Approximately 35% of suprachiasmatic nucleus (SCN) cells express the neuropeptide receptor VPAC2, which plays a critical role in circadian rhythm regulation.
Deletion of the VPAC2 receptor in these cells lengthened the intrinsic circadian rhythm period.
The lengthening of the circadian rhythm period was also observed in the behavioral rhythms of male mice.
Variability in circadian periods increased in SCN slices from mice with VPAC2 cell deletion.
Circadian behavioral rhythms were severely disrupted when VPAC2-expressing cells lost their circadian competence.
VPAC2-expressing cells are a distinct subset within the SCN circuit, essential for maintaining circadian rhythm stability.
Simplified
Circadian (approximately daily) rhythms pervade mammalian behavior. They are generated by cell-autonomous, transcriptional/translational feedback loops (TTFLs), active in all tissues. This distributed clock network is coordinated by the principal circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN). Its robust and accurate time-keeping arises from circuit-level interactions that bind its individual cellular clocks into a coherent time-keeper. Cells that express the neuropeptide vasoactive intestinal peptide (VIP) mediate retinal entrainment of the SCN; and in the absence of VIP, or its cognate receptor VPAC2, circadian behavior is compromised because SCN cells cannot synchronize. The contributions to pace-making of other cell types, including VPAC2-expressing target cells of VIP, are, however, not understood. We therefore used intersectional genetics to manipulate the cell-autonomous TTFLs of VPAC2-expressing cells. Measuring circadian behavioral and SCN rhythmicity in these temporally chimeric male mice thus enabled us to determine the contribution of VPAC2-expressing cells (∼35% of SCN cells) to SCN time-keeping. Lengthening of the intrinsic TTFL period of by deletion of theallele concomitantly lengthened the period of circadian behavioral rhythms. It also increased the variability of the circadian period of bioluminescent TTFL rhythms in SCN slices recordedAbrogation of circadian competence in VPAC2 cells by deletion ofseverely disrupted circadian behavioral rhythms and compromised TTFL time-keeping in the corresponding SCN slices. Thus, VPAC2-expressing cells are a distinct, functionally powerful subset of the SCN circuit, contributing to computation of ensemble period and maintenance of circadian robustness. These findings extend our understanding of SCN circuit topology. CK1ε Tau ex vivo Bmal1
Key numbers
24 h
Period Lengthening
Behavioral period of VPAC2-Cre mice with intact .
∼35%
Cell Deletion Impact
Proportion of SCN cells expressing VPAC2.
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