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Distinct Patterns of Period Gene Expression in the Suprachiasmatic Nucleus Underlie Circadian Clock Photoentrainment by Advances Or Delays

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Distinct Patterns of Period Gene Expression in the Suprachiasmatic Nucleus Underlie Circadian Clock Photoentrainment by Advances Or Delays University of Massachusetts Medical School eScholarship@UMMS Neurobiology Publications and Presentations Neurobiology 2011-10-11 Distinct patterns of Period gene expression in the suprachiasmatic nucleus underlie circadian clock photoentrainment by advances or delays William J. Schwartz University of Massachusetts Medical School Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/neurobiology_pp Part of the Neuroscience and Neurobiology Commons Repository Citation Schwartz WJ, Tavakoli-Nezhad M, Lambert CM, Weaver DR, de la Iglesia HO. (2011). Distinct patterns of Period gene expression in the suprachiasmatic nucleus underlie circadian clock photoentrainment by advances or delays. Neurobiology Publications and Presentations. https://doi.org/10.1073/ pnas.1107848108. Retrieved from https://escholarship.umassmed.edu/neurobiology_pp/114 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Neurobiology Publications and Presentations by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. Distinct patterns of Period gene expression in the suprachiasmatic nucleus underlie circadian clock photoentrainment by advances or delays William J. Schwartza,1, Mahboubeh Tavakoli-Nezhada, Christopher M. Lambertb, David R. Weaverb, and Horacio O. de la Iglesiac,1 Departments of aNeurology and bNeurobiology, University of Massachusetts Medical School, Worcester, MA 01655; and cDepartment of Biology, University of Washington, Seattle, WA 98195 Edited by Michael Rosbash, Howard Hughes Medical Institute, Waltham, MA, and approved September 9, 2011 (received for review May 19, 2011) The circadian clock in the mammalian hypothalamic suprachias- and Per3) genes is activated. PER proteins accumulate in the matic nucleus (SCN) is entrained by the ambient light/dark cycle, cytoplasm, are regulated through their phosphorylation and their which differentially acts to cause the clock to advance or delay. association with proteins encoded by the Cryptochrome (Cry1 and Light-induced changes in the rhythmic expression of SCN clock Cry2) genes, and translocate to the nucleus to negatively regulate genes are believed to be a critical step in this process, but how the their own transcription by interfering with the activity of the two entrainment modalities—advances vs. delays—engage the CLOCK:BMAL1 dimers. PER2 and Rev-erb-α proteins are part molecular clockwork remains incompletely understood. We inves- of a second feedback loop that regulates rhythmic Bmal1 gene tigated molecular substrates of photic entrainment of the clock in transcription. Photic entrainment of the clock must impact the the SCN by stably entraining hamsters to T cycles (non–24-h light/ activities or levels of the molecular components of these loops, dark cycles) consisting of a single 1-h light pulse repeated as either and the induction of Per1 and Per2 gene expression is believed to a short (23.33-h) or a long (24.67-h) cycle; under these conditions, be a critical step in this process (for references and discussion, the light pulse of the short cycle acts as “dawn,” whereas that of see ref. 6), but the precise mechanisms underlying shifts of the the long cycle acts as “dusk.” Analyses of the expression of the phase of the clock or changes in its velocity are not certain. photoinducible and rhythmic clock genes Period 1 and 2 (Per1 and Here we report our analysis of molecular substrates of en- Per2 ) in the SCN revealed fundamental differences under these trainment in the SCN of animals photically entrained to T cycles, two entrainment modes. Light at dawn advanced the clock, ad- i.e., non–24-h Zeitgeber cycles. We have used a previously de- Per1 vancing the onset of the mRNA rhythm and acutely increasing scribed paradigm (7, 8) in which circadian locomotor (wheel mRNA transcription, whereas light at dusk delayed the clock, running) activity of Syrian hamsters can be stably entrained by Per2 delaying the offset of the mRNA rhythm and tonically increas- a single 1-h light pulse repeated as a T cycle that is either shorter ing mRNA stability. The results suggest that the underlying molec- or longer than 24 h by 40 min per cycle. As shown in Fig. 1, the ular mechanisms of circadian entrainment differ with morning light pulse in the short (23.33-h) or long (24.67-h) cycle falls at a (advancing) or evening (delaying) light exposure, and such differ- different phase of the clock’s oscillation to attain steady-state en- ences may reflect how entrainment takes place in nocturnal ani- trainment, specifically as a phase-advancing/period-accelerating mals under natural conditions. pulse acting as the short cycle’s “dawn” (following the locomotor bout for the nocturnally active hamster) or as a phase-delaying/ circadian synchronization | circadian clock resetting | light entrainment period-decelerating pulse acting as the long cycle’s “dusk” (preceding the locomotor bout). To determine how differential fundamental feature of the circadian clock that regulates entrainment by a morning or an evening light pulse affects SCN A daily behavioral and physiological rhythmicity is its en- clock genes, we analyzed the expression of the rhythmic, pho- trainment to the environmental cycle of light and darkness. By toinducible genes Per1 and Per2 in groups of hamsters killed at ’ “ ” matching the clock s endogenous ( free-running ) period to that different phases of these cycles. Our results indicate that Per of the ambient day/night cycle, entrainment ensures that the gene expression patterns differ under entrainment to short or phase relationship between clock and external day remains stable long T cycles, and suggest that distinct molecular mechanisms over time, thereby synchronizing body rhythms to local time. underlie these contrasting entrainment modes. Light is the clock’s preeminent entraining cue (Zeitgeber), and the clock responds to light by changing its angular velocity and shifting Results its phase. To match its oscillation to that of the Zeitgeber, the clock ’ Differential Phase of Entrainment to Short and Long T Cycles. The can increase its velocity and advance its phase if the clock s free- different patterns of entrainment to short and long T cycles running period is too long, or it can decrease its velocity and delay shown in Fig. 1 are predicted by entrainment theory and pre- its phase if its free-running period is too short (1, 2). viously confirmed in several species, including Syrian hamsters In mammals, the master circadian clock is located in the (7, 9, 10). To collect and compare data from groups of animals suprachiasmatic nucleus (SCN) in the anterior hypothalamus (3). entrained to these two schedules, we converted time (in hours) to The SCN is composed of multiple, coupled single-cell circadian degrees of arc, where one circadian cycle equals 360° (thus, 1° is oscillators (4), and analyses of induced and spontaneous muta- tions, gene sequence homologies, and protein-protein inter- actions have identified candidate regulatory molecules and Author contributions: W.J.S., D.R.W., and H.O.d.l.I. designed research; W.J.S., M.T.-N., biochemical processes that are likely to constitute the basic in- C.M.L., D.R.W., and H.O.d.l.I. performed research; C.M.L. and D.R.W. contributed new tracellular oscillatory mechanism (5). Genes at the core of the reagents/analytic tools; W.J.S., D.R.W., and H.O.d.l.I. analyzed data; and W.J.S., D.R.W., clock function within autoregulatory feedback loops, with pro- and H.O.d.l.I. wrote the paper. teins rhythmically suppressing the transcription of their own The authors declare no conflict of interest. mRNAs. When the basic helix–loop–helix transcription factors This article is a PNAS Direct Submission. CLOCK (or NPAS2) and BMAL1 dimerize and bind to E-box 1To whom correspondence may be addressed. E-mail: [email protected] NEUROSCIENCE enhancer elements, the transcription of the Period (Per1, Per2, or [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1107848108 PNAS | October 11, 2011 | vol. 108 | no. 41 | 17219–17224 Fig. 1. T-cycle entrainment by advances or delays in Syrian hamsters. (Left) Representative double-plotted actogram of wheel-running for an animal entrained to a 1-h light pulse (white diagonal bar) every 23.33 h; the light pulse falls in the late subjective night (as dawn, at the end of the locomotor activity bout). (Right) Representative actogram of wheel-running for an animal entrained to a 1-h light pulse every 24.67 h; the light pulse falls in the early subjective night (as dusk, at the beginning of the locomotor activity bout). Note that under both T cycles, time 0° corresponds to the end of subjective night. ∼0.0648 h for animals in the short 23.33-h T cycle and 0.0685 h for animals in the long 24.67-h T cycle). By convention for nocturnally active animals, 0° represents dawn (following the subjective night, coinciding with the end of the light pulse in the short T cycle) and 180° represents dusk (preceding the subjective night, coinciding with the end of the light pulse in the long T Fig. 2. Characterization of T-cycle entrainment by advances or delays. (A) cycle; Fig. 1). Adult male hamsters entrained to these cycles were Pineal melatonin content of glands pooled from animals entrained to either killed in groups at 45° intervals across the circadian cycle (n =3 the 23.33-h or the 24.67-h T cycle and killed during subjective day (at 0°, 45°, animals at each of eight time points for each T-cycle group, with 90°, and 135°) or subjective night (at 180°, 225°, 270°, and 315°; n =2–3 time points from 0° to 135° designated as subjective day and those animals per time point for each T-cycle group, as a few glands were lost at from 180° to 315° as subjective night), and their brains were cut some time points; mean ± SEM).
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