Soriano award lecture: Light, circadian rhythms and sleep: Mechanisms to new therapeutics

Abstract

Until recently, it seemed inconceivable to most vision researchers and ophthalmologists that there could be an unrecognised class of light sensor (photoreceptor) within the eye. However, by studying how circadian rhythms and sleep are regulated by the dawn/dusk cycle we demonstrated that there exists a “3rd class” of photoreceptor within the eye based upon a small number of photosensitive retinal ganglion cells (pRGCs) that utilise the blue light sensitive photopigment melanopsin (OPN4). The first part of the presentation will consider the discovery and clinical importance of the “third” photoreceptor system of the eye. The second part of the talk will address how these photoreceptors signal light to the molecular clockwork and by what means this pathway is modified by sleep history. There has been remarkable progress in understanding the complex intracellular mechanisms that generate circadian rhythms, the molecular pathways whereby the pRGCs entrain circadian biology and sleep has remained poorly understood. The suprachiasmatic nuclei (SCN) are the site of the primary circadian pacemakers within the mammalian brain. Until recently, the model for entrainment involved a simple linear pathway whereby glutamate release from the pRGCs resulted in Ca2+ influx and raised intracellular cAMP in SCN neurones, which in turn resulted in CREB phosphorylation leading to increased transcription of two key clock genes, Per1 and Per2. This signal then advanced or delayed the molecular clockwork. However, an important feature of entrainment is that circadian responses to light are limited – as typified by jet-lag. Full recovery from jet-lag requires a day for every time-zone crossed. We addressed this issue and have identified and characterized a key role for Salt Inducible Kinase 1 (SIK1) and the CREB-regulated transcription co-activator 1 (CRTC1) in clock re-setting. However, our most recent findings have shown that light entrainment also involves the parallel activation of a Ca2+-ERK1/2-AP-1 signalling pathway. Thus both CRE and AP-1 regulatory elements drive light-induced clock gene expression. In addition, whilst light activation of the Ca2+-ERK1/2-AP-1 signalling pathway increases Per1 and Per2 expression, sleep/wake behaviour alters the effects of light on the clock. Our proposed mechanism suggests that adenosine acts as a signalling molecule that encodes wake duration. Adenosine acts via inhibitory A1 receptors on the SCN to inhibit the Ca2+-ERK1/2-AP-1 signalling pathway, which in turn, reduces the expression of Per1 and Per2. Thus sleep/wake history, encoded by adenosine, reduces the phase shifting effects of light upon the circadian system, altering sleep/wake timing. Finally, the talk will explore how such signalling pathways provide a new target for the regulation of circadian rhythms and the “pharmacological” replacement of light for sleep/wake re-setting in individuals lacking eyes or other individuals with severe circadian rhythm disruption.