Abstract
Exposure to a harsh environment in early life increases in the risk of post-traumatic stress disorder (PTSD) of an individual. Brain derived neurotrophic factor (BDNF) plays an important role in neurodevelopment in developmental stages. Both chronic and traumatic stresses induce a decrease in the level of BDNF and reduce neural plasticity, which is linked to the pathogenesis of PTSD. Also, studies have shown that stress alters the epigenetic marker H3K9me2, which can bind to the promoter region of the Bdnf gene and reduce BDNF protein level. However, the long-term effects of traumatic stress during adolescence on H3K9me2, BDNF expression and dendrite development are not well-known. The present study established a model of PTSD in adolescent rats using an inescapable foot shock (IFS) procedure. Anxiety-like behaviors, social interaction behavior and memory function were assessed by the open field test, elevated plus maze test, three-chamber sociability test and Morris water maze test. In addition, neuronal development and H3K9me2/BDNF expression in hippocampus (HIP) and prefrontal cortex (PFC) were evaluated by Golgi staining, western blotting, qRT-PCR analysis and CHIP-qPCR analysis. Additionally, the Unc0642, a small molecule inhibitor of histone methyltransferase (EHMT2) was used for intervention. The results showed that the IFS procedure induced the PTSD-like behaviors in rats, resulted in fewer dendrite branches and shorter dendrite length in CA1 of HIP and PFC, increased H3K9me2 level and decreased BDNF expression in HIP and PFC. Also, although all the changes can persist to adulthood, Unc0642 administration relieved most of alterations. Our study suggests that traumatic stress in adolescence leads to immediate and long-term mental disorders, neuronal morphological changes, lower BDNF level and increased H3K9me2 level in the HIP and PFC, indicating that H3K9me2/BDNF dysfunction plays a key role in pathogenesis of PTSD.
Highlights
Exposure to a harsh environment has a negative impact on brain structure that may lead to impairment of cognitive and emotional function in humans (Wang R. et al, 2018; Xu et al, 2019)
These findings suggest that the H3K9me2/Brain derived neurotrophic factor (BDNF) axis is involved in the regulation of the pathogenesis of post-traumatic stress disorder (PTSD)
The results showed that there are significant differences in the total number of intersections among groups, which is reflected in the length of each neuron and its degree of branch richness
Summary
Exposure to a harsh environment has a negative impact on brain structure that may lead to impairment of cognitive and emotional function in humans (Wang R. et al, 2018; Xu et al, 2019). Experiencing stress in early childhood may affect neuronal structure and function, thereby leading to substance abuse, anxiety, depression and even learning function and social communication impairments (SalzmannErikson and Hicdurmaz, 2017; Cowan et al, 2018; Postel et al, 2019; Ohta et al, 2020). The clinical symptoms of PTSD include recurrent and intrusive traumatic memories, avoidance of traumatic event-related stimuli, cognitive impairment, negative emotions, hyper-aroused state, hyper-vigilance, clinical distress, and social impairment (Richter-Levin et al, 2019). Dysregulation of dendrite development and synaptogenesis has been confirmed as a key factor in the etiology of PTSD (Heun-Johnson and Levitt, 2018)
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