Melanopsin as a sleep modulator: circadian gating of the direct effects of light on sleep and altered sleep homeostasis in Opn4(-/-) mice.
Melanopsin as a sleep modulator: circadian gating of the direct effects of light on sleep and altered sleep homeostasis in Opn4(-/-) mice.
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DOI：
10.1371/journal.pbio.1000125
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发表时间：
2009-06-09
期刊：
影响因子：
9.8
通讯作者：
Bourgin P
中科院分区：
文献类型：
--
作者：
Tsai JW;Hannibal J;Hagiwara G;Colas D;Ruppert E;Ruby NF;Heller HC;Franken P;Bourgin P
对缺乏蓝光敏感色素黑视蛋白的小鼠进行的分析表明，光对行为和脑电图的直接影响取决于一天中的时间。这些数据进一步表明黑视蛋白在睡眠稳态中发挥着意想不到的作用。光可以通过明确的昼夜节律途径间接影响睡眠和警觉性，也可以通过尚不清楚的机制直接影响睡眠和警觉性。黑视蛋白 (Opn4) 是一种视网膜感光色素，对于向大脑传递非视觉光信息至关重要。通过对黑视蛋白缺陷 (Opn4−/−) 小鼠在各种光暗 (LD) 时间表下的睡眠和皮层电图 (ECoG) 的广泛表征，我们评估了黑视蛋白在介导光对睡眠和 ECoG 活动的影响中的作用。在对照小鼠中，在习惯性黑暗时期给予的光脉冲很容易诱导睡眠，而在习惯性光照期间给予的暗脉冲则诱导醒来，并伴有明显的 theta (7-10 Hz) 和 gamma (40-70 Hz) 活动，ECoG 与警觉性相关。相比之下，光无法诱导 Opn4−/− 小鼠睡眠，并且暗脉冲诱导的 θ 和 γ 活性增加被延迟。根据 LD 1-h∶1-h 时间表进行的 24 小时记录表明，Opn4−/− 小鼠对光的反应失败仅限于主观黑暗期。在 Opn4−/− 小鼠中，光诱导的视交叉上核 (SCN) 和睡眠活跃的腹外侧视前神经元 (VLPO) 神经元中的 c-Fos 免疫反应性显着降低，这表明这两种睡眠调节结构都参与了黑视蛋白介导的光效应。除了这些急性光效应外，Opn4−/− 小鼠在 LD 12:12 时间表的 12 小时光照期内睡眠时间减少了 1 小时，原因是清醒时间延长。尽管睡眠时间减少，但 Opn4−/− 小鼠的 ECoG delta 功率（睡眠需求的标志）在大部分（主观）黑暗期中都减少了。 Opn4−/− 小鼠在 6 小时睡眠剥夺后达到的 Delta 功率也同样降低。在小鼠中，黑视蛋白对光对睡眠的直接影响的贡献仅限于黑暗或活跃时期，这表明在这个昼夜节律阶段，黑视蛋白补偿了其他光编码通路（例如视杆细胞和视锥细胞）的光敏感性的昼夜节律变化。此外，我们的研究表明，黑视蛋白的缺乏会改变睡眠稳态。这些发现要求重新评估光对哺乳动物生理和行为的作用。光以两种方式影响睡眠：间接通过昼夜节律的相位调整，以及直接通过独立于昼夜节律系统的非视觉机制。光的直接影响包括促进夜间活动动物的睡眠和昼夜动物的警觉性。我们分析了缺乏黑视蛋白（Opn4 -/-）的小鼠在各种明暗方案下的睡眠和脑电图（EEG），黑视蛋白是一种视网膜感光色素，对于向大脑传递光级信息至关重要，以确定黑视蛋白（而不是视杆细胞和视锥细胞）在调节光的这些直接影响中的作用。我们发现，黑视蛋白在主观黑暗时期介导光的直接影响，而视杆细胞和视锥细胞在光照时期促成这些影响。我们发现 Opn4 −/− 小鼠下丘脑前部的“睡眠活跃”（即甘丙肽阳性）神经元不会被光激活，这表明这些神经元是光促进睡眠的回路的一部分。此外，根据脑电图 theta 和 gamma 活动增加的减少来判断 Opn4 −/− 小鼠中，过渡到黑暗的警报效果不太明显。最后，出乎意料的是，在基线和睡眠剥夺条件下，Opn4 -/− 小鼠在清醒期间积累的睡眠需求率（量化为脑电图增量功率）均有所减少，这表明感光色素参与了睡眠的稳态调节。我们得出的结论是，黑视蛋白有助于光和黑暗的直接影响，并与昼夜节律和稳态驱动相互作用，决定睡眠和清醒的发生和质量。如果在人类身上得到证实，我们的观察结果将应用于光的临床使用以及社会照明条件。
Analyses in mice deficient for the blue-light-sensitive photopigment melanopsin show that direct effects of light on behavior and EEG depend on the time of day. The data further suggest an unexpected role for melanopsin in sleep homeostasis. Light influences sleep and alertness either indirectly through a well-characterized circadian pathway or directly through yet poorly understood mechanisms. Melanopsin (Opn4) is a retinal photopigment crucial for conveying nonvisual light information to the brain. Through extensive characterization of sleep and the electrocorticogram (ECoG) in melanopsin-deficient (Opn4−/−) mice under various light–dark (LD) schedules, we assessed the role of melanopsin in mediating the effects of light on sleep and ECoG activity. In control mice, a light pulse given during the habitual dark period readily induced sleep, whereas a dark pulse given during the habitual light period induced waking with pronounced theta (7–10 Hz) and gamma (40–70 Hz) activity, the ECoG correlates of alertness. In contrast, light failed to induce sleep in Opn4−/− mice, and the dark-pulse-induced increase in theta and gamma activity was delayed. A 24-h recording under a LD 1-h∶1-h schedule revealed that the failure to respond to light in Opn4−/− mice was restricted to the subjective dark period. Light induced c-Fos immunoreactivity