mTBI brain injury increases vulnerability to PTSD

Mild traumatic brain injury increases vulnerability to post-traumatic stress disorder in rats and the possible role of hippocampal DNA methylation 

Yujie Niu; Department of Neurosurgery, The 940 Hospital of PLA Joint Logistic Support Force, Lanzhou, Gansu, China; The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China

Zhibiao Cai; Department of Neurosurgery, The 940 Hospital of PLA Joint Logistic Support Force, Lanzhou, Gansu, China

Junkai Cheng; Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China

Jie Zhou; Department of Neurosurgery, The 940 Hospital of PLA Joint Logistic Support Force, Lanzhou, Gansu, China

Xiaodong Qu; Department of Neurosurgery, The 940 Hospital of PLA Joint Logistic Support Force, Lanzhou, Gansu, China

Changdong Li; Department of Neurosurgery, The 940 Hospital of PLA Joint Logistic Support Force, Lanzhou, Gansu, China

Zhongjing Zhang; Department of Neurosurgery, The 940 Hospital of PLA Joint Logistic Support Force, Lanzhou, Gansu, China

Shenghao Zhang; Department of Neurosurgery, The 940 Hospital of PLA Joint Logistic Support Force, Lanzhou, Gansu, China

Yaqiang Nan; Department of Neurosurgery, The 940 Hospital of PLA Joint Logistic Support Force, Lanzhou, Gansu, China

Qifeng Tang; Department of Neurosurgery, The 940 Hospital of PLA Joint Logistic Support Force, Lanzhou, Gansu, China

Lei Zhang; Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China

Yelu Hao; Department of Neurosurgery, The 940 Hospital of PLA Joint Logistic Support Force, Lanzhou, Gansu, China

Introduction: Clinical studies have established that patients with mild traumatic brain injury (mTBI) are at an increased risk for developing post-traumatic stress disorder (PTSD), suggesting that mTBI increases vulnerability to subsequent PTSD onset. However, preclinical animal studies investigating this link remain scarce, and the specific biological mechanism through which mTBI increases vulnerability to PTSD is largely unknown. 

Methods: In this study, we modeled mTBI in rats using a mild, closed-head, weight-drop injury, followed 72 h later by exposure to single prolonged stress (SPS) to simulate PTSD. Then, we investigated the impact of mTBI on subsequent PTSD development by observing the behaviors of rats in a series of validated behavioral tests and further explored the possible role of hippocampal DNA methylation. 

Results: We found that, compared with rats in the PTSD-only group, those in the mTBI + PTSD group exhibited higher anxiety levels, higher depression levels, and impaired spatial learning and memory as determined in the open field test, the forced swimming test, and the Morris water maze test, respectively. Rats in the mTBI + PTSD group also exhibited higher hippocampal DNMT3b protein expression compared with those in the PTSD group. 

Conclusion: In conclusion, our results demonstrated that mTBI increases vulnerability to PTSD in rats, possibly through alterations in hippocampal DNA methylation patterns. 

mild traumatic brain injury, post-traumatic stress disorder, vulnerability, behavior, hippocampus, DNA methylation 

“Comorbid mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) have received increasing clinical attention over recent years due to the high rates of mTBI-PTSD co-occurrence among military personnel. Clinical studies have shown that patients with mTBI are at an increased risk for developing PTSD, suggesting that mTBI increases vulnerability to subsequent PTSD onset. Given the high comorbidity between mTBI and PTSD, it is crucial to understand the mechanisms through which mTBI enhances vulnerability to PTSD to develop effective preventative treatments” (p. 1-2).

“In this study, we explored the impact of mTBI on subsequent PTSD development using the rat as a model. mTBI was induced by a mild, closed-head, weight-drop injury, followed 72 h later by PTSD simulation through exposure to single prolonged stress (SPS). Subsequently, the behaviors of rats were evaluated in a series of validated behavioral tests, and the potential role of hippocampal DNA methylation in mediating the increased vulnerability to PTSD following mTBI was explored” (p. 2). 

“A total of 56 pathogen-free male Sprague–Dawley rats (approximately 6 weeks old and weighing 210 ± 20 g) were purchased from the Laboratory Animal Center of Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences (Lanzhou, China) and utilized as subjects… On arrival, the rats were habituated to the animal facility conditions for 7 days before any experimental procedures. After habituation, the animals were randomly assigned to the following four experimental groups: control, PTSD, mTBI, and mTBI + PTSD (n = 14 per group)” (p. 2).

“In the current study, we demonstrated that mTBI increases vulnerability to PTSD in rats. Compared with the PTSD group, rats in the mTBI + PTSD group exhibited higher anxiety levels in the OFT, higher depression levels in the FST, and impaired spatial learning and memory in the MWM test. Rats in the mTBI + PTSD group also exhibited increased hippocampal protein expression of DNMT3b compared with the PTSD group, indicating that hippocampal DNA methylation may play a role, at least in part, in the promotive effect of mTBI on vulnerability to PTSD” (p. 6).

Comorbidity Awareness: The study confirms that mild traumatic brain injury (mTBI) increases vulnerability to post-traumatic stress disorder (PTSD), supporting existing clinical concerns about the high co-occurrence of these conditions, particularly in populations such as military personnel.

Potential Value of Early Screening: Given that rats with both mTBI and PTSD exhibited significantly elevated anxiety and depression behaviors, early screening for PTSD symptoms following mTBI may be beneficial in identifying individuals at higher risk for symptom development.

Neurobiological Indicators: Elevated hippocampal DNMT3b protein expression in the mTBI + PTSD group indicates a potential neurobiological mechanism. These findings support further research into hippocampal DNA methylation as a possible contributor to PTSD vulnerability following mTBI.

Time Window for Intervention: The study applied stress 72 hours after mTBI and observed increased PTSD vulnerability within that timeframe. This suggests that there may be a critical window for monitoring or intervention following injury, though this requires additional validation in clinical populations.

“This study had some limitations. First, we only included male rats. Rodent models of PTSD showed an increased vulnerability in females (Whitaker et al., 2014). Comparisons between male and female rats should be incorporated in future studies of comorbid mTBI and PTSD. Second, the time interval between mTBI and PTSD induction in this study was set at 3 days. The effects reported in this study may vary with different time intervals or changes in the order of mTBI and PTSD induction. Finally, we only investigated the protein levels of DNMT1 and DNMT3b in the hippocampus using western blotting. Future studies should check the expression and localization of DNMT1 and DNMT3b and assess DNA methylation patterns for 5hmC and 5mC in the hippocampus of rats by immunohistochemistry. Also, future studies should examine global DNA methylation levels in the hippocampus or the methylation of promotor regions of genes that may be involved in the interaction between mTBI and PTSD” (p. 8).