Abstract
The mammalian pacemaker in the suprachiasmatic nucleus (SCN) contains a population of neural oscillators capable of sustaining cell-autonomous rhythms in gene expression and electrical firing. A critical question for understanding pacemaker function is how SCN oscillators are organized into a coherent tissue capable of coordinating circadian rhythms in behavior and physiology. Here we undertake a comprehensive analysis of oscillatory function across the SCN of the adult PER2::LUC mouse by developing a novel approach involving multi-position bioluminescence imaging and unbiased computational analyses. We demonstrate that there is phase heterogeneity across all three dimensions of the SCN that is intrinsically regulated and extrinsically modulated by light in a region-specific manner. By investigating the mechanistic bases of SCN phase heterogeneity, we show for the first time that phase differences are not systematically related to regional differences in period, waveform, amplitude, or brightness. Furthermore, phase differences are not related to regional differences in the expression of arginine vasopressin and vasoactive intestinal polypeptide, two key neuropeptides characterizing functionally distinct subdivisions of the SCN. The consistency of SCN spatiotemporal organization across individuals and across planes of section suggests that the precise phasing of oscillators is a robust feature of the pacemaker important for its function.
Highlights
The mammalian circadian system controlling daily rhythms in behavior and physiology is an assembly of oscillators regulated by a central pacemaker within the suprachiasmatic nucleus (SCN) of the anterior hypothalamus [1]
Since peak width can be influenced by the phase relationships of underlying oscillators, we assessed the range and deviation of peak times displayed by cell-like regions of interest (ROIs) in the rostral, central, and caudal SCN (Materials and Methods)
Regional differences in period or waveform do not account for regional phase differences Classic theories of circadian organization propose that phase heterogeneity is determined by differences in other oscillatory parameters; we investigated the mechanistic bases of SCN spatiotemporal organization by testing whether SCN regions differed in other circadian parameters that could account for phase differences
Summary
The mammalian circadian system controlling daily rhythms in behavior and physiology is an assembly of oscillators regulated by a central pacemaker within the suprachiasmatic nucleus (SCN) of the anterior hypothalamus [1]. The SCN displays robust electrical and biochemical rhythms that persist in individual neurons after synaptic communication is disrupted [2,3]. Within cells of both the SCN and peripheral tissues, transcriptional-translational feedback loops regulate the rhythmic expression of clock genes and their protein products [4]. The shell and core model indicates that the SCN contains a diverse neural population organized into functional subunits, but it has been argued that dichotomous organizational schemas should be supplemented with topographical descriptions of pacemaker function [14]. Mapping SCN function, has been limited by its complex organization
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