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. 2026 Jan 2;399(6):8491–8501. doi: 10.1007/s00210-025-04938-7

Sertraline can alleviate neuronal and synaptic damage in the hippocampus of PTSD mice and inhibit the increase in myelin

Jiaying Lu 1,2,3, Luodong Yang 1,2,3, Keke Lu 1,2,3, Wenlong Xing 1, Min Hu 1,2,3, Guiqing Zhang 1,2,3,✉
PMCID: PMC13086749  PMID: 41483188

Abstract

Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder, and previous studies have suggested that its pathogenesis is related to hippocampal dysfunction. Sertraline, a commonly used medication for treating PTSD, has an unclear mechanism of action. In this study, we assessed the behavioral performance of PTSD mice through the open field test, Y-maze, and forced swimming test. We also examined changes in hippocampal neurons, synapses, and myelin sheaths in PTSD mice using hematoxylin–eosin staining, Nissl staining, Luxol fast blue staining, and transmission electron microscopy. Furthermore, in order to simulate clinical conditions, we administered sertraline treatment to the PTSD group of mice. The results showed that sertraline significantly improved anxiety, despair, and learning and memory in PTSD mice. Histological analysis revealed that sertraline inhibited neuronal damage, restored synaptic function, and reduced excessive myelin sheath proliferation. In conclusion, the findings of this study may provide a basis for the future use of sertraline in the treatment of PTSD.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00210-025-04938-7.

Keywords: PTSD, Hippocampus, Sertraline, Synapses, Myelin, Neurons

Introduction

Posttraumatic stress disorder (PTSD) is a prevalent, disabling, and complex psychiatric disorder that typically occurs following exposure to death threats, severe injury, natural disasters, or other traumatic events. Its hallmark symptoms include intrusive memories, avoidance of trauma-related events, negative changes in mood and cognition, and heightened arousal (American Psychiatric Association 2013). These symptoms are also associated with lower levels of self-care, reduced adherence to medical treatment, and higher rates of substance use (Katrinli et al. 2024). In addition, PTSD is often accompanied by severe depression, substance abuse, suicidal tendencies, and significant impairment in social functioning (Yuan et al. 2024). Currently, especially in the context of natural disasters, the global COVID-19 pandemic, and armed conflicts, exposure to traumatic events has become increasingly common. However, effective treatments for PTSD remain limited. Only a portion of patients experience symptom relief following psychological and pharmacological interventions, and even within this group, there is a high relapse rate within a year after successful treatment (Amir Hamzah et al. 2025; Raymond et al. 2025). Therefore, understanding the neurobiological mechanisms underlying the development of PTSD and exploring the therapeutic effects of drugs are crucial for advancing research on this disorder.

In recent years, with the advancement of neuroimaging, an increasing number of magnetic resonance imaging studies have found evidence of reduced hippocampal volume in PTSD patients. Researchers believe that a smaller hippocampal volume is closely associated with the severity of PTSD symptoms and poorer treatment outcomes (Misaki et al. 2021; Tu et al. 2021; Del Casale et al. 2022). Therefore, the hippocampus is a critical brain region in the pathogenesis of PTSD, playing an essential role in memory function and emotional regulation. During traumatic events, the hippocampus is involved in context-dependent fear learning, as well as the consolidation and retrieval of fear memories (Xie et al. 2024). A deeper understanding of the role of the hippocampus in the pathogenesis of PTSD may provide valuable insights for the treatment of the disorder.

