Role of the metabotropic glutamate receptor subtype 5 in circadian rhythmmisalignment and depression: Implications for treatment

在2011年，有人说：“生理系统和情绪之间似乎有很强的联系。 监管，尽管这种联系背后的机制尚不清楚。我们令人兴奋的初步数据 提示代谢型谷氨酸受体亚型5(MGluR5)提供了这种共同的机制，并且 我们建议在重度抑郁障碍(MDD)中研究这种关联。这项提议的时机是 严重，因为这种高度流行的慢性和复发性疾病预计将是全球 到2030年疾病负担。此外，传统的MDD治疗成功率很低，有可能 因为经历昼夜节律障碍的MDD患者(这可能是一个重要的子集，如 MDD中睡眠障碍的高发生率表明)不是传统的最佳治疗方法 治疗学。幸运的是，对于这种损伤(计时生物学)，有多种可用的治疗方法 反复证明有效，起效迅速，无副作用。事实上，快速抗抑郁药， 氯胺酮和时间生物学治疗，睡眠剥夺，共享共同的机制，包括在 MGluR5。尽管有这些有利的特性，但由于以下原因，计时生物的利用严重不足： 无法确定那些最有可能做出反应的人，以及缺乏对昼夜节律障碍及其原因的了解 经治疗后得到纠正。对mGluR5的研究可能提供这一所需信息。MGluR5全天 用正电子发射断层扫描(PET)在啮齿类动物体内显示了变异。我们是第一个 在人类身上观察这一点。此外，mGluR5功能障碍也与临床前和临床研究有关。 MDD。在这个创新的提案中，我们利用了数十年来对昼夜节律的研究，这些研究已经 为评估昼夜节律时间提供了一种有效可行的方法。具体地说，上涨之间的时间 褪黑激素分泌水平和睡眠/清醒周期的中点被称为相角 差异(PAD)，健康对照组的最佳时间为6小时。我们将评估36例MDD和16例健康人的PAD 控制参与者(男女代表平等)，以确定偏差的大小 最佳PAD与抑郁症的严重程度相关。我们还将使用PET对mGluR5进行量化 昼夜节律周期内的标准化时间，以确认mGluR5-昼夜节律关系并确定 MGluR5的日变化是否不恰当是非最佳PAD的基础。这将第一次确立， 人类mGluR5表达与昼夜节律的关系(这对 疾病超越了MDD，可能是情绪和昼夜节律的性别差异的基础)。最后，我们会 评估睡眠剥夺疗法对抑郁症患者和对照组昼夜节律的影响。这 将确定哪些时型最适合治疗，以及最佳PAD的修复是否 是治疗效果所必需的。不管结果如何，这项研究将增加我们对昼夜节律的理解 MDD的节律(和错位)以及时间生物学治疗的作用机制。

In 2011, it was stated: “there appears to be a strong association between the circadian system and mood regulation, although the mechanisms that underlie this association are unclear.” Our exciting preliminary data suggests that the metabotropic glutamate receptor subtype 5 (mGluR5) provides this shared mechanism, and we propose to examine this association in Major Depressive Disorder (MDD). The timing of this proposal is critical, as this highly prevalent, chronic and recurrent disorder is predicted to be the leading cause of global disease burden by the year 2030. Further, conventional MDD treatments have low success rates, potentially because MDD patients experiencing circadian rhythm impairment (which may be a significant subset, as suggested by the high rates of sleep disturbances in MDD) are not optimally treated by conventional therapeutics. Luckily, there are multiple available treatments for such impairment (chronobiotics), with repeatedly demonstrated efficacy, rapidity of action, and lack of side effects. In fact, the rapid antidepressant, ketamine, and the chronobiotic treatment, sleep deprivation, share common mechanisms, including action at mGluR5. Despite these advantageous properties, chronobiotics are significantly underutilized due to: the inability to identify those most likely to respond and a lack of understanding of circadian dysfunction and how it is corrected with treatment. Investigation of mGluR5 may provide this needed information. MGluR5 diurnal variation has been shown in vivo using Positron Emission Tomography (PET) in rodents. We were the first to observe this in humans. Further, mGluR5 dysfunction has been implicated in preclinical and clinical studies of MDD. In this innovative proposal, we take advantage of decades of circadian rhythms research that has provided an effective and feasible method of assessing circadian time. Specifically, the time between the rise of melatonin secretion levels and the midpoint of the sleep/wake cycle is referred to as the phase angle difference (PAD), and is optimally 6 hours in healthy controls. We will assess PAD in 36 MDD and 16 healthy control participants (with equal representation of each sex) to determine whether the magnitude of deviation from optimal PAD is associated with depression severity. We will also quantify mGluR5 using PET at standardized times within the circadian cycle, to confirm the mGluR5-circadian relationship and determine whether improper mGluR5 diurnal variation underlies non-optimal PAD. This will establish, for the first time, the relationship between mGluR5 expression and circadian rhythms in humans (which has implications for diseases beyond MDD and may underlie sex differences in mood and circadian regulation). Finally, we will assess the effect of sleep deprivation therapy on circadian rhythms in depressed and control individuals. This will establish which chronotypes are most amendable to treatment and whether restoration of optimal PAD is required for treatment efficacy. Regardless of outcome, this study will increase our understanding of circadian rhythms (and misalignment) in MDD as well as the mechanism of action of chronobiotic treatments.