Mild Traumatic Brain Injury Increases Vulnerability to Post-traumatic Stress Disorder in Rats and the Possible Role of Hippocampal DNA Methylation

Yujie Niu ¹ Zhibiao Cai ² Junkai Cheng ³ Jie Zhou ² Xiaodong Qu ² Changdong Li ² Zhongjing Zhang ² Shenghao Zhang ² Yaqiang Nan ² Qifeng Tang ² Lei Zhang ^3* Yelu Hao ^2*

• ¹ The first Clinical Medical College of Lanzhou University, Lanzhou, Gansu Province, China
• ² Department of Neurosurgery, The 940 Hospital of PLA Joint Logistic Support Force, Lanzhou, Gansu Province, China
• ³ Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, China

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