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The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice
Published on: October 24, 2018
miR-29a-5p rescues depressive-like behaviors in a CUMS-induced mouse model by facilitating microglia M2-polarization
Jing-Cheng Yang1, Jun Zhao1, Yi-Huan Chen2
1Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Air Force Medical University, Xi'an 710038, Shaanxi Province, China.
Background:
Depression accounts for a high proportion of neuropsychiatric disorders and is associated with abnormal states of neurons in specific brain regions. Microglia play a pivotal role in the inflammatory state during depression development; however, the exact mechanism underlying chronic mood states remains unknown. Thus, the present study aimed to determine whether microRNAs (miRNAs) alleviate stress-induced depression-like behavior in mice by regulating the expression levels of their target genes, explore the role of neuroinflammation induced by microglial activation in the pathogenesis and progression of depression, and determine whether the role of the miR-29a-5p/transmembrane protein 33 (TMEM33) axis.
Methods:
In this study, chronic unpredictable mild stress (CUMS) mouse depression model, various behavioral tests, western blotting, dual-luciferase reporter assay, enzyme-linked immunosorbent assay, real-time quantitative reverse transcription PCR, immunofluorescence and lentivirus-mediated gene transfer were used.
Results:
After exposure to the CUMS paradigm, miR-29a-5p was significantly down-regulated. This downregulation subsequently promoted the polarization of microglia M1 by upregulating the expression of TMEM33, resulting in enhanced inflammatory chemokines affecting neurons. Conversely, the upregulation of miR-29a-5p within the prefrontal cortex (PFC) suppressed TMEM33 expression, facilitated microglia M2-polarization, and ameliorated depressive-like behavior.
Limitations:
Only rodent models of depression were used, and human samples were not included.
Conclusions:
The results of this study suggest that miR-29a-5p deficits within the PFC mediate microglial anomalies and contribute to depressive-like behaviors. miR-29a-5p and TMEM33 may, therefore, serve as potential therapeutic targets for the treatment of depression.
Insights
MicroRNA-29a-5p deficits in the prefrontal cortex worsen depression by activating microglia via TMEM33. Restoring miR-29a-5p alleviates depression-like behaviors in mice.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Depression is a major neuropsychiatric disorder linked to neuronal dysfunction.
- Microglia are implicated in depression's neuroinflammatory processes, but mechanisms remain unclear.
- The role of microRNAs and the miR-29a-5p/TMEM33 axis in depression requires elucidation.
Purpose of the Study:
- Investigate if microRNAs alleviate stress-induced depression-like behavior in mice.
- Explore microglial activation and neuroinflammation in depression pathogenesis.
- Determine the function of the miR-29a-5p/transmembrane protein 33 (TMEM33) axis in depression.
Main Methods:
- Utilized a chronic unpredictable mild stress (CUMS) mouse model.
- Employed behavioral tests, western blotting, and molecular assays (luciferase, ELISA, qPCR).
- Used immunofluorescence and lentivirus-mediated gene transfer for mechanistic studies.
Main Results:
- CUMS exposure downregulated miR-29a-5p, increasing TMEM33 and M1 microglia polarization.
- This led to enhanced inflammatory chemokines impacting neurons.
- Upregulating miR-29a-5p in the prefrontal cortex suppressed TMEM33, promoted M2 microglia, and reduced depression-like behavior.
Conclusions:
- miR-29a-5p deficiency in the prefrontal cortex drives microglial dysfunction and depression-like behaviors.
- The miR-29a-5p/TMEM33 pathway is crucial in depression pathogenesis.
- miR-29a-5p and TMEM33 represent potential therapeutic targets for depression.