Myelin, a crucial component of the central nervous system, is a lipid layer formed by oligodendrocytes that wraps around neurons. It plays a vital role in the propagation of action potentials within the central nervous system. Studies have shown that myelin responds to and regulates neuronal function throughout the lifespan, with the ability to undergo adaptive dynamic changes (Pease-Raissi and Chan 2021). Multiple clinical studies have previously found evidence of increased myelin in PTSD patients (Chao et al. 2015; Jak et al. 2020). Furthermore, basic research has also revealed an increase in myelin content in rodent PTSD models, with fluoxetine shown to inhibit this pathological phenomenon (Yang et al. 2024; Yin et al. 2024). Synapses are the connection points between neurons, through which signals are transmitted from the presynaptic neuron to the postsynaptic neuron via the release of synaptic vesicles (Gao et al. 2025). In previous basic research, synaptic plasticity impairment has been considered another key pathological basis of PTSD. Numerous studies have found evidence of synaptic damage in rodent models of PTSD (Chen et al. 2020; Guan et al. 2022). Moreover, medications such as ketamine and salidroside can reverse this damage (Chen et al. 2023; Wang et al. 2024a).

Currently, in terms of pharmacological treatment for PTSD, only two selective serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, have received approval from the Food and Drug Administration (Davis et al. 2025). However, the mechanisms of action of these medications have not been fully elucidated. In particular, the regulatory effects of sertraline on the neuropathological features of PTSD, namely abnormal myelination and synaptic damage, remain underexplored. Based on the existing evidence, we propose the following scientific hypotheses: (1) The hippocampus of PTSD model mice may exhibit a dual pathological characteristic, with increased myelin content accompanied by synaptic structural damage. (2) Sertraline treatment may exert therapeutic effects by modulating these two types of neuropathological changes.

In this study, we established a PTSD model in male mice using a single prolonged stress and footshock stimulation (SPS&S) protocol. Through behavioral, molecular biology, and ultrastructural analyses, we aimed to provide new evidence for the mechanisms of myelin-synapse alterations in PTSD and to offer experimental support for optimizing clinical treatment strategies.

Materials and methods

Animals

The study selected male C57BL/6j mice (4–6 weeks old) with a body weight of approximately 18 ± 2 g, purchased from Spebford (Beijing) Biotechnology Co., Ltd., with the experimental animal license number (SCXK (Beijing) 2024–0001). The animals were housed at the Experimental Animal Centre of Shihezi University (clean grade), with environmental conditions of a temperature of (23 ± 2) °C, relative humidity of (55 ± 5) %, and a 12-h light/dark cycle. All mice had free access to food and water, with four mice per cage. The mice were allowed to acclimatize to the environment for 1 week before the experiment. This study was approved by the Ethics Committee of Shihezi University (approval number: A2024-361), and all animal procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health.

Experimental grouping and establishment of the PTSD model

Firstly, 24 healthy male C57BL/6j mice were randomly divided into a control group and a PTSD group. The model of PTSD was established using the SPS&S method as previously described by Teng et al. (2024). Specifically, the mice were first placed in a restrainer for 2 h; immediately afterwards, they were placed into a plastic container filled with water and forced to swim for 20 min at a water temperature of (24 ± 1) °C. The mice were then dried and allowed to rest in their cages for 15 min. Following this, the mice were placed in a plastic box containing sevoflurane until they lost consciousness. After a 30-min recovery period, the mice underwent two unavoidable foot shocks, each with an intensity of 0.8 mA, an interval of 10 s, and a duration of 10 s per shock. After staying in the shock chamber for an additional 30 s, the mice were returned to clean cages for further breeding. The specific experimental process is shown in Fig. 1A.

Fig. 1.

Fig. 1

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Flow chart of the experiment. (A) First part of the experimental timeline and procedure. (B) Second part of the experimental timeline and procedure

Subsequently, to further investigate the therapeutic effect of sertraline (SER) on PTSD, 45 healthy male C57BL/6j mice were randomly divided into the control + Nacl group, PTSD + Nacl group, and PTSD + SER group. PTSD was induced using the SPS&S method. On the second day after SPS&S, the PTSD + SER group began receiving continuous intraperitoneal injections of sertraline (15 mg/kg/day) for 14 days (Wang et al. 2024b), while the control + Nacl and PTSD + Nacl groups were simultaneously given intraperitoneal injections of 0.9% saline. The specific experimental process is shown in Fig. 1B.

