Photic Entrainment of the Circadian System

Abstract

Circadian rhythms are essential for the survival of all organisms, enabling them to predict daily changes in the environment and time their behaviour appropriately. The molecular basis of such rhythms is the circadian clock, a self-sustaining molecular oscillator comprising a transcriptional-translational feedback loop. This must be continually readjusted to remain in alignment with the external world through a process termed entrainment, in which the phase of the master circadian clock in the suprachiasmatic nuclei (SCN) is adjusted in response to external time cues. In mammals, the primary time cue, or "zeitgeber", is light, which inputs directly to the SCN where it is integrated with additional non-photic zeitgebers. The molecular mechanisms underlying photic entrainment are complex, comprising a number of regulatory factors. This review will outline the photoreception pathways mediating photic entrainment, and our current understanding of the molecular pathways that drive it in the SCN.

Keywords: SCN; circadian; clock; entrainment; light; zeitgeber.

Figure 1

The circadian clock. The core circadian clock consists of a molecular transcriptional-translational feedback loop in which the transcription factors, CLOCK and BMAL1, heterodimerise and induce expression of the core clock genes, Per and Cry, via E-box response elements. PER and CRY then feedback onto CLOCK and BMAL1 by inhibiting their transcriptional activity. This feedback loop cycles with a period of around 24 h, therefore it must be continually readjusted to be aligned with the external world. The primary time cue for this is the daily light/dark cycle. Light information is transmitted via the retinohypothalamic tract (RHT) directly to the master clock in the suprachiasmatic nucleus (SCN).

Figure 2

The phase response curve. The phase response curve demonstrates the effect of light exposure at different times of the circadian cycle on the phase of the circadian clock. Light delivered during the subjective day, the ‘dead-zone’ will have no effect on the phase of the clock (A). Light exposure during the early subjective night will lead to delays in the phase of the clock (B). Whereas light exposure at the end of the subjective night will lead to phase advances (C). This is demonstrated by representative actograms showing free running rest/activity rhythms (panels A–C); black bars represent periods of activity and black lines indicate rest.

Figure 3

Molecular photoentrainment of the SCN. The light-induced release of glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP) from the RHT nerve terminals leads to a rise in intracellular Ca²⁺ and cAMP levels in the SCN. These trigger a cascade of events including activation of protein kinase A (PKA), which activates the transcription factor cAMP response element-binding protein (CREB), together with co-activators such as CREB-regulated transcription coactivator 1 (CRTC1). This leads to the upregulation of CRE-driven genes, including the core clock component, Per1 (1). In addition, Sik1 is upregulated, which feedbacks on the CREB pathway by phosphorylation of CRTC1. This deactivates CRTC1 leading to a decline in CREB-induced gene transcription and therefore a decline in Per1 expression (2). In parallel, the activation of ERK1/2 by Ca²⁺ influx leads to the upregulation of the immediate-early transcription factors JUN and FOS. These heterodimerise to form AP-1, which drives Per2 transcription leading to an increase in Per2 expression (3). Adenosine, which accumulates in the extracellular space during wakefulness, modulates these light-activated signalling pathways. Adenosine predominantly signals through the G_i (inhibitory) coupled A₁ receptor in the SCN, which results in a decrease in intracellular cAMP and Ca²⁺ levels, and therefore a downregulation of the subsequent signalling events (4). Figure created with BioRender.com.