Abstract
Posttraumatic stress disorder is developed by exposure to a threatening and/or a horrifying event and characterized by the presence of anxiety, hyperarousal, avoidance, and sleep abnormality for a prolonged period of time. To elucidate the potential molecular mechanisms, we constructed a mouse model by electric foot shock followed by situational reminders and performed transcriptome analysis in brain tissues. The stressed mice acquired anxiety-like behavior after 2 weeks and exaggerated startle response after 4 weeks. Avoidance latency and freezing behavior were sustained up to 5 weeks post stress and abnormal static behavior was observed during the sleep period. RNA sequencing was performed in two of the emotional regulatory regions, anterior cingulate cortex and amygdala, at 2 and 5 weeks post stress. More than 1000 differentially expressed genes were identified at 2 weeks in both regions. The number of the regulated genes remained constant in amygdala at 5 weeks post stress, whereas those in anterior cingulate cortex were plummeted. Although synaptic remodeling and endocrine system were the most enriched signaling pathways in both anterior cingulate cortex and amygdala, the individual gene expression profile was regulated in a region- and time-dependent manner. In addition, several genes associated with PTSD involved in Hypothalamic-Pituitary-Adrenal axis were differentially regulated. These findings suggested that global gene expression profile was dynamically regulated in accordance with the disease development stage, and therefore targeting the distinct signaling molecules in different region and development stage might be critical for effective treatment to PTSD.
Highlights
Post-traumatic stress disorder (PTSD) is a psychiatric disorder defined by profound disturbances in cognition, emotion, behavior and physiological function in response to a life threatening or a horrifying traumatic event
Anxiety disorders including PTSD encompass heterogeneous conditions that are associated with abnormalities in brain regions controlling fear response such as Tanaka et al Molecular Brain (2019) 12:25 the medial prefrontal cortex, amygdala (AMY), hippocampus, and nucleus accumbens [1, 2]
Anxiety-like behavior emerged at 2 weeks post stress As anxiety is a typical behavioral feature in PTSD, we examined if stressed mice acquired and sustained anxiety using several behavioral tests
Summary
Post-traumatic stress disorder (PTSD) is a psychiatric disorder defined by profound disturbances in cognition, emotion, behavior and physiological function in response to a life threatening or a horrifying traumatic event. PTSD patients may exhibit impaired cognition, working memory, and reduced social activities. Another characteristic of PTSD is that those symptoms emerge long after traumatic events in some patients, suggesting that disease can develop after an extended asymptomatic period. Anxiety disorders including PTSD encompass heterogeneous conditions that are associated with abnormalities in brain regions controlling fear response such as Tanaka et al Molecular Brain (2019) 12:25 the medial prefrontal cortex, amygdala (AMY), hippocampus, and nucleus accumbens [1, 2]. With extensive connection to limbic structures including AMY, ACC is thought to be the direct topdown regulator of PTSD susceptibility through modulating AMY activation to threatening stimuli [7, 8].
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