Mouse behavioral assessment

After the SPS&S modeling in mice, all the mice underwent the open field test (OFT), Y-maze test, and forced swimming test (FST) to assess anxiety, feelings of despair, as well as learning and memory impairments. In the OFT, the time spent by the mice and the distance traveled in the center area within 5 min were recorded (Wei et al. 2021); in the Y-maze test, the percentage of alternations made by the mice within 8 min was recorded (Lee et al. 2024); in the FST, the immobility time of the mice between 2 and 6 min was recorded (Malikowska-Racia et al. 2019). After each test, the maze was wiped clean and the water was changed to prevent any influence on subsequent behavioral tests with other mice.

Western blot (WB)

After the behavioral tests, the mice were anesthetized with an intraperitoneal injection of sodium pentobarbital (50 mg/kg), and the brain tissues were extracted to isolate the hippocampus. The tissue was immediately frozen in liquid nitrogen and then transferred to a − 80 °C freezer for storage. The hippocampal tissue was homogenized with the corresponding amount of RIPA and PMSF in a ratio of hippocampus:RIPA:PMSF (10:100:1). The homogenate was then placed in a pre-cooled 4 °C high-speed centrifuge and centrifuged at 12,000 rpm for 15 min. The supernatant containing the protein was collected. The protein concentration was measured using the BCA method and adjusted to a suitable concentration. After SDS-PAGE electrophoresis, the proteins were transferred to a membrane and blocked with 5% non-fat milk (in TBST) on a shaker at room temperature for 2.5 h. Primary antibodies were incubated overnight at 4 °C, including anti-BDNF antibody (1:1000, WL0168, Wanlei Biotechnology, China), anti-SYP antibody (1:1000, WL03058, Wanlei Biotechnology, China), anti-PSD95 antibody (1:1500, WL05046, Wanlei Biotechnology, China), and anti-GAPDH antibody (1:20,000, TA-08, Zhongshan Goldenbridge Biotechnology, China). The corresponding secondary antibody (1:20,000, ZB-2306, Zhongshan Goldenbridge Biotechnology, China) was then incubated at room temperature for 1.5 h. After adding ECL solution, the membrane was developed. The gel imaging system was used to detect the film, which was then scanned and archived. The image was processed and decolored using PhotoShop software. GAPDH was used as an internal reference, and the relative expression of each protein was calculated using ImageJ.

Hematoxylin–eosin (HE) staining

The paraffin-embedded tissue sections were deparaffinized and dehydrated through a graded ethanol series. The sections were then immersed in HE staining solution for stepwise staining, followed by a rapid rinse in distilled water. The sections were subsequently subjected to dehydration, infiltration, and sealing. The sections were observed and photographed under a microscope, ensuring consistent background lighting for each photo.

Nissl staining

The tissue sections were deparaffinized, dehydrated through a graded ethanol series, and stained with Nissl staining solution for 5 min. After staining, the sections were rinsed with water and then treated with 0.1% acetic acid for differentiation. The differentiation was stopped using tap water. The sections were then dehydrated, infiltrated, and sealed. Brain tissue was selected for imaging under a microscope, ensuring that the tissue filled the entire field of view and that the background lighting remained consistent for each photo. After imaging, Image-Pro Plus 6.0 analysis software was used to analyze the images, with all measurements standardized to millimeters. The number of neurons in three fields of view per section was counted, along with the corresponding field area. Neuron density was calculated as the number of neurons per field area.

Luxol fast blue (LFB) staining

The paraffin-embedded tissue sections were deparaffinized and dehydrated through a graded ethanol series. The myelin staining solution was preheated in a 65 °C oven for 30 min. The sections were then immersed in the myelin staining solution, covered with a coverslip, and stained for 1 h. After staining, the sections were quickly rinsed with distilled water. Under the microscope, staining was considered complete when the myelin appeared blue and the background was nearly colorless. The sections were then sequentially dehydrated, infiltrated, and sealed. The sections were observed and photographed under the microscope, ensuring consistent background lighting for each photo.

