Network-mediated encoding of circadian time: the suprachiasmatic nucleus (SCN) from genes to neurons to circuits, and back

Abstract

The transcriptional architecture of intracellular circadian clocks is similar across phyla, but in mammals interneuronal mechanisms confer a higher level of circadian integration. The suprachiasmatic nucleus (SCN) is a unique model to study these mechanisms, as it operates as a ∼24 h clock not only in the living animal, but also when isolated in culture. This "clock in a dish" can be used to address fundamental questions, such as how intraneuronal mechanisms are translated by SCN neurons into circuit-level emergent properties and how the circuit decodes, and responds to, light input. This review addresses recent developments in understanding the relationship between electrical activity, [Ca(2+)]i, and intracellular clocks. Furthermore, optogenetic and chemogenetic approaches to investigate the distinct roles of neurons and glial cells in circuit encoding of circadian time will be discussed, as well as the epigenetic and circuit-level mechanisms that enable the SCN to translate light input into coherent daily rhythms.

Figure 1.

Encoding circadian time in mammals from genes to behavior. A, A simplified model of the intracellular molecular clockwork sustaining ∼24 h oscillations in SCN neurons. TTFLs, based on E-boxes, are synchronized to circadian oscillations of cytosolic Ca²⁺ and cAMP, via CRE boxes. GPCR-mediated peptidergic signaling and synaptic connectivity provide circuit-derived reinforcement cues to the intracellular clocks, by impinging on the Ca²⁺ and cAMP oscillations and CREs. B, Representation of the spatiotemporal wave of clock gene expression traveling across SCN tissue (frontal view). The anatomical and cellular architecture of the SCN, as well as the spatiotemporal wave, are preserved in isolated SCN cultures, thus showing them as intrinsic features of the SCN circuit. C, The intrinsically generated spatiotemporal wave is modified in vivo by subjective experience of light. Under short day lengths, SCN neurons display a similar timing of rhythms in protein expression. This phase clustering produces an overall waveform with short duration of peak expression. Phase differences among SCN neurons increase with day length, and this temporal segregation increases peak width at population level. Changes in the spatiotemporal wave are then translated into adaptive behavioral responses, such as variations in locomotor activity.