Photic Entrainment ofPeriodMutant Mice is Predicted from Their Phase Response Curves

Abstract

A fundamental property of circadian clocks is that they entrain to environmental cues. The circadian genes, Period1 and Period2, are involved in entrainment of the mammalian circadian system. To investigate the roles of the Period genes in photic entrainment, we constructed phase response curves (PRC) to light pulses for C57BL/6J wild-type, Per1 Ϫ/Ϫ , Per2, and Per3 Ϫ/Ϫ mice and tested whether the PRCs accurately predict entrainment to non-24 light-dark cycles (T-cycles) and constant light (LL). The PRCs of wild-type and Per3 Ϫ/Ϫ mice are similar in shape and amplitude and have relatively large delay zones and small advance zones, resulting in successful entrainment to 26 h T-cycles (T26), but not T21, with similar phase angles. Per1 Ϫ/Ϫ mice have a high-amplitude PRC, resulting in entrainment to a broad range of T-cycles. Per2 Ϫ/Ϫ mice also entrain to a wide range of T-cycles because the advance portion of their PRC is larger than wild types. Period aftereffects following entrainment to T-cycles were similar among all genotypes. We found that the ratio of the advance portion to the delay portion of the PRC accurately predicts the lengthening of the period of the activity rhythm in LL. Wild-type, Per1Ϫ/Ϫ , and Per3 Ϫ/Ϫ mice had larger delay zones than advance zones and lengthened (Ͼ24 h) periods in LL, whereas Per2 Ϫ/Ϫ mice had delay and advance zones that were equal in size and no period lengthening in LL. Together, these results demonstrate that PRCs are powerful tools for predicting and understanding photic entrainment of circadian mutant mice.

Brief light stimulation during the mouse nocturnal activity phase simultaneously induces a decline in core temperature and locomotor activity followed by EEG-determined sleep

“…The typical mouse PRC (see Fig. 3) has a phase delay portion, which is large and a phase advance portion which is very small (32). The T c response curve here presented for the mouse is consistent with the PRC from the same strain to the extent that the largest T c changes elicited are in response to light at CT15 and CT18, with very little change occurring at other circadian times.…”

Mis-expression of the BK K+ channel disrupts suprachiasmatic nucleus circuit rhythmicity and alters clock-controlled behavior

“…High amplitude circuit activity has also been proposed to render the SCN more resistant to external stimuli (51,65). Consistent with this, loss of high amplitude circuit activity is correlated with increased sensitivity to behavioral perturbation in Tg-BK R207Q mice, demonstrated by larger light-induced phase delays and more rapid reentrainment to a phase advance of the LD cycle (Table 1).…”

Distinct patterns of Period gene expression in the suprachiasmatic nucleus underlie circadian clock photoentrainment by advances or delays

“…It has been proposed that M and E oscillators might represent transcription-translation loops of clock genes, with Per1 a part of M and Per2 a part of E (33). Evidence both for and against this proposition has been gathered using animals genetically deficient in Per and Cry genes (6,(34)(35)(36)(37), although Per1-and Per2-deficient mice can show intact phase-shifting responses. Though our results do link Per1 with dawn and Per2 with dusk, they intimate that M and E oscillator components are not only affected by different genes but also may be entrained by distinct molecular mechanisms.…”

“…Photic entrainment of the clock must impact the activities or levels of the molecular components of these loops, and the induction of Per1 and Per2 gene expression is believed to be a critical step in this process (for references and discussion, see ref. 6), but the precise mechanisms underlying shifts of the phase of the clock or changes in its velocity are not certain.…”