Serotonin agonist quipazine induces photic-like phase shifts of the circadian activity rhythm and c-Fos expression in the rat suprachiasmatic nucleus

Nonphotic stimuli can reset and entrain circadian activity rhythms in hamsters and mice, and serotonin is thought to be involved in the phase-resetting effects of these stimuli. In the present study, the authors examined the effect of the serotonin agonist quipazine on circadian activity rhythms in three inbred strains of rats (ACI, BH, and LEW). Furthermore, they investigated the effect of quipazine on the expression of c-Fos in the mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN). Quipazine reduced the amount of running wheel activity for 3 h after treatment, however, no long-term changes in tau and in the activity level were observed. More important, quipazine induced significant phase advances of the activity rhythm and c-Fos production in the SCN at the end of the subjective night (Circadian Time [CT] 22), whereas neither phase shifts nor c-Fos induction were observed during the subjective day. Quipazine injections also resulted in moderate phase delays at the beginning of the subjective night (CT 14). A similar phase-response characteristic typically can be observed for photic stimuli. By contrast, nonphotic stimuli normally produce phase advances during the subjective day. The present results suggest species differences between the hamster and the rat with respect to the serotonergic action on circadian timekeeping and indicate that serotonergic pathways play a role in the transmission of photic information to the SCN of rats.     

Signaling in the mammalian circadian clock: the NO/cGMP pathway

Mammalian circadian rhythms are generated by a hypothalamic suprachiasmatic nuclei (SCN) clock. Light pulses synchronize body rhythms by inducing phase delays during the early night and phase advances during the late night. Phosphorylation events are known to be involved in circadian phase shifting, both for delays and advances. Pharmacological inhibition of the cGMP-dependent kinase (cGK) or Ca2+/calmodulin-dependent kinase (CaMK), or of neuronal nitric oxide synthase (nNOS) blocks the circadian responses to light in vivo. Light pulses administered during the subjective night, but not during the day, induce rapid phosphorylation of both p-CAMKII and p-nNOS (specifically phosphorylated by CaMKII). CaMKII inhibitors block light-induced nNOS activity and phosphorylation, suggesting a direct pathway between both enzymes. Furthermore, SCN cGMP exhibits diurnal and circadian rhythms with maximal values during the day or subjective day. This variation of cGMP levels appears to be related to temporal changes in phosphodiesterase (PDE) activity and not to guanylyl cyclase (GC) activity. Light pulses increase SCN cGMP levels at circadian time (CT) 18 (when light causes phase advances of rhythms) but not at CT 14 (the time for light-induced phase delays). cGK II is expressed in the hamster SCN and also exhibits circadian changes in its levels, peaking during the day. Light pulses increase cGK activity at CT 18 but not at CT 14. In addition, cGK and GC inhibition by KT-5823 and ODQ significantly attenuated light-induced phase shifts at CT 18. This inhibition did not change c-Fos expression SCN but affected the expression of the clock gene per in the SCN. These results suggest a signal transduction pathway responsible for light-induced phase advances of the circadian clock which could be summarized as follows: Glu-Ca2+-CaMKII-nNOS-GC-cGMP-cGK-->-->clock genes. This pathway offers a signaling window that allows peering into the circadian clock machinery in order to decipher its temporal cogs and wheels.     

Cocaine modulates pathways for photic and nonphotic entrainment of the mammalian SCN circadian clock

Cocaine abuse is highly disruptive to circadian physiological and behavioral rhythms. The present study was undertaken to determine whether such effects are manifest through actions on critical photic and nonphotic regulatory pathways in the master circadian clock of the mouse suprachiasmatic nucleus (SCN). Impairment of SCN photic signaling by systemic (intraperitoneal) cocaine injection was evidenced by strong (60%) attenuation of light-induced phase-delay shifts of circadian locomotor activity during the early night. A nonphotic action of cocaine was apparent from its induction of 1-h circadian phase-advance shifts at midday. The serotonin receptor antagonist, metergoline, blocked shifting by 80%, implicating a serotonergic mechanism. Reverse microdialysis perfusion of the SCN with cocaine at midday induced 3.7 h phase-advance shifts. Control perfusions with lidocaine and artificial cerebrospinal fluid had little shifting effect. In complementary in vitro experiments, photic-like phase-delay shifts of the SCN circadian neuronal activity rhythm induced by glutamate application to the SCN were completely blocked by cocaine. Cocaine treatment of SCN slices alone at subjective midday, but not the subjective night, induced 3-h phase-advance shifts. Lidocaine had no shifting effect. Cocaine-induced phase shifts were completely blocked by metergoline, but not by the dopamine receptor antagonist, fluphenazine. Finally, pretreatment of SCN slices for 2 h with a low concentration of serotonin agonist (to block subsequent serotonergic phase resetting) abolished cocaine-induced phase shifts at subjective midday. These results reveal multiple effects of cocaine on adult circadian clock regulation that are registered within the SCN and involve enhanced serotonergic transmission.     

Adjustability of the circadian clock in the cockroaches: a comparative study of two closely related species, Blattella germanica and Blattella bisignata.

