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Updated: Jun 30, 2025
Animal Models of Depression - Chronic Despair Model CDM
Published on: September 23, 2021
Polarization to M1-type microglia in the hippocampus is involved in depression-like behavior in a mouse model of
Kohei Takahashi1, Minoru Tsuji1, Osamu Nakagawasai2
1Department of Pharmacology, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Ohtawara, Tochigi, 324-8501, Japan.
Abstract:
Impaired olfactory function may be associated with the development of psychiatric disorders such as depression and anxiety; however, knowledge on the mechanisms underlying psychiatric disorders is incomplete. A reversible model of olfactory dysfunction, zinc sulfate (ZnSO4) nasal-treated mice, exhibit depression-like behavior accompanying olfactory dysfunction. Therefore, we investigated olfactory function and depression-like behaviors in ZnSO4-treated mice using the buried food finding test and tail suspension test, respectively; investigated the changes in the hippocampal microglial activity and neurogenesis in the dentate gyrus by immunohistochemistry; and evaluated the inflammation and microglial polarity related-proteins in the hippocampus using western blot study. On day 14 after treatment, ZnSO4-treated mice showed depression-like behavior in the tail suspension test and recovery of the olfactory function in the buried food finding test. In the hippocampus of ZnSO4-treated mice, expression levels of ionized calcium-binding adapter molecule 1 (Iba1), cluster of differentiation 40, inducible nitric oxide synthase, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, cleaved caspase-3, as well as the number of Iba1-positive cells and cell body size increased, and arginase-1 expression and neurogenesis decreased. Except for the increased IL-6, these changes were prevented by a microglia activation inhibitor, minocycline. The findings suggest that neuroinflammation due to polarization of M1-type hippocampal microglia is involved in depression accompanied with olfactory dysfunction.
Insights
Zinc sulfate-induced olfactory dysfunction in mice led to depression-like behaviors and hippocampal neuroinflammation. Minocycline treatment reversed these effects, suggesting M1 microglia polarization contributes to depression with olfactory dysfunction.
Area of Science:
- Neuroscience
- Psychiatry
- Immunology
Background:
- Impaired olfactory function is linked to psychiatric disorders like depression and anxiety.
- Mechanisms underlying psychiatric disorders, particularly those involving olfactory dysfunction, remain incompletely understood.
- Zinc sulfate (ZnSO4) nasal treatment provides a reversible model for studying olfactory dysfunction and associated behaviors.
Purpose of the Study:
- To investigate the relationship between olfactory dysfunction and depression-like behaviors in a mouse model.
- To examine changes in hippocampal microglial activity, neurogenesis, and neuroinflammation.
- To evaluate the role of M1-type microglia polarization in depression associated with olfactory dysfunction.
Main Methods:
- Zinc sulfate (ZnSO4) nasal treatment in mice to induce olfactory dysfunction.
- Behavioral tests: buried food finding test (olfactory function) and tail suspension test (depression-like behavior).
- Immunohistochemistry and Western blot analysis of hippocampal tissue to assess microglial activity, neurogenesis, inflammation, and related proteins.
Main Results:
- ZnSO4-treated mice exhibited depression-like behavior and olfactory dysfunction, which recovered by day 14.
- Increased hippocampal expression of markers for microglial activation (Iba1), M1-type polarization (CD40, iNOS, IL-1β, TNF-α), and apoptosis (cleaved caspase-3).
- Decreased neurogenesis and arginase-1 expression in the hippocampus of ZnSO4-treated mice; these changes were largely reversed by minocycline.
Conclusions:
- Neuroinflammation, driven by the polarization of M1-type hippocampal microglia, plays a significant role in depression accompanied by olfactory dysfunction.
- Minocycline, a microglia activation inhibitor, demonstrated a protective effect, highlighting the therapeutic potential of targeting neuroinflammation.
- This study provides mechanistic insights into the link between olfactory deficits and depression, suggesting novel therapeutic targets.
