Clocking in to the brain’s activity

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Science Translational Medicine  13 Jan 2016:
Vol. 8, Issue 321, pp. 321ec6
DOI: 10.1126/scitranslmed.aaf0854

Most physiological functions display a circadian rhythm. Whereas the suprachiasmatic nucleus supervises the 24-hour circadian clock, molecular mini-clocks control gene expression at the cellular level, thereby achieving activity in individual tissues at the appropriate time of day. In a recent study, Chen et al. assessed gene expression in the human brain to determine whether there is a circadian pattern of gene expression and, if so, how it is affected by aging.

Using microarray analysis, they assessed gene expression in two orbital prefrontal cortical regions (BA11 and BA47) in postmortem brain samples from 146 individuals. Time and location of death were used to determine the zeitgeber time of death, such that gene expression could be analyzed in terms of zeitgeber time (that is, time relative to circadian rhythms). With this method, the investigators identified 235 genes with a significant circadian expression pattern, including core clock-related genes such as BMAL1 and PER genes, as well as genes that previously had not been known to have circadian rhythmicity or function. They then compared data from 31 younger individuals (<40 years) and 37 older individuals (>60 years). They found that PER1 and PER2 circadian rhythm expression was reduced in amplitude and shifted earlier in the older group. This finding echoes the reduced amplitude and phase advances of sleep-activity patterns with aging. Additionally, they identified 1186 genes in BA11 and 1591 genes in BA47 that differed in rhythmicity in the older group compared with the younger group. Differences in rhythmicity of gene expression included a shift in the baseline level, changes in amplitude, phase shift, loss of rhythmicity, and—quite remarkably—a gain in rhythmicity. Approximately 45% of genes in BA11 and 27% of genes in BA47 showed no rhythmicity in the younger group but showed a significant circadian rhythm in the older group, suggesting that these genes gained circadian rhythmicity with aging. There are limitations to the study, such as lack of information about sleep-activity patterns prior to death, potential effects of cardiovascular and other chronic diseases more prevalent in the older group, and effects of death-to-autopsy time (mean 17 hours) on brain tissue. Despite these limitations, this study demonstrates circadian rhythmicity of gene expression in the brain, including a subset of genes that gain circadian rhythmicity with aging, indicating redundant and resilient mechanisms that in the future may be able to be harnessed for potential therapeutic applications.

C.-Y. Chen et al., Effects of aging on circadian patterns of gene expression in the human prefrontal cortex. Proc. Natl. Acad. Sci. U.S.A. 113, 206–211 (2016). [Abstract]

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