伴隨著抑郁癥出現(xiàn)的睡眠紊亂或者其他生理節(jié)奏混亂,，有可能對大腦產(chǎn)生影響。關(guān)于大腦基因活性的研究表明,，抑郁癥患者的日常生物鐘可能是紊亂的,。這項研究結(jié)果刊登在5月13日的《美國國家科學院院刊》（PNAS）上。
“這是一項非常重要的研究,，相當令人吃驚,。”特拉維夫大學研究生物周期節(jié)律的生理學家Noga Kronfeld-Schor說，“我們已經(jīng)有一些間接證據(jù),，但這確實說明了生物鐘紊亂和抑郁癥有聯(lián)系,。”
對于哺乳動物，諸如睡覺,、激素代謝以及飲食方式這些日常節(jié)律,，都遵循著大腦中的主時鐘，而主時鐘的節(jié)奏由部分基因以及晝夜交替來維持,。主時鐘也可以和大腦或身體其他部位的時鐘不同步,。密歇根大學的統(tǒng)計遺傳學家李軍（音譯）說，這種不同步,，會產(chǎn)生例如時差感這樣的身體不適,。
抑郁癥患者通常還會有生理節(jié)奏的紊亂。但是造成紊亂的分子和細胞機制尚未確定,。李教授和他的同事采用了一組相當不尋常的樣本——34位抑郁癥患者和55位非抑郁癥者死亡后的大腦,。李教授說，這些人都是死于突發(fā)性原因,，比如心臟病或者自殺,，他們的大腦都是立即被凍存起來的。
在計算出死者的死亡時間與日出時間的差值后,，研究小組收集并研究了六個腦區(qū)的12000條基因打開的活性記錄,。李軍指出，非抑郁癥者的基因活性記錄都是有規(guī)律可循的，有些死者的基因活性在日出時達到頂峰,，其余的則在正午達到峰值,；而抑郁癥患者的基因活性似乎與時間無聯(lián)系，也不可預測,。
這項研究沒有證明到底是抑郁癥導致了晝夜節(jié)律的紊亂,，還是晝夜節(jié)律混亂導致了抑郁癥，但加州大學的分子生物學家,、遺傳學家傅嫈惠表示,，它證實了兩者之間是有聯(lián)系的，也可能對受到影響的生理過程展開進一步的研究,。
研究中分析的大腦只研究了基因活動的一個時間點,，那就是死亡的時候。晝夜節(jié)律的研究人員通常只對死者大腦在24小時內(nèi)的表現(xiàn)進行測試,。但這個方法適用于采樣血細胞,，并不適用于大腦。傅教授說,，大腦數(shù)據(jù)采集于幾所大學,，包括加州大學歐文分校腦庫，數(shù)據(jù)雖不完美,，但還是令人印象深刻,。
“這組數(shù)據(jù)非常可靠,，”傅教授說,，“至于要收集30至50個大腦樣本？光是采集血液或頰上皮細胞就夠難的了,。”（生物谷Bioon.com）
doi:10.1073/pnas.1305814110
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Circadian patterns of gene expression in the human brain and disruption in major depressive disorder
Jun Z. Lia,1, Blynn G. Bunneyb, Fan Mengc, Megan H. Hagenauerc, David M. Walshb, Marquis P. Vawterb, Simon J. Evansc, Prabhakara V. Choudaryd, Preston Cartagenab, Jack D. Barchase, Alan F. Schatzbergf, Edward G. Jonesd,2, Richard M. Myersg, Stanley J. Watson, Jr.c, Huda Akilc,1, and William E. Bunneyb
A cardinal symptom of major depressive disorder (MDD) is the disruption of circadian patterns. However, to date, there is no direct evidence of circadian clock dysregulation in the brains of patients who have MDD. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain were difficult to characterize. Here, we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-h cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses (“controls”) and 34 patients with MDD. Our dataset covered ∼12,000 transcripts in the dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum. Several hundred transcripts in each region showed 24-h cyclic patterns in controls, and >100 transcripts exhibited consistent rhythmicity and phase synchrony across regions. Among the top-ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1(REV-ERBa), DBP, BHLHE40 (DEC1), and BHLHE41(DEC2). The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in the brains of patients with MDD due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This transcriptome-wide analysis of the human brain demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggests potentially important molecular targets for treatment of mood disorders.