The transmission electron microscopy (TEM)

The mouse brain tissue was carefully isolated to obtain the hippocampus, which was then trimmed into 1 mm3 blocks using a surgical scalpel. These tissue blocks were immediately placed in electron microscopy fixative (2.5% glutaraldehyde) and fixed at room temperature for 2 h. After fixation, the tissue underwent dehydration using a graded ethanol and acetone series. Following dehydration, the tissue was infiltrated and embedded using pure embedding medium for 5–8 h. The tissue was then placed in embedding molds and polymerized at 37 °C overnight, followed by a 48-h polymerization at 60 °C. After the production of semi-thin sections, the tissue was stained with toluidine blue for light microscopy localization. The sections were then double-stained while placed on copper grids, cleaned, and dried. Finally, the sections were observed and imaged using transmission electron microscopy.

Statistical analysis

Data analysis was performed using SPSS 26.0 and GraphPad Prism 9.0 software. After normality testing, all data are presented as mean ± standard deviation. Intergroup comparisons were made using independent samples t-test, while comparisons among three groups were conducted using one-way analysis of variance (ANOVA), followed by pairwise comparisons with the least significant difference (LSD) test. In all analyses, a P-value of less than 0.05 was considered statistically significant.

Results

PTSD mice exhibit anxiety, despair, and learning and memory impairments

In the OFT, there was no difference in the total distance traveled between PTSD mice and control mice (t = 1.833, P > 0.05) (Fig. 2B). However, compared to the control group, PTSD mice showed reduced distance and time spent in the center area (t = 2.812, 8.186, P < 0.05) (Fig. 2C, D). In the FST, PTSD mice exhibited an increase in the number of rest episodes and the duration of rest compared to control mice (t = 10.69, 7.040, P < 0.05) (Fig. 2E, F). In the Y-maze test, PTSD mice showed a reduced percentage of alternations compared to the control group (t = 2.724, P < 0.05) (Fig. 2G). Overall, these behavioral results indicate that PTSD mice exhibit anxiety-like behaviors, despair, and learning and memory impairments.

Fig. 2.

Fig. 2

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Behavioral and synaptic protein changes in PTSD mice induced by single prolonged stress and footshock stimulation (SPS&S). A Schematic diagram of the two groups of mice in the open field test (OFT). B–D Total distance traveled, distance traveled in the center area, and time spent in the center area for the two groups of mice in the OFT. E, F Rest time and number of rest episodes for the two groups of mice in the forced swim test (FST). G Percentage of alternations in the Y-maze for the two groups of mice. H Western blot results of synaptic-related proteins in the hippocampus of the two groups of mice. I–K Statistical data of BDNF, PSD95, and SYP protein levels in the hippocampus of the two groups of mice. Behavioral experiments (n = 12), Western blot (n = 3). *P < 0.05; **P < 0.01; ***P < 0.001. PTSD, posttraumatic stress disorder

The expression levels of BDNF, PSD95, and SYP in the hippocampal region of PTSD mice were altered

To investigate whether synaptic changes occurred in the hippocampus of PTSD mice, we performed WB analysis on hippocampal tissue. The results showed that, compared to the control group, the expression of BDNF (t = 4.601, P < 0.05) (Fig. 2H, I), PSD95 (t = 3.828, P < 0.05) (Fig. 2H–J), and SYP (t = 4.826, P < 0.05) (Fig. 2H–K) proteins in the hippocampus of the PTSD group was significantly decreased.

The effects of sertraline on the behavior of PTSD mice induced by SPS&S

To investigate whether sertraline can alleviate anxiety, despair, and learning and memory impairments in PTSD mice, we administered intraperitoneal injections of sertraline to the PTSD + SER group. The results showed that, in the OFT, there was no difference in the total distance traveled between the control + Nacl group, PTSD + SER group, and PTSD + Nacl mice (F = 1.970, P > 0.05) (Fig. 3B). However, compared to the PTSD + Nacl group, both the control + Nacl and PTSD + SER groups spent more time and covered more distance in the center area (F = 6.351, 5.796, P < 0.05) (Fig. 3C, D). In the FST, the control + Nacl and PTSD + SER groups showed a reduction in the number of rest episodes and the duration of rest compared to the PTSD + Nacl group (F = 41.350, 17.08, P < 0.05) (Fig. 3E, F). In the Y-maze, the control + Nacl and PTSD + SER groups exhibited a higher percentage of alternations compared to the PTSD + Nacl group (F = 3.979, P < 0.05) (Fig. 3G). These results suggest that sertraline treatment may help alleviate anxiety, despair, and learning and memory impairments induced by SPS&S.

