The role of Salt Inducible Kinases in regulating sleep

尽管人们越来越认识到睡眠和昼夜节律在多个健康领域的根本重要性，但我们对睡眠的原因以及支撑这一关键行为的分子机制的理解在很大程度上仍然未知。我们建议在分子、神经元和行为水平上研究睡眠信号的基础生物学，以确定调节睡眠的分子途径。为了使睡眠具有恢复作用，突触——神经冲动将信息从一个神经元传递到另一个神经元的点——必须在睡眠期间被重塑，以编码新的记忆和经历。最近的变革性研究表明，突触上的蛋白质被磷酸化，以一种追踪清醒时间的方式标记，这可能是突触在睡眠期间如何重塑的基础。蛋白质被激酶磷酸化，我们之前已经证明盐诱导激酶1调节大脑的昼夜节律。在这项工作的基础上，我们提出了研究盐诱导激酶（SIK）家族在突触蛋白调节中的作用及其在睡眠调节中的作用的实验。我们的方法将包括监测表达单个SIKs不活跃版本的转基因小鼠的睡眠和昼夜节律。小鼠将面临以不同方式改变睡眠和昼夜节律的挑战。这些包括睡眠剥夺，唤醒或促进睡眠的药物，如咖啡因，或夜间光照。然后，我们将评估小鼠的睡眠、昼夜节律行为和突触蛋白磷酸化情况。我们还将通过记录电活动来研究蛋白质磷酸化的变化是否会影响信息在突触中的传递方式。我们预测SIKs活性的丧失将损害或增强对诱导睡眠至关重要的蛋白质磷酸化的某些方面。总的来说，这些实验将提供在分子水平上调节睡眠的关键途径的理解。

Despite the growing appreciation of the fundamental importance of sleep and circadian rhythms across multiple domains of health, our understanding of why we sleep and the molecular mechanisms that underpin this critical behaviour, remain largely unknown. We propose to study the fundamental biology of how sleep is signalled at a molecular, neuronal and behavioural level, to identify the molecular pathways that regulate sleep. In order for sleep to have its restorative effects, synapses - the points at which nerve impulses pass information from one neuron to another - must be remodelled during sleep to encode fresh memories and experiences. Recent transformative research shows that proteins at the synapse are tagged by phosphorylation in a manner that tracks the time spent awake, and that this may underlie the basis of how synapses can be remodelled during sleep. Proteins are phosphorylated by kinases, and we have shown previously that Salt Inducible Kinase 1 regulates circadian rhythms in the brain. Building upon this work, we propose experiments that will investigate the role of the Salt Inducible Kinase (SIK) family on the regulation of synaptic proteins and their role in the regulation of sleep. Our approaches will include monitoring sleep and circadian rhythms in genetically altered mice that express inactive versions of the individual SIKs. The mice will be exposed to challenges that alter sleep and circadian rhythms in different ways. These include sleep deprivation, wake or sleep promoting drugs such as caffeine, or nocturnal light exposure. We will then assess the mice for their resulting sleep and circadian behaviour and protein phosphorylation at the synapse. We will also examine whether the changes in protein phosphorylation affect how information is transmitted at the synapse by recording electrical activity. We predict that the loss of activity of SIKs will impair or enhance certain aspects of protein phosphorylation that are essential for the induction of sleep. Collectively, these experiments will provide an understanding of the key pathways by which sleep is regulated at the molecular level.