Fine-Tuning Circadian Rhythms: The Importance of Bmal1 Expression in the Ventral Forebrain.
Fine-Tuning Circadian Rhythms: The Importance of Bmal1 Expression in the Ventral Forebrain.
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DOI：
10.3389/fnins.2017.00055
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发表时间：
2017
影响因子：
4.3
通讯作者：
Sakurai T
中科院分区：
文献类型：
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作者：
Mieda M;Hasegawa E;Kessaris N;Sakurai T
尽管下丘脑的视交叉上核（SCN）充当哺乳动物的中央时钟，但时钟基因的昼夜节律表达不仅在SCN中得到证实，而且在SCN以外的周围组织和脑区域中也得到证实。然而，大脑中视交叉上核外生物钟的生理作用在很大程度上仍然难以捉摸。作为回应，我们培育了 Nkx2.1-Bmal1−/− 小鼠，其中 Bmal1（一种重要的时钟成分）在腹侧前脑（包括视前区、对角带核和除 SCN 之外的大部分下丘脑）中被基因删除。正如预期的那样，在这些小鼠中，下丘脑内侧基底外植体中的 PER2::LUC 振荡急剧减弱，而 SCN 中的 PER2::LUC 振荡则保持不变。尽管 Nkx2.1-Bmal1−/− 小鼠具有节律性和夜间活动性，但它们在 12:12 小时的光：暗循环中以及在持续黑暗的主观夜晚中表现出改变的运动活动模式。对照小鼠在黑暗阶段或主观夜间的前半段比后半段更活跃，而 Nkx2.1-Bmal1−/− 小鼠则表现出相反的运动活动模式。睡眠-觉醒和进食的时间模式也相应改变。这些结果表明，与 SCN 中的机制一样，腹侧前脑中局部 Bmal1 依赖性时钟对于生成昼夜节律行为的精确时间模式至关重要。
Although, the suprachiasmatic nucleus (SCN) of the hypothalamus acts as the central clock in mammals, the circadian expression of clock genes has been demonstrated not only in the SCN, but also in peripheral tissues and brain regions outside the SCN. However, the physiological roles of extra-SCN circadian clocks in the brain remain largely elusive. In response, we generated Nkx2.1-Bmal1−/− mice in which Bmal1, an essential clock component, was genetically deleted specifically in the ventral forebrain, including the preoptic area, nucleus of the diagonal band, and most of the hypothalamus except the SCN. In these mice, as expected, PER2::LUC oscillation was drastically attenuated in the explants of mediobasal hypothalamus, whereas it was maintained in those of the SCN. Although, Nkx2.1-Bmal1−/− mice were rhythmic and nocturnal, they showed altered patterns of locomotor activity during the night in a 12:12-h light:dark cycle and during subjective night in constant darkness. Control mice were more active during the first half than the second half of the dark phase or subjective night, whereas Nkx2.1-Bmal1−/− mice showed the opposite pattern of locomotor activity. Temporal patterns of sleep-wakefulness and feeding also changed accordingly. Such results suggest that along with mechanisms in the SCN, local Bmal1–dependent clocks in the ventral forebrain are critical for generating precise temporal patterns of circadian behaviors.