Non-circadian Role for Clock Genes in Sleep Homeostasis

时钟基因在睡眠稳态中的非昼夜节律作用

• 批准号: 7263210
• 负责人: H Craig Heller
• 金额: $ 40.44万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-04 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7263210
• 关键词: Acute; Animals; Area; Arrhythmia; Behavior; Behavioral; Brain; Brain region; Cerebral cortex; Chronic; Circadian Rhythms; Condition; Coupled; Crying; Drosophila genus; Electroencephalography; Enzymes; Exhibits; Gene Expression; Gene Family; Generations; Genes; Homeostasis; Inbred Strains Mice; Individual; Knock-out; Knockout Mice; Lesion; Measures; Messenger RNA; Metabolism; Modeling; Molecular; Molecular Genetics; Monitor; Motor Activity; Mus; Mutant Strains Mice; Mutation; Neurons; Output; Oxidation-Reduction; Periodicity; Pharmaceutical Preparations; Phase; Phenotype; Play; Process; Prosencephalon; Proteins; Recording of previous events; Recovery; Regulation; Relative (related person); Reporting; Research Personnel; Role; Sleep; Sleep Deprivation; Sleep Disorders; Specificity; Structure; Study models; System; Testing; Time; Transcriptional Regulation; Translating; Wakefulness; Wild Type Mouse; awake; base; circadian pacemaker; cryptochrome; day; design; improved; insight; interest; lactate dehydrogenase A; non rapid eye movement; paralogous gene; pressure; response; sleep regulation

DESCRIPTION (provided by applicant): The mechanisms of the homeostatic regulation of sleep are largely unknown, although a role for gene expression seems likely based on genetic and molecular studies. In this proposal we suggest that several of the genes identified as critical components of the circadian pacemaker in the SCN also have a separate, non-circadian role in the cerebral cortex (and perhaps other brain regions) in sleep homeostasis. We found that mice lacking the circadian 'clock'-genes cryptochrome (cry1,2-/-), not only lack circadian rhythms but also exhibit all the electrocortical hallmarks of high sleep pressure. This unexpected phenotype was associated with elevated brain expression of the transcriptional regulators period (per)l, and per2, which are transcriptionally inhibited by CRY1,2. Wild-type mice following sleep deprivation also have elevated levels of per1,2 mRNA in the cortex specifically. Here we propose to confirm and further characterize the relationship between sleep-wake and these molecular changes at both mRNA and protein levels. Determining this relationship and the neuro-anatomical specificity of these changes is critical to test the hypothesis that a transcriptional network of interacting clock genes outside the SCN underlies the sleep homeostat. To separate homeostatic from circadian sleep regulatory aspects, SCN lesions will be performed. We expect that in the absence of circadian output provided by the SCN, the cortical oscillation in per expression will be driven by sleep and wake, as in intact animals. We will directly manipulate this clock-gene network by examining sleep regulation in mice lacking cry1, cry2, per1, per2, clock, and npas2. Mice lacking either cry1 or cry2 will be recorded to assess whether inactivation of only one cry gene can replicate the cry1,2-/-sleep phenotype. CLOCK and NPAS2 are positive transcriptional regulators of per1,2, cry1,2, and other genes, and should provide an important contrast to the cry1,2-/- phenotype. Given the partial redundancy in these gene families, we expect comparisons of mice lacking both per1,2, or both npas2,clock, to be especially informative. An improved understanding of the molecular substrate of sleep homeostasis could be helpful to a wide variety of individuals with acute or chronic sleep problems.

描述（由申请人提供）：尽管基因表达的作用似乎可能基于遗传和分子研究，但睡眠体内稳态调节的机制在很大程度上是未知的。在该提案中，我们建议在SCN中鉴定为昼夜节律起搏器的关键组成部分的几个基因在睡眠稳态中在大脑皮层（也许还有其他大脑区域）中具有单独的非circadian作用。我们发现缺乏昼夜节律的小鼠（Cry1,2 - / - ），不仅缺乏昼夜节律，而且还表现出所有高睡眠压力的电气标志。这种意外的表型与转录调节剂周期（PER）L和PER2的脑表达升高有关，该表型在转录抑制CRY1,2上。睡眠剥夺后的野生型小鼠在皮质中的PER1,2 mRNA水平也升高。在这里，我们建议在mRNA和蛋白质水平上确认并进一步表征睡眠效益与这些分子变化之间的关系。确定这些变化的这种关系和神经 - 动物特异性对于检验SCN以外的相互作用时钟基因的转录网络是睡眠体内稳态的基础至关重要的。为了将体内稳态与昼夜节律调节方面分开，将进行SCN病变。我们预计，在没有SCN提供的昼夜节目的情况下，每个表达中的皮质振荡将由睡眠和唤醒驱动，就像完整的动物一样。我们将通过检查缺乏CRY1，CRY2，PER1，PER2，Clock和NPAS2的小鼠的睡眠调节来直接操纵这个时钟基因网络。将记录缺乏CRY1或CRY2的小鼠，以评估仅一个Cry基因的失活是否可以复制Cry1,2 - / - 睡眠表型。时钟和NPAS2是PER1,2，CRY1,2和其他基因的正转录调节剂，应与CRY1,2 - / - 表型提供重要的对比。鉴于这些基因家族的部分冗余，我们预计缺乏Per1,2或NPAS2，Clock的小鼠的比较特别有用。对睡眠稳态的分子底物的提高理解可能对患有急性或慢性睡眠问题的各种各样的人有所帮助。

项目成果

A non-circadian role for clock-genes in sleep homeostasis: a strain comparison.

• DOI: 10.1186/1471-2202-8-87
• 发表时间: 2007-10-18
• 期刊: BMC neuroscience
• 影响因子: 2.4
• 作者: Franken P;Thomason R;Heller HC;O'Hara BF
• 通讯作者: O'Hara BF

Melanopsin as a sleep modulator: circadian gating of the direct effects of light on sleep and altered sleep homeostasis in Opn4(-/-) mice.

• DOI: 10.1371/journal.pbio.1000125
• 发表时间: 2009-06-09
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Tsai JW;Hannibal J;Hagiwara G;Colas D;Ruppert E;Ruby NF;Heller HC;Franken P;Bourgin P
• 通讯作者: Bourgin P

cGMP-dependent protein kinase type I is implicated in the regulation of the timing and quality of sleep and wakefulness.

• DOI: 10.1371/journal.pone.0004238
• 发表时间: 2009
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Langmesser S;Franken P;Feil S;Emmenegger Y;Albrecht U;Feil R
• 通讯作者: Feil R