A single 2h light pulse (250 lux) was given at various times to phase shift the locomotor circadian rhythm of two species of closely related cockroaches, Blattella bisignata and Blatella germanica. The phase-response curve (PRC) of both species showed a similar pattern. Phase delays and advances were induced by light pulse during the early and late subjective night, respectively, while no clear phase shifting was elicited during the subjective day. However, the magnitude of the phase delay (1.89h +/- 0.66h) and advance (0.69h +/- 0.36h) of B. bisignata was significantly larger than that of B. germanica (0.78h +/- 0.38h and 0.35h +/- 0.18h, respectively). This result indicates the superior adjustability of the circadian clock in B. bisignata. The period-response curve (PdRC) was also constructed for both species. Although both species did not show great flexibility in circadian period changes, the phase shifts were significantly correlated with the period changes in the advance zone of B. bisignata (r = 0.72, P < .1). This allowed the circadian clock of B. bisignata to display better entrainability since the phase advance adjustment was significantly more difficult than that of phase delay. The results indicate the overall adjustability of the circadian clock of B. germanica is inferior to that of B. bisignata. The significance of this finding is discussed from an ecological perspective.     

Locomotor Activity Rhythm in the Field Mouse Mus booduga Phase-shifts to Melatonin Injections in a Dose-dependent Manner

Melatonin is known to shift the phase of the locomotor activity rhythm in the field mouse Mus booduga in accordance with a type-I phase response curve (PRC), with phase delays during the subjective day and phase advances during late subjective night and the early subjective day. At CT4 (circadian time 4; i.e. 16 hr. after activity onset) and CT22 of the circadian cycle, a single dose of melatonin (1 mg/kg) is known to evoke maximum delay and maximum advance phase-shifts, respectively. We investigated the dose-dependent responses of the circadian pacemaker of these mice to a single dose of melatonin at the times for maximum delay and maximum advance. The circadian pacemaker responsible for the locomotor activity rhythm in these mice responded to various doses of melatonin in a dose-dependent manner with the magnitude of phase shifts increasing with dose.     

Locomotor Activity Rhythm in the Field Mouse Mus booduga Phase-shifts to Melatonin Injections in a Dose-dependent Manner

Melatonin is known to shift the phase of the locomotor activity rhythm in the field mouse Mus booduga in accordance with a type-I phase response curve (PRC), with phase delays during the subjective day and phase advances during late subjective night and the early subjective day. At CT4 (circadian time 4; i.e. 16 hr. after activity onset) and CT22 of the circadian cycle, a single dose of melatonin (1 mg/kg) is known to evoke maximum delay and maximum advance phase-shifts, respectively. We investigated the dose-dependent responses of the circadian pacemaker of these mice to a single dose of melatonin at the times for maximum delay and maximum advance. The circadian pacemaker responsible for the locomotor activity rhythm in these mice responded to various doses of melatonin in a dose-dependent manner with the magnitude of phase shifts increasing with dose.     

Response of the mouse circadian system to serotonin 1A/2/7 agonists in vivo: surprisingly little

Serotonin (5-HT) is thought to play a role in regulating nonphotic phase shifts and modulating photic phase shifts of the mammalian circadian system, but results with different species (rats vs. hamsters) and techniques (in vivo vs. in vitro; systemic vs. intracerebral drug delivery) have been discordant. Here we examined the effects of the 5-HT1A/7 agonist 8-OH-DPAT and the 5-HT1/2 agonist quipazine on the circadian system in mice, with some parallel experiments conducted with hamsters for comparative purposes. In mice, neither drug, delivered systemically at a range of circadian phases and doses, induced phase shifts significantly different from vehicle injections. In hamsters, quipazine intraperitoneally (i.p.) did not induce phase shifts, whereas 8-OH-DPAT induced phase shifts after i.p. but not intra-SCN injections. In mice, quipazine modestly increased c-Fos expression in the SCN (site of the circadian pacemaker) during the subjective day, whereas 8-OH-DPAT did not affect SCN c-Fos. In hamsters, both drugs suppressed SCN c-Fos in the subjective day. In both species, both drugs strongly induced c-Fos in the paraventricular nucleus (within-subject positive control). 8-OH-DPAT did not significantly attenuate light-induced phase shifts in mice but did in hamsters (between-species positive control). These results indicate that in the intact mouse in vivo, acute activation of 5-HT1A/2/7 receptors in the circadian system is not sufficient to reset the SCN pacemaker or to oppose phase-shifting effects of light. There appear to be significant species differences in the susceptibility of the circadian system to modulation by systemically delivered serotonergics.     

ADJUSTABILITY OF THE CIRCADIAN CLOCK IN THE COCKROACHES: A COMPARATIVE STUDY OF TWO CLOSELY,RELATED SPECIES,BLATTELLA GERMANICA AND BLATTELLA BISIGNATA

A single 2h light pulse (250 lux) was given at various times to phase shift the locomotor circadian rhythm of two species of closely related cockroaches, Blattella bisignata and Blatella germanica. The phase-response curve (PRC) of both species showed a similar pattern. Phase delays and advances were induced by light pulse during the early and late subjective night, respectively, while no clear phase shifting was elicited during the subjective day. However, the magnitude of the phase delay (1.89h ± 0.66h) and advance (0.69h ± 0.36h) of B. bisignata was significantly larger than that of B. germanica (0.78h ± 0.38h and 0.35h ± 0.18h, respectively). This result indicates the superior adjustability of the circadian clock in B. bisignata. The periodresponse curve (PdRC) was also constructed for both species. Although both species did not show great flexibility in circadian period changes, the phase shifts were significantly correlated with the period changes in the advance zone of B. bisignata (r = 0.72, P <. 1). This allowed the circadian clock of B. bisignata to display better entrainability since the phase advance adjustment was significantly more difficult than that of phase delay. The results indicate the overall adjustability of the circadian clock of B. germanica is inferior to that of B. bisignata. The significance