Traumatic Brain Injury-Induced Dysregulation of the Circadian Clock

作者：Deborah R. Boone, Stacy L. Sell, Maria‐Adelaide Micci, Jeanna M. Crookshanks, Margaret A. Parsley, Tatsuo Uchida, Donald S. Prough, Douglas S. DeWitt, Helen L. Hellmich · 发表于：PLoS ONE · 年份：2012 · DOI：10.1371/journal.pone.0046204 · 被引用次数：106 · 研究领域：Circadian rhythm and melatonin、Spaceflight effects on biology、Anesthesia and Neurotoxicity Research

Circadian rhythm disturbances are frequently reported in patients recovering from traumatic brain injury (TBI). Since circadian clock output is mediated by some of the same molecular signaling cascades that regulate memory formation (cAMP/MAPK/CREB), cognitive problems reported by TBI survivors may be related to injury-induced dysregulation of the circadian clock. In laboratory animals, aberrant circadian rhythms in the hippocampus have been linked to cognitive and memory dysfunction. Here, we addressed the hypothesis that circadian rhythm disruption after TBI is mediated by changes in expression of clock genes in the suprachiasmatic nuclei (SCN) and hippocampus. After fluid-percussion TBI or sham surgery, male Sprague-Dawley rats were euthanized at 4 h intervals, over a 48 h period for tissue collection. Expression of circadian clock genes was measured using quantitative real-time PCR in the SCN and hippocampus obtained by laser capture and manual microdissection respectively. Immunofluorescence and Western blot analysis were used to correlate TBI-induced changes in circadian gene expression with changes in protein expression. In separate groups of rats, locomotor activity was monitored for 48 h. TBI altered circadian gene expression patterns in both the SCN and the hippocampus. Dysregulated expression of key circadian clock genes, such as Bmal1 and Cry1, was detected, suggesting perturbation of transcriptional-translational feedback loops that are central to circadian timin...