Effects of the Duper Mutation on Responses to Light

Abstract

The duper mutation in Syrian hamsters shortens the free-running period (τDD) of locomotor activity by approximately 1 h when expressed on the wild-type background and by 2 h on the tau mutant background ("super duper"). In either case, duper markedly amplifies the phase response curve (PRC) of the light pulse. This work examined whether the duper mutation alters parametric as well as nonparametric properties, intensity thresholds, and noncircadian responses to light. Furthermore, it assessed the effects of duper on the range of entrainment and circadian aftereffects. In the first study, duper mutant and wild-type (wt) hamsters showed a similar intensity threshold for light-induced phase shifts. In the second, wt, tau mutant, and super duper hamsters were exposed to LD cycles whose period (T) progressively shortened. Regardless of whether the light phase was held at 50% of T or fixed at 3 h, super duper mutants entrained to a wider range of T cycles and showed aftereffects upon release into DD. In the third study, τLL was measured in mutant and wt hamsters that were maintained for 30-day intervals in constant light of progressively greater intensities. With increasing light intensity, the circadian period shortened in duper mutants. Circadian rhythms of super duper hamsters were disrupted at light intensities considerably below those that induced arrhythmicity in wt, tau heterozygote, or duper homozygote hamsters. In the fourth study, hamsters that were wt or homozygous for duper received two 15-min light pulses: the first at CT14 to CT16 or CT17 to CT19 and the second 2 h later. As expected, wt and duper mutants showed weak and strong resetting, respectively. Light pulses in early subjective night had an additive effect in mutant but not in wt hamsters, indicating that larger phase shifts of the pacemaker take longer to complete. Finally, super duper hamsters showed slightly but not significantly more negative masking than did wt or duper mutant hamsters. These results indicate that the duper mutation affects the properties of the central circadian pacemaker. The mutant allele affects not only the PRC but also parametric responses to light.

Phase Resetting in Duper Hamsters

“…Although the duper mutation does not affect the stability or precision of free-running circadian rhythms in DD (Bittman, 2012, 2014), several of our observations of responses to photic manipulations provide evidence of lability and can be used to gain insight into circadian organization. First, we found that more than half of the duper hamsters transferred from LL to DD at CT 18 experienced a striking loss of circadian rhythmicity.…”

“…We sought to determine whether a reduction of coupling strength could reproduce the essential features of the duper behavioral phenotype: shortened period, reduced amplitude (suggested by the gene expression analysis in Krug et al, 2011), type 0 photic PRC, increased range of entrainment (Bittman, 2014), and large, variable shifts following LL to DD transitions at CT 18, sometimes with transient loss of circadian rhythms. To this end, we employed a relatively simple model (Figure 7) consisting of coupled Goodwin oscillators adapted from Gonze et al (2005).…”

“…Thus, it seems possible that the duper mutation may disrupt the SCN function or block its output or that the integration of cellular rhythms may be altered in a way similar to that seen in constant bright light. To evaluate these possibilities, we used autocorrelation analysis to compare these records of duper hamsters showing ultradian rhythms after this transition with those of SCN-lesioned tau mutant hamsters in DD (Bittman and Monecke, unpublished data) or of dupers in constant bright light (~300 lux; Bittman, 2014). SCN-lesioned tau hamsters displayed weak circadian rhythms or were arrhythmic but did not show ultradian wheel-running activity.…”

Suprachiasmatic function in a circadian period mutant: Duper alters light‐induced activation of vasoactive intestinal peptide cells and PERIOD1 immunostaining

“…The finding that the duper allele amplifies the phase response curve (Krug et al, 2011; Bittman, 2014; Manoogian et al, 2015) and alters the latency with which hamsters entrain upon a shift of photoperiod (Kumar et al, unpublished) suggests that this mutation alters communication between the SCN core and shell. VIP coordinates the phase of cell autonomous oscillators throughout the SCN (Harmar et al, 2002; Maywood et al, 2011), exerting concentration-dependent effects upon SCN cell synchrony and entrainment (An et al, 2013).…”

“…Unlike tau hamsters, duper mutants entrain to a 14:10LD cycle and show a high amplitude phase response curve (Krug et al, 2011; Manoogian et al, 2015). The duper phenotype is not attributable to a change in retinal sensitivity, as the intensity threshold for light-induced phase shifts is similar to the wild type (Bittman, 2014). The duper mutation speeds oscillations of a Bmal1 luminescent reporter in SCN slices, but does not alter the period of embryonic fibroblasts or adult liver cell cultures (Kumar and Bittman, unpublished data).…”