Fig. 3.

Fig. 3

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Therapeutic effects of sertraline on PTSD mice induced by single prolonged stress and footshock stimulation (SPS&S). A Schematic diagram of the three groups of mice in the open field test (OFT). B–D Total distance traveled, distance traveled in the center area, and time spent in the center area for the three groups of mice in the OFT. E, F Rest time and number of rest episodes for the three groups of mice in the forced swim test (FST). G Percentage of alternations in the Y-maze for the three groups of mice. H Western blot results of synaptic-related proteins in the hippocampus of the three groups of mice. I–K Statistical analysis of BDNF, PSD95, and SYP protein levels in the hippocampus of the three groups of mice. Behavioral experiments (n = 15), Western blot (n = 6). *P < 0.05; **P < 0.01; ***P < 0.001. PTSD, posttraumatic stress disorder; SER, sertraline

Sertraline treatment restored the abnormalities in BDNF, PSD95, and SYP proteins in the hippocampal region

WB results showed that, compared to the PTSD + Nacl group, the expression of BDNF (F = 5.500, P < 0.05) (Fig. 3H, I), PSD95 (F = 6.517, P < 0.05) (Fig. 3H–J), and SYP (F = 10.430, P < 0.05) (Fig. 3H–K) proteins in the hippocampus of the PTSD + SER group was restored.

Sertraline inhibited the damage to hippocampal neurons in the PTSD group of mice

HE staining revealed that, compared to the control + Nacl group, the hippocampal tissue cells in the PTSD + Nacl group exhibited shrinkage, reduced volume, deeper staining, and unclear cytoplasm-nucleus boundaries. In contrast, the hippocampal neurons in the PTSD + SER group showed even staining, orderly arrangement, clear layering, large and round nuclei, uniformly pale blue in color, and distinct nucleoli. No significant necrosis or inflammatory cell infiltration was observed (Fig. 4A).

Fig. 4.

Fig. 4

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Effects of sertraline on hippocampal neurons and myelin in PTSD mice induced by single prolonged stress and footshock stimulation (SPS&S). A Hematoxylin–eosin staining results in the hippocampus of the three groups of mice (n = 3). B Nissl staining results in the hippocampus of the three groups of mice (n = 3). C, D Statistical analysis of the number and density of neurons in the hippocampus of the three groups of mice based on Nissl staining. E Luxol fast blue staining results in the hippocampus of the three groups of mice (n = 3). Data are presented as mean ± standard deviation, compared with the control group. *P < 0.05; **P < 0.01. PTSD, posttraumatic stress disorder; SER, sertraline

Nissl staining showed that the cytoplasmic Nissl staining was lighter in the PTSD + Nacl group, and sertraline treatment significantly improved this abnormality. Specifically, compared to the control + Nacl group, the PTSD + Nacl group had lighter Nissl staining in the hippocampal cytoplasm and fewer neurons. In contrast, in the PTSD + SER group, the cytoplasmic Nissl staining was darker, and both the number and density of neurons were increased (F = 9.909, 9.910, P < 0.05) (Fig. 4B–D). These results suggest that sertraline has a protective effect on hippocampal neurons in mice.

LFB staining was used to observe the effect of sertraline on myelin in the hippocampus of PTSD mice

The LFB staining results showed that, compared to the Control + Nacl group, the PTSD + Nacl group exhibited deeper LFB staining in the hippocampus with a higher number of myelin sheaths. In contrast, in the PTSD + SER group, the LFB staining was lighter, and the number of myelin sheaths was reduced. These results suggest that sertraline can inhibit the increase in myelin content in the hippocampus (Fig. 4E).

