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Updated: Jul 28, 2025
A Chronic Immobilization Stress Protocol for Inducing Depression-Like Behavior in Mice
Published on: May 15, 2019
Intranasal administration of lipopolysaccharide reverses chronic stress-induced depression-like behavior in mice by
Chao Huang1, Ting Ye1, Bingran Chen1
1Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu Province, China.
Abstract:
We recently reported that intraperitoneal injection of a low dose of lipopolysaccharide (LPS) reversed depression-like behavior in mice induced by chronic stress by stimulating microglia in the hippocampus. In this study, we found that a single intranasal administration of LPS at a dose of 5 or 10 μg/mouse, but not at a dose of 1 μg/mouse, rapidly reversed depression-like behavior in mice stimulated with chronic unpredictable stress (CUS). In the time-dependent experiment, a single intranasal administration of LPS (10 μg/mouse) reversed CUS-induced depression-like behavior in mice 5 and 8 h but not 3 h after drug administration. The antidepressant effect of a single intranasal LPS administration (10 μg/mouse) lasted at least 10 days and disappeared 14 days after administration. Fourteen days after the first intranasal LPS administration, a second intranasal LPS administration (10 μg/mouse) still reversed the increased immobility time in TST and FST and the decreased sucrose uptake in SPT in CUS mice, which again exhibited depression-like behaviors 5 h after LPS administration. The antidepressant effect of intranasal LPS administration was dependent on microglial activation, because inhibition of microglia by pretreatment with minocycline (40 mg/kg) or depletion of microglia by pretreatment with PLX3397 (290 mg/kg) prevented the antidepressant effect of intranasal LPS administration in CUS mice. These results suggest that stimulation of the microglia-mediated innate immune response by intranasal administration of LPS can produce rapid and sustained antidepressant effects in animals under chronic stress conditions.
Insights
Intranasal lipopolysaccharide (LPS) rapidly reverses depression-like behaviors in mice by activating microglia. This effect is sustained for at least 10 days and relies on microglial activation for its antidepressant properties.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Chronic stress induces depression-like behaviors in mice.
- Microglia activation in the hippocampus has been shown to reverse these behaviors.
- Lipopolysaccharide (LPS) is a potent immune stimulator.
Purpose of the Study:
- To investigate the antidepressant effects of intranasal LPS administration in a mouse model of chronic stress.
- To determine the optimal dose, timing, and duration of LPS's antidepressant effects.
- To elucidate the role of microglial activation in mediating LPS's antidepressant action.
Main Methods:
- Mice subjected to chronic unpredictable stress (CUS) were administered varying doses of LPS intranasally.
- Behavioral tests (forced swim test, tail suspension test, sucrose uptake test) were used to assess depression-like behaviors.
- Microglial activity was modulated using minocycline and PLX3397 to assess its impact on LPS's effects.
Main Results:
- A single intranasal LPS dose of 5 or 10 μg/mouse rapidly reversed CUS-induced depression-like behaviors.
- The antidepressant effect was observed 5 and 8 hours post-administration and lasted at least 10 days.
- Inhibition or depletion of microglia abolished the antidepressant effect of intranasal LPS.
Conclusions:
- Intranasal LPS administration provides a rapid and sustained antidepressant effect in a mouse model of chronic stress.
- Microglial activation is essential for the observed antidepressant effects of intranasal LPS.
- This study highlights the potential of targeting the innate immune response via intranasal delivery for depression treatment.
