Postdoctoral Fellow Walter Reed Army Institute of Research
Abstract Text:
Background: Blast-induced traumatic brain injury (bTBI) frequently results in sleep and circadian rhythm disturbances. Circadian rhythm is mainly regulated by suprachiasmatic nuclei (SCN) in the hypothalamus and its interaction with pineal gland and other regions of the brain through core circadian genes (Bmal1, Clock, Per1, Per2, Cry1 and Cry2). The effect of bTBI on the circadian gene regulation is less studied and hence efficacious treatments against blast-induced sleep disturbances are lacking.
Objective: To investigate if injury-induced dysregulation of circadian rhythm after bTBI is mediated by changes in expression of clock genes in the SCN and the pineal gland at acute (24 hours) and chronic (1 month) time points.
Methods: Sprague Dawley rats were exposed to single and tightly coupled repeated blasts using an advanced blast simulator. Rats were euthanized at 24 hours or 1-month post-blast. The SCN and pineal glands were collected in the morning under day-light (1000 hours) or at night (2200 hours). Expression of core circadian genes in the SCN and pineal glands were quantified using quantitative real-time polymerase chain reaction.
Results: Blast-exposed rats showed statistically significant increase in Bmal1 and decrease in Cry2, Per1 and Per2 in the pineal gland at 24 hours post-blast in rats euthanized at night. No statistically significant changes in any of the core circadian genes were observed in the pineal gland collected in the night at 1 month post-blast injury. In the hypothalamus, decrease in Bmal1, clock and Cry2 were noted along with increase in Per1 gene expression at 24 hours post-blast in rats euthanized at night. No statistically significant changes in the expression of any of the clock genes were detected in the hypothalamus or pineal gland samples collected during day light.
Conclusion: Blast exposure causes differential expression of core circadian genes in the hypothalamus and pineal gland during nighttime, which might be playing a vital role in the sleep disruptions associated with bTBI. Further mechanistic studies in diurnal animal models of bTBI needs to be carried out to determine the disruption of circadian regulation and its effects on sleep after blast exposure.
