24小时节律控制着几乎所有的生理过程,比如睡眠循环,代谢,警觉与认知,这些每天都在发生的节律模式受到一些特定基因的调控,而几乎所有细胞中都有这些调控基因的表达,但是对于人类大脑的研究一直较少。
有研究表明老年人的大脑倾向于早上进行复杂的认知任务,而在白天内其他时间这种能力就会变差。我们也知道节律会随衰老过程发生变化,这导致老年人在早上醒得更早,睡眠时间更短,体温的调节能力也更差。
在这项研究中,研究人员对146个没有精神疾病史的人类脑组织样本进行了检测,他们根据组织来源的年龄是否小于40岁或者是否大于60岁进行了分组,利用一种新的统计学方法对前额皮质内几千个基因的节律基因活性以及表达情况进行了分析。
研究人员共发现235个核心基因,组成了前额皮质的分子生物钟。作者表示:"正如我们所预期,年轻人所有经典的生物钟基因都有正常的节律变化,但是老年人的脑组织中许多生物钟基因都出现节律紊乱,这或许可以解释老年人在睡眠,认知以及情绪上发生的一些变化。"
令人意想不到的是,研究人员在老年人的脑组织中发现了一组基因获得了新的节律特性,他们认为这一信息或可帮助开发治疗随衰老出现的认知和睡眠障碍的方法。
研究人员表示他们将利用动物模型继续探索大脑节律基因的功能,同时也会在患有精神疾病的病人中检测是否存在相关基因的变化。
Effects of aging on circadian patterns of gene expression in the human prefrontal cortex
Cho-Yi Chena, Ryan W. Loganb, Tianzhou Maa, David A. Lewisb, George C. Tsenga, Etienne Sibilleb,c,d,e, and Colleen A. McClung
With aging, significant changes in circadian rhythms occur, including a shift in phase toward a "morning" chronotype and a loss of rhythmicity in circulating hormones. However, the effects of aging on molecular rhythms in the human brain have remained elusive. Here, we used a previously described time-of-death analysis to identify transcripts throughout the genome that have a significant circadian rhythm in expression in the human prefrontal cortex [Brodmann's area 11 (BA11) and BA47]. expression levels were determined by microarray analysis in 146 individuals. Rhythmicity in expression was found in ?10% of detected transcripts (P < 0.05). Using a metaanalysis across the two brain areas, we identified a core set of 235 genes (q < 0.05) with significant circadian rhythms of expression. These 235 genes showed 92% concordance in the phase of expression between the two areas. In addition to the canonical core circadian genes, a number of other genes were found to exhibit rhythmic expression in the brain.
Notably, we identified more than 1,000 genes (1,186 in BA11; 1,591 in BA47) that exhibited age-dependent rhythmicity or alterations in rhythmicity patterns with aging. Interestingly, a set of transcripts gained rhythmicity in older individuals, which may represent a compensatory mechanism due to a loss of canonical clock function. Thus, we confirm that rhythmic gene expression can be reliably measured in human brain and identified for the first time (to our knowledge) significant changes in molecular rhythms with aging that may contribute to altered cognition, sleep, and mood in later life.