Fluoxetine Rescues Excessive Myelin Formation and Psychological Behaviors in a Murine PTSD Model

Background

Post-traumatic stress disorder (PTSD) is a complex mental disorder characterized by spontaneous intrusions of traumatic memories, avoidance of trauma-related stimuli, negative emotions and cognitions, and hyperarousal. Although existing first-line treatments have shown some effectiveness in reducing PTSD symptoms, a large number of patients still have significant residual symptoms, indicating that the pathogenesis of PTSD needs further elucidation. Recent studies suggest that newly formed myelin can affect neural circuit function and participate in the preservation of fear memories. However, the role of these myelin sheaths in PTSD remains unclear.

Paper Source

This study was conducted by Chen Ruiyin, Luo Kefei, Zhu Xinyue, Zheng Ronghang, Wang Yu, Yu Guangdan, Wang Xiaorui, She Fei, Chen Xiaoying, Li Tao, Chen Jingfei, Bianbaduo Jie, Su Yixun, and Niu Jianqin, from institutions including the Third Military Medical University of China, General Hospital of the People’s Liberation Army, Astronaut Research and Training Center, and Xinqiao Hospital. The paper was published in Neuroscience Bulletin in 2024.

Experimental Procedures

Research Subjects and Model Establishment

Male C57BL/6 mice were used in the experiment. These mice were placed in perforated plastic tubes for 2 hours daily for 14 consecutive days to establish the PTSD mouse model. Behavioral tests were conducted at 24 hours and 30 days to assess PTSD-related neuropsychiatric disorders.

Behavioral Tests

These included contextual fear conditioning test, forced swim test, elevated plus maze test, open field test, and tail suspension test. These tests aimed to validate the effectiveness of the PTSD mouse model and evaluate the therapeutic effects of different drugs (fluoxetine, risperidone, and sertraline) on model mice.

Myelin Abnormality Assessment

Immunohistochemistry and electron microscopy techniques were used to analyze mouse brain sections, focusing on PTSD-related brain regions (posterior parietal cortex and hippocampus).

Drug Treatment

Model mice were given fluoxetine, risperidone, and sertraline daily via oral gavage to assess the effects of each drug on neuropsychiatric behaviors and myelin abnormalities.

Data Statistics and Analysis

Data were statistically analyzed using GraphPad Prism software, with unpaired T-tests or one-way/two-way analysis of variance (ANOVA) used to compare group differences.

Experimental Results

Behavioral Abnormalities

PTSD model mice showed increased freezing behavior in the remote contextual fear conditioning test, increased immobility time in the forced swim test, and decreased time in open arms in the elevated plus maze test, all indicating significant abnormalities in traumatic memory intrusion, depressive symptoms, and anxiety symptoms.

Myelin Abnormalities

In the posterior parietal cortex and hippocampal CA3 region, model mice showed significantly increased myelin with reduced myelin thickness, exhibiting characteristics of newly formed myelin.

Therapeutic Effect of Fluoxetine

Fluoxetine significantly reduced abnormal behaviors in PTSD mice during behavioral tests and restored myelin abnormalities, while risperidone and sertraline did not show significant effects.

Fluoxetine’s Effect on OPC Differentiation

Fluoxetine directly inhibited the differentiation of oligodendrocyte precursor cells (OPCs) by upregulating the Wnt signaling pathway, reducing excessive myelin formation.

Conclusions and Significance

This study demonstrates for the first time that PTSD is closely associated with myelin abnormalities and suggests that the oligodendrocyte lineage may be a new target for PTSD treatment. Fluoxetine improved neuropsychiatric disorders in PTSD by inhibiting OPC differentiation and myelin formation, providing new ideas and strategies for PTSD treatment.

Research Highlights

1. New Discovery: First revealed PTSD-related myelin abnormalities and elucidated the mechanism by which fluoxetine intervenes in OPC differentiation through the Wnt signaling pathway.
2. Pathological Mechanism: Provided an important link between PTSD symptoms and myelin formation, offering a new perspective for understanding the pathological mechanism of PTSD.
3. Therapeutic Target: Proposed the oligodendrocyte lineage as a new target for PTSD treatment, with significant potential for clinical application.

Other Valuable Information

• Data Support: Detailed behavioral test results and myelin ultrastructure analysis ensure the reliability of research conclusions.
• Methodological Innovation: Used multiple behavioral tests and immunohistochemistry techniques, combined with electron microscopy, to comprehensively assess the neuropsychiatric performance and myelin status of PTSD mice.
• Future Directions: Suggests further research on the effects of other antidepressants on myelin formation to provide broader evidence for clinical treatment.

Summary

This study systematically explored the relationship between PTSD and myelin abnormalities, revealing the mechanism by which fluoxetine regulates neural circuits and behavior through the Wnt signaling pathway, providing new therapeutic ideas and potential targets. The research results not only deepen the understanding of PTSD’s pathological mechanism but also provide important references for developing more effective treatment methods.