TEM was used to observe the effects of sertraline on myelin and synapses in the hippocampus of PTSD mice

TEM results showed that the PTSD + Nacl group exhibited an increased number of myelin sheaths in the hippocampus, and sertraline treatment suppressed this pathological phenomenon (F = 19.500, P < 0.05). Additionally, compared to the control + Nacl group, the PTSD + Nacl group showed a decrease in the number of synaptic vesicles, as well as a reduction in the thickness and area of the postsynaptic density. In contrast, following sertraline treatment, the number of synaptic vesicles increased (F = 8.849, P < 0.05), and both the thickness and area of the postsynaptic density were enlarged (F = 7.168, 8.044, P < 0.05). However, no significant differences were observed in the synaptic cleft width among the three groups (F = 0.102, P > 0.05). These results further confirm that sertraline can inhibit the increase in myelin content induced by PTSD and regulate the synaptic alterations caused by PTSD (Fig. 5A).

Fig. 5.

Fig. 5

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Transmission electron microscopy analysis of sertraline’s effects on synaptic structures and myelin sheaths (n = 3). A Impact of sertraline on myelination and synaptic morphology in the hippocampus of a PTSD mouse model induced by single prolonged stress and footshock stimulation. B–F Statistical analysis of myelin quantity, synaptic vesicle number, postsynaptic density thickness, postsynaptic density gap, and postsynaptic density area levels in the hippocampus of the three groups of mice. PTSD, posttraumatic stress disorder; SER, sertraline

Discussion

Previous studies have found that hippocampal dysfunction is a key pathological feature of PTSD. In this study, we first assessed the behavioral performance of mice subjected to SPS&S in the open field test, Y-maze, and forced swimming test. The results showed that after SPS&S, the mice exhibited anxiety, despair, and learning and memory impairments. Subsequently, Western blot analysis revealed a reduction in key synaptic proteins (BDNF, PSD95, and SYP) in the hippocampus of SPS&S mice. Since traumatic events cannot be predicted in everyday life, and to better replicate clinical conditions, we began intraperitoneal injections of sertraline hydrochloride on the second day after SPS&S (Wang et al. 2024b). The results showed that sertraline improved the behavioral abnormalities of PTSD mice, alleviated neuronal and synaptic damage, and inhibited excessive myelin proliferation. These findings also suggest that the therapeutic effects of sertraline in PTSD may be related to synaptic plasticity, myelin changes, and neuronal apoptosis. To our knowledge, this is the first study to investigate the mechanism of sertraline treatment in SPS&S-induced PTSD mice (Fig. 6).

Fig. 6.

Fig. 6

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The possible mechanism of sertraline in treating PTSD mice

PTSD is a psychiatric disorder with a clear etiology, but due to its complex and diverse presentation, there are relatively few clinical treatment options available. To date, most treatments for PTSD are focused on managing its symptoms. Therefore, the choice of model is crucial for exploring the disease. In this study, we employed the SPS&S model, which is an enhancement of the classic SPS model by incorporating unavoidable foot shocks to intensify fear memory in mice, thus providing a better simulation of PTSD-related behaviors. Our findings in this study show that SPS&S induces anxiety, despair, and learning and memory impairments, which are consistent with previous research results (Xi et al. 2021; Li et al. 2022). Previous studies have shown that fear in mice following acute electric shock stress is caused by changes in neurotransmitters within neurons, and that fluoxetine can inhibit these neurotransmitter alterations (Li et al. 2024). In preclinical studies, multiple research findings have provided evidence of neuronal damage in rodent models of PTSD (Chen et al. 2021; Hu et al. 2023). Clinical studies have also found that neuronal dysfunction in PTSD patients may be associated with a reduction in hippocampal volume (Logue et al. 2018). Our findings are consistent with this, as using HE and Nissl staining, we observed neuronal damage in the hippocampus of PTSD mice following SPS&S. However, sertraline was found to improve this neuronal damage. Although we did not investigate whether the specific mechanisms underlying neuronal changes in PTSD mice are related to neurotransmitters, based on previous research, it is likely that sertraline and fluoxetine exert similar effects and mechanisms.

