Research Report on FMOD Alleviating Depressive Behavior After Traumatic Brain Injury

Traumatic Brain Injury (TBI) is a global health issue with far-reaching impacts, causing not only brain dysfunction but also often leading to mental disorders. One of the most common mental illnesses following TBI is depression, affecting approximately 25-50% of TBI patients. This type of depression significantly impacts an individual’s quality of life and may even result in lifelong disability. Recent studies have suggested that Fibromodulin (FMOD) may play a crucial regulatory role after TBI, but its relationship with post-TBI depression and potential mechanisms remain unclear.

This article explores the role of FMOD in post-TBI depression and its potential mechanisms. The study assessed depressive symptoms in TBI patients using the Self-Rating Depression Scale (SDS) and found that reduced FMOD levels were associated with TBI-related depression. Subsequently, the protective effects of FMOD were verified in mice and primary neuronal cells, revealing potential mechanisms through the PI3K/AKT/mTOR signaling pathway.

Research Background and Objectives

Depression is one of the most common mental disorders following TBI, affecting the quality of life of many patients. Although existing research indicates that TBI may lead to complex neurobiological changes, the specific mechanisms of depression are still not well understood. Fibromodulin (FMOD) is a small leucine-rich proteoglycan mainly present in the extracellular matrix (ECM). ECM remodeling has a significant impact on the pathophysiological process of TBI, and studies have shown that FMOD, as a key gene involved in ECM-related regulation, plays a role in tissue repair and remodeling after TBI. However, the specific biological function of FMOD in post-TBI depression is not yet fully clear.

Authors and Publication Information

This study was jointly conducted by Xuekang Huang, Ziyu Zhu, Mengran Du, Chenrui Wu, Jiayuanyuan Fu, Jie Zhang, Weilin Tan, Biying Wu, Lian Liu, and Z.B. Liao from the Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University. The paper was published in the journal “Neuromolecular Medicine” (Volume 26, Issue 24, 2024), with the DOI: 10.1007/s12017-024-08793-2.

Research Methods and Procedures

Clinical Sample Collection and Depression Assessment

• Blood Sample Collection: Venous blood was collected from 40 TBI patients and 20 healthy volunteers, and FMOD serum levels were detected using qPCR. Healthy volunteers were randomly selected based on age, gender, and body mass index.
• Depression Assessment: The Chinese version of the Self-Rating Depression Scale (SDS) was used to assess depressive symptoms in TBI patients. An SDS total score above 53 was considered indicative of depressive symptoms.

Animal Experiments

• Animal Model Establishment: 6-8 week old male C57BL/6 mice were used to establish a TBI model through Controlled Cortical Impact (CCI).
• Behavioral Tests: Including Modified Neurological Severity Score (MNSS), Forced Swim Test (FST), Tail Suspension Test (TST), and Sucrose Preference Test (SPT).
• Brain Tissue Examination: Immunofluorescence, transmission electron microscopy, and Golgi-Cox staining were used to observe the morphological characteristics of hippocampal synapses in mice.
• Protein Expression Detection: Western blot was used to detect the expression levels of FMOD, MAP2, SYP, and PSD95 proteins, as well as the phosphorylation levels of the PI3K/AKT/mTOR signaling pathway.

Experimental Design and Data Analysis

The study used various experimental methods (such as qPCR, Western blot, immunofluorescence, etc.) to detect and analyze changes in FMOD expression at different time points after TBI, assessing its impact on neurological function recovery and depressive-like behavior. Additionally, the PI3K pathway protein was inhibited to verify whether FMOD-mediated synaptic protein regulation depends on this signaling pathway.

Primary Neuron Culture and Transfection

The study isolated and cultured primary hippocampal neurons from C57BL/6 mice and conducted transient transfection experiments to further explore the role of FMOD at the cellular level. A Scratch Assay was used to evaluate cell migration ability, combined with immunofluorescence microscopy to observe changes in neuronal synaptic proteins.

Research Results and Discussion

Through a series of experiments, the article found that FMOD was significantly downregulated in TBI patients and mouse models. Further trials showed that overexpression of FMOD could enhance neurological function recovery, alleviate depressive-like behavior, increase synaptic protein expression, and induce ultrastructural changes in hippocampal neurons. Furthermore, FMOD exerts its protective effects by activating the PI3K/AKT/mTOR signaling pathway.

• Clinical Sample Analysis: FMOD expression levels in the serum of TBI patients were significantly reduced and negatively correlated with depressive symptoms.
• Animal Model Results: MNSS scores showed that mice overexpressing FMOD had significantly improved neurological function; in FST and TST, mice showed significantly reduced immobility time, indicating alleviation of depressive-like behavior.
• Protein Expression and Synaptic Structure: FMOD improved the decline in synaptic number and function after TBI by enhancing the expression of MAP2, PSD95, and SYP proteins. Additionally, transmission electron microscopy and Golgi-Cox staining results showed that overexpression of FMOD significantly increased the number of synaptic vesicles and the length of postsynaptic densities (PSD).

In summary, these results suggest that FMOD regulates neural and synaptic function after TBI by affecting the PI3K/AKT/mTOR signaling pathway, thereby alleviating depressive symptoms and improving cognitive function.

Research Significance and Value

This study is the first to reveal the role of FMOD in post-TBI depression and its potential mechanisms, further clarifying the potential of FMOD as a therapeutic target for post-TBI depression. This research not only provides new insights into the pathophysiological mechanisms of post-TBI depression but also provides important theoretical basis for the development of related therapeutic strategies, with significant scientific value and application prospects.

Research Highlights

• Innovation: First exploration of FMOD’s role in post-TBI depression and its mechanism through the PI3K/AKT/mTOR signaling pathway, providing a new direction for neuroprotective strategies after TBI.
• Comprehensiveness: Comprehensive use of multiple behavioral tests, immunofluorescence, transmission electron microscopy, Golgi-Cox staining, and other methods to thoroughly assess the role of FMOD in neurological function and synaptic protein expression.
• Integration of Clinical and Basic Research: Combining clinical sample analysis with animal and cellular experiments to systematically verify the potential of FMOD as a therapeutic target for post-TBI depression.

Conclusion

This study reveals FMOD as a potential target for treating post-TBI depression, utilizing the PI3K/AKT/mTOR signaling pathway to enhance synaptic plasticity and alleviate depressive-like behavior. This discovery provides important evidence for the development of new therapeutic strategies in the future, offering new hope for TBI patients.