Rebecca Beam

Introduction. Post-traumatic stress disorder (PTSD) is a psychiatric disorder arising from a traumatic event that impacts multiple systems of the body including the circadian and stress systems.^1,2,3 Fear inhibition, through exposure therapy, has been a method used to treat PTSD patients; however, this treatment has shown low efficacy to date.^1,3,4 Studies have demonstrated that PTSD’s effects on the circadian and stress systems negatively affect the fear inhibition process, potentially signaling through clock gene expression in the prefrontal cortex.^1,2,3,5,6,7 Targeting these clock genes in combination with fear inhibition treatment could help improve its efficacy as a treatment for PTSD patients. Methods. The effect of stress responses, like those that occur in PTSD patients, on clock genes were first examined in a study that induced stress on rats and monitored their clock gene levels in different areas of the brain including the prefrontal cortex (PFC).⁸ Next, to mechanistically understand the role of clock genes in the fear inhibition process, the Per1 clock gene was knocked down in the prefrontal cortex of rats. The rats then were subjected to a fear associated stimulus and underwent a fear inhibition paradigm.⁷ Lastly, a study was conducted on mice to show the connection between disrupted circadian rhythm and fear inhibition. Mice with disrupted circadian rhythms were exposed to fear-associated stimulus and then underwent the fear inhibition process.⁴ Results. Stress is associated with an increase outside of the regular biphasic expression of the Per1 clock gene most significantly seen in the prefrontal cortex.⁸ Furthermore, rats lacking Per1 in the prefrontal cortex showed a significant decrease in efficacy of fear inhibition through exposure-based therapy.⁷ Lastly, disrupted circadian cycles in mice, specifically disrupted REM sleep, also showed decreased efficacy of fear inhibition through exposure-based therapy.⁴  Conclusion. Per1 clock gene regulation in the prefrontal cortex and regulated circadian rhythm, both of which are disrupted in PTSD patients, play an important role in the fear inhibition process. With a combination of fear inhibition and targeting the regulation of the circadian rhythm and Per1 clock gene in the prefrontal cortex, the efficacy of fear inhibition as a treatment for PTSD patients could potentially be enhanced.

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