Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of huntington's disease
Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of huntington's disease
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DOI：
10.1523/jneurosci.0649-07.2007
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发表时间：
2007-07-18
影响因子：
5.3
通讯作者：
Morton, A. Jennifer
中科院分区：
文献类型：
--
作者：
Pallier, Patrick N.;Maywood, Elizabeth S.;Morton, A. Jennifer
携带亨廷顿病 (HD) 突变的转基因 R6/2 小鼠表现出昼夜节律紊乱，并且随着疾病的进展而恶化。到 15 周龄时，它们的异常昼夜节律行为与 HD 患者中的情况相似，并伴有昼夜节律起搏器视交叉上核 (SCN) 中的时钟基因表达失调。然而，我们发现体外检测的 SCN 电生理输出正常。此外，通过对从行为节律瓦解的小鼠身上取出的器官典型SCN切片进行荧光素酶成像体外监测，昼夜节律基因表达的内源节律也正常。我们得出的结论是，在 R6/2 小鼠体内观察到的异常行为和分子昼夜节律是由于传入 SCN 的大脑回路功能障碍引起的，而不是起搏器本身的主要缺陷。由于昼夜节律睡眠中断对认知功能有害，并且 R6/2 小鼠的认知能力下降明显，因此我们测试了是否可以通过使用镇静药物对 R6/2 小鼠进行每日睡眠周期来逆转昼夜节律和认知障碍。每天使用阿普唑仑治疗可以逆转 Per2 和 Prok2 的失调表达，Prok2 是控制行为节律的 SCN 输出因子。它还显着提高了 R6/2 小鼠在两项选择视觉辨别任务中的认知表现。总之，我们的数据首次表明，旨在恢复昼夜节律的治疗不仅可以减缓 HD 的破坏性特征——认知能力下降，还可以改善在这种疾病中受损的其他昼夜节律基因调节功能。
Transgenic R6/2 mice carrying the Huntington's disease (HD) mutation show disrupted circadian rhythms that worsen as the disease progresses. By 15 weeks of age, their abnormal circadian behavior mirrors that seen in HD patients and is accompanied by dysregulated clock gene expression in the circadian pacemaker, the suprachiasmatic nucleus (SCN). We found, however, that the electrophysiological output of the SCN assayed in vitro was normal. Furthermore, the endogenous rhythm of circadian gene expression, monitored in vitro by luciferase imaging of organotypical SCN slices removed from mice with disintegrated behavioral rhythms, was also normal. We concluded that abnormal behavioral and molecular circadian rhythms observed in R6/2 mice in vivo arise from dysfunction of brain circuitry afferent to the SCN, rather than from a primary deficiency within the pacemaker itself. Because circadian sleep disruption is deleterious to cognitive function, and cognitive decline is pronounced in R6/2 mice, we tested whether circadian and cognitive disturbances could be reversed by using a sedative drug to impose a daily cycle of sleep in R6/2 mice. Daily treatment with Alprazolam reversed the dysregulated expression of Per2 and also Prok2, an output factor of the SCN that controls behavioral rhythms. It also markedly improved cognitive performance of R6/2 mice in a two- choice visual discrimination task. Together, our data show for the first time that treatments aimed at restoring circadian rhythms may not only slow the cognitive decline that is such a devastating feature of HD but may also improve other circadian gene-regulated functions that are impaired in this disease.