Lateralization of the central circadian pacemaker output: a test of neural control of peripheral oscillator phase.

To evaluate the contribution of neural pathways to the determination of the circadian oscillator phase in peripheral organs, we assessed lateralization of clock gene expression in Syrian hamsters induced to split rhythms of locomotor activity by exposure to constant light. We measured the ratio of haPer1, haPer2, and haBmal1 mRNA on the high vs. low (H/L) side at 3-h intervals prior to the predicted activity onset (pAO). We also calculated expression on the sides ipsilateral vs. contralateral (I/C) to the side of the suprachiasmatic nucleus (SCN) expressing higher haPer1. The extent of asymmetry in split hamsters varied between specific genes, phases, and organs. Although the magnitude of asymmetry in peripheral organs was never as great as that in the SCN, we observed significantly greater lateralization of clock gene expression in the adrenal medulla and cortex, lung, and skeletal muscle, but not in liver or kidney, of split hamsters than of unsplit controls. We observed fivefold lateralization of expression of the clock-controlled gene, albumin site D-element binding protein (Dbp), in skeletal muscle (H/L: 10.7 +/- 3.7 at 3 h vs. 2.2 +/- 0.3 at 0 h pAO; P = 0.03). Furthermore, tyrosine hydroxylase expression was asymmetrical in the adrenal medulla of split (H/L: 1.9 +/- 0.5 at 0 h) vs. unsplit hamsters (1.2 +/- 0.04; P < 0.05). Consistent with a model of neurally controlled gene expression, we found significant correlations between the phase angle between morning and evening components (psi(me)) and the level of asymmetry (H/L or I/C). Our results indicate that neural pathways contribute to, but cannot completely account for, SCN regulation of the phase of peripheral oscillators.

Circadian organization of tau mutant hamsters: aftereffects and splitting.

Homozygous tau mutant (tau(ss)) hamsters show an extremely short (20 h) circadian period (tau) that is attributable to altered enzymatic activity of casein kinase 1epsilon. It has been proposed that coupling of constituent circadian oscillators is strengthened in tau(ss) hamsters, explaining their tendency to show strong resetting after prolonged exposure to constant darkness. To evaluate further the circadian organization of tau(ss) hamsters, the authors assessed the extent of shortening of period as an aftereffect of exposure to light:dark cycles whose period (T) is 91% of tau and the ability of constant light to induce splitting. They find that tau(ss) hamsters show aftereffects comparable to wild types, indicating that normal CK1epsilon activity is not required for T cycles to shorten tau. This finding also contradicts the proposal that circadian period is homeostatically conserved. However, the authors find that tau(ss) hamsters rarely show splitting in constant light. Furthermore, LL does not induce lengthening of tau or reduction of activity duration (alpha) in these mutants. The authors' findings support the conclusion that the tau mutation alters the coupling between constituent circadian oscillators.