced decrease in microglial numbers and Iba-1 mRNA levels in the hippocampus was reversed markedly, and inhibition of microglia by minocycline (40 mg/kg) or PLX33297 (290 mg/kg) prevented the antidepressant effect of LPS in CUS mice. These results indicate that a single LPS injection displays rapid and sustained antidepressant effects in chronically stressed mice likely through stimulating hippocampal microglia.
Insights
A single lipopolysaccharide (LPS) injection rapidly reverses depression-like behaviors in stressed mice by stimulating hippocampal microglia. This effect is sustained for at least 10 days and depends on microglial activation.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Hippocampal microglia decrease is linked to depression onset.
- Reversing microglial decrease may treat stress-induced depression.
- The therapeutic properties of this strategy require further investigation.
Purpose of the Study:
- To investigate the antidepressant effects of lipopolysaccharide (LPS) in chronic unpredictable stress (CUS) mice.
- To determine the optimal dose, timing, and duration of LPS's antidepressant effects.
- To elucidate the role of microglia in mediating LPS's antidepressant action.
Main Methods:
- Administered varying doses of LPS to CUS mice and assessed behavioral changes.
- Evaluated the time course and duration of LPS's antidepressant effects.
- Investigated the impact of microglial inhibition (minocycline, PLX33297) on LPS efficacy.
Main Results:
- LPS (75 and 100 μg/kg) showed antidepressant effects at 5 hours post-injection in CUS mice.
- Antidepressant effects were observed at 5 and 8 hours, but not 3 hours, after LPS administration.
- The antidepressant effect persisted for at least 10 days, with a second LPS dose remaining effective.
- LPS reversed CUS-induced decreases in hippocampal microglia and Iba-1 mRNA.
- Microglial inhibition blocked the antidepressant effect of LPS.
Conclusions:
- Single lipopolysaccharide (LPS) injections demonstrate rapid and sustained antidepressant effects in chronically stressed mice.
- LPS likely exerts its antidepressant effects by stimulating hippocampal microglia.
- This study highlights the potential of targeting microglia for depression treatment.
