Disrupted circadian rhythms in VIP- and PHI-deficient mice
Disrupted circadian rhythms in VIP- and PHI-deficient mice
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DOI：
10.1152/ajpregu.00200.2003
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发表时间：
2003-11-01
影响因子：
2.8
通讯作者：
Waschek, JA
中科院分区：
文献类型：
--
作者：
Colwell, CS;Michel, S;Waschek, JA
相关的神经肽血管活性肠肽（VIP）和肽组氨酸异亮氨酸（PHI）在视交叉上核（SCN）的神经元中以高水平表达，但它们在昼夜节律调节中的功能尚不清楚。为了研究这些肽在体内对昼夜节律系统的作用，开发了一种新的小鼠模型，其中VIP和PHI基因通过同源重组被破坏。在一个光-暗周期中，这些小鼠表现出昼夜节律的活动，这在很大程度上与野生型对照没有区别。在持续黑暗中，VIP/PHI缺陷小鼠的昼夜节律系统表现出明显的异常。活动模式开始类似8小时前预测的前一个光周期。此外，缺乏VIP/ PHI导致自由奔跑时间缩短，昼夜运动活动节律的连贯性和精确性丧失。在大约四分之一的VIP/ PHI小鼠中，在持续黑暗中数周后，轮跑节奏变得缓慢。这些缺陷的另一个突出例子是突变小鼠暴露于骨骼光周期时表达的分裂活动模式。此外，VIP/PHI缺陷型小鼠的昼夜节律系统对光的反应出现缺陷。电生理分析表明，VIP增强野生型和VIP/PHI缺陷小鼠SCN内的抑制性突触传递。总之，观察结果表明，VIP/ PHI肽在昼夜节律振荡的产生以及这些节律与光的正常同步中起着关键作用。
The related neuropeptides vasoactive intestinal peptide ( VIP) and peptide histidine isoleucine ( PHI) are expressed at high levels in the neurons of the suprachiasmatic nucleus (SCN), but their function in the regulation of circadian rhythms is unknown. To study the role of these peptides on the circadian system in vivo, a new mouse model was developed in which both VIP and PHI genes were disrupted by homologous recombination. In a light-dark cycle, these mice exhibited diurnal rhythms in activity which were largely indistinguishable from wild-type controls. In constant darkness, the VIP/PHI-deficient mice exhibited pronounced abnormalities in their circadian system. The activity patterns started similar to 8 h earlier than predicted by the previous light cycle. In addition, lack of VIP/ PHI led to a shortened free-running period and a loss of the coherence and precision of the circadian locomotor activity rhythm. In about one-quarter of VIP/ PHI mice examined, the wheel-running rhythm became arrhythmic after several weeks in constant darkness. Another striking example of these deficits is seen in the split-activity patterns expressed by the mutant mice when they were exposed to a skeleton photoperiod. In addition, the VIP/ PHI-deficient mice exhibited deficits in the response of their circadian system to light. Electrophysiological analysis indicates that VIP enhances inhibitory synaptic transmission within the SCN of wild-type and VIP/ PHI-deficient mice. Together, the observations suggest that VIP/ PHI peptides are critically involved in both the generation of circadian oscillations as well as the normal synchronization of these rhythms to light.