in the suprachiasmatic nuclei (SCN) and in sleep-active ventrolateral preoptic (VLPO) neurons was importantly reduced in Opn4−/− mice, implicating both sleep-regulatory structures in the melanopsin-mediated effects of light. In addition to these acute light effects, Opn4−/− mice slept 1 h less during the 12-h light period of a LD 12∶12 schedule owing to a lengthening of waking bouts. Despite this reduction in sleep time, ECoG delta power, a marker of sleep need, was decreased in Opn4−/− mice for most of the (subjective) dark period. Delta power reached after a 6-h sleep deprivation was similarly reduced in Opn4−/− mice. In mice, melanopsin's contribution to the direct effects of light on sleep is limited to the dark or active period, suggesting that at this circadian phase, melanopsin compensates for circadian variations in the photo sensitivity of other light-encoding pathways such as rod and cones. Our study, furthermore, demonstrates that lack of melanopsin alters sleep homeostasis. These findings call for a reevaluation of the role of light on mammalian physiology and behavior. Light affects sleep in two ways: indirectly through the phase adjustment of circadian rhythms and directly through nonvisual mechanisms that are independent of the circadian system. The direct effects of light include the promotion of sleep in night-active animals and of alertness in diurnal species. We analyzed sleep and the electroencephalogram (EEG) under various light–dark regimens in mice lacking melanopsin (Opn4 −/−), a retinal photopigment crucial for conveying light-level information to the brain, to determine the role of melanopsin, as opposed to rod and cones, in mediating these direct effects of light. We show that melanopsin mediates the direct effects of light during the subjective dark period, whereas rods and cones contribute to these effects in the light period. Our finding that “sleep-active” (i.e., galanin-positive) neurons of the anterior hypothalamus are not activated by light in Opn4 −/− mice suggests that these neurons are part of the circuitry whereby light promotes sleep. Also, the alerting effects of transitions into darkness were less pronounced in Opn4 −/− mice judged on the reduced increase in EEG theta and gamma activity. Finally, and unexpectedly, the rate at which the need for sleep, quantified as EEG delta power, accumulated during wakefulness was found to be reduced in Opn4 −/− mice both during baseline and sleep deprivation conditions, implicating a photopigment in the homeostatic regulation of sleep. We conclude that melanopsin contributes to the direct effects of light and darkness, and in interaction with circadian and homeostatic drive, determines the occurrence and quality of both sleep and waking. If confirmed in humans, our observations will have applications for the clinical use of light as well as for societal lighting conditions.
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影响因子：
3.3
作者：
Gaus, SE;Strecker, RE;Saper, CB
通讯作者：
Saper, CB
影响因子：
25
作者：
Gooley, JJ;Lu, J;Saper, CB
通讯作者：
Saper, CB
影响因子：
64.8
作者：
Gueler, Ali D.;Ecker, Jennifer L.;Hattar, Samer
通讯作者：
Hattar, Samer
影响因子：
2.9
作者：
BORBELY, AA;HUSTON, JP;WASER, PG
通讯作者：
WASER, PG
DOI：
10.1073/pnas.0602006103
发表时间：
2006-05-02
影响因子：
11.1
作者：
Franken, P;Dudley, CA;McKnight, SL
通讯作者：
McKnight, SL