Synapses are crucial structures that connect neurons. Previous studies have shown that synaptic plasticity in the hippocampus can influence learning and memory (Fuchsberger and Paulsen 2022; Fujikawa et al. 2024). In this study, we also observed changes in the hippocampal synaptic proteins BDNF, PSD95, and SYP in PTSD mice following SPS&S. Transmission electron microscopy revealed a reduction in synaptic vesicles, as well as a decrease in the area and thickness of the postsynaptic density. However, sertraline treatment improved these abnormalities in PTSD mice induced by SPS&S. These findings are largely consistent with previous studies, which have shown that drugs such as chlorogenic acid, sevoflurane, and artemisinin can improve synaptic plasticity in PTSD rodent models (Gu et al. 2023; Liu et al. 2024; Tang et al. 2025). Myelin is an important tissue that surrounds neurons. Although research on myelin in PTSD is limited, both clinical and basic studies have found evidence of increased myelin content in PTSD (Chao et al. 2015; Jak et al. 2020; Yang et al. 2024; Yin et al. 2024). In addition, gene expression studies have also revealed changes in genes related to myelination in the prefrontal cortex (Logue et al. 2021). Our findings are consistent with this. We observed an increase in myelin content in the hippocampus of PTSD mice following SPS&S, and treatment with intraperitoneal injections of sertraline was able to reverse these myelin changes. This may reflect a reactive process of myelin repair following neural injury. While myelin repair is generally considered protective, excessive myelin proliferation could lead to abnormal nerve conduction, thereby hindering recovery from the disease. This also highlights the therapeutic effect of sertraline.

Although we found that sertraline effectively improved behavioral abnormalities in PTSD mice and played a role in regulating neuronal injury recovery, synaptic plasticity, and myelin proliferation, our study still has certain limitations, and many questions remain to be addressed. Firstly, our study was conducted solely in male mice and did not account for potential sex differences. Secondly, the precise mechanisms of action of sertraline remain incompletely elucidated. Future studies should therefore include female animals to verify the generalizability of the findings and explore possible sex-specific effects, as well as to investigate in greater detail the impact of sertraline on synapses, myelin, and neuronal injury. Furthermore, the efficacy of sertraline in different stress models and its potential in combination with other therapeutic agents warrant further investigation.

Conclusion

This study investigated the neuropathological mechanisms of PTSD using the SPS&S mouse model and evaluated the therapeutic effects of sertraline. The results suggest that sertraline may improve PTSD symptoms by modulating synaptic plasticity, myelin changes, and neuronal apoptosis. These findings provide new theoretical insights into the treatment of PTSD and offer valuable directions for drug development.

Supplementary Information

Below is the link to the electronic supplementary material.

ESM 1 (1.7MB, docx)

(DOCX 1.69 MB)

Author contributions

Jiaying Lu: Writing-original draft, Methodology, Investigation, Data curation, review & editing. Luodong Yang: Writing-original draft, Methodology, review & editing. Keke Lu: Formal analysis, Methodology. Wenlong Xing: Formal analysis, Methodology. Min Hu: Supervision, Conceptualization. Guiqing Zhang: Funding acquisition, Project administration, Writing-review & editing. The authors declare that all data were generated in-house and that no paper mill was used.

Funding

This work was supported by the National Natural Science Foundation of China (32260208) and the Shihezi University First Affiliated Hospital Institutional-Level Science and Technology Programme Project (LC2025001).

Data availability

All source data for this work (or generated in this study) are available upon reasonable request.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Jiaying Lu and Luodong Yang are Co-first author.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Supplementary Materials

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Data Availability Statement

All source data for this work (or generated in this study) are available upon reasonable request.

Articles from Naunyn-Schmiedeberg's Archives of Pharmacology are provided here courtesy of Springer

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