The role of Salt Inducible Kinases in regulating sleep

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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.