Department of Psychiatry, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
J Biol Rhythms. 2012 Oct;27(5):339-52. doi: 10.1177/0748730412456367.
Bipolar disorder (BD) and major depressive disorder (MDD) are heritable neuropsychiatric disorders associated with disrupted circadian rhythms. The hypothesis that circadian clock dysfunction plays a causal role in these disorders has endured for decades but has been difficult to test and remains controversial. In the meantime, the discovery of clock genes and cellular clocks has revolutionized our understanding of circadian timing. Cellular circadian clocks are located in the suprachiasmatic nucleus (SCN), the brain's primary circadian pacemaker, but also throughout the brain and peripheral tissues. In BD and MDD patients, defects have been found in SCN-dependent rhythms of body temperature and melatonin release. However, these are imperfect and indirect indicators of SCN function. Moreover, the SCN may not be particularly relevant to mood regulation, whereas the lateral habenula, ventral tegmentum, and hippocampus, which also contain cellular clocks, have established roles in this regard. Dysfunction in these non-SCN clocks could contribute directly to the pathophysiology of BD/MDD. We hypothesize that circadian clock dysfunction in non-SCN clocks is a trait marker of mood disorders, encoded by pathological genetic variants. Because network features of the SCN render it uniquely resistant to perturbation, previous studies of SCN outputs in mood disorders patients may have failed to detect genetic defects affecting non-SCN clocks, which include not only mood-regulating neurons in the brain but also peripheral cells accessible in human subjects. Therefore, reporters of rhythmic clock gene expression in cells from patients or mouse models could provide a direct assay of the molecular gears of the clock, in cellular clocks that are likely to be more representative than the SCN of mood-regulating neurons in patients. This approach, informed by the new insights and tools of modern chronobiology, will allow a more definitive test of the role of cellular circadian clocks in mood disorders.
双相情感障碍（BD）和重度抑郁症（MDD）是遗传性神经精神疾病，与昼夜节律紊乱有关。昼夜节律功能障碍在这些疾病中起因果作用的假设已经存在了几十年，但一直难以验证，并且存在争议。与此同时，时钟基因和细胞时钟的发现彻底改变了我们对昼夜节律计时的理解。细胞生物钟位于视交叉上核（SCN），即大脑的主要昼夜节律起搏器，但也存在于大脑和外周组织中。在 BD 和 MDD 患者中，已经发现体温和褪黑素释放的 SCN 依赖性节律存在缺陷。然而，这些都是 SCN 功能的不完善和间接指标。此外，SCN 可能与情绪调节无关，而 lateral habenula、ventral tegmentum 和 hippocampus 也包含细胞时钟，它们在这方面具有重要作用。这些非 SCN 时钟的功能障碍可能直接导致 BD/MDD 的病理生理学变化。我们假设，非 SCN 时钟的昼夜节律功能障碍是情绪障碍的特征标志物，由病理性遗传变异编码。由于 SCN 的网络特征使其特别不易受到干扰，因此先前对 MDD 患者 SCN 输出的研究可能未能检测到影响非 SCN 时钟的遗传缺陷，这些时钟不仅包括大脑中的情绪调节神经元，还包括在人类受试者中可触及的外周细胞。因此，来自患者或小鼠模型的细胞中节律性时钟基因表达的报告者可以提供对时钟分子齿轮的直接检测，这些时钟在患者中可能比 SCN 更能代表调节情绪的神经元。这种方法受到现代生物钟学新见解和工具的启发，将更明确地测试细胞昼夜节律时钟在情绪障碍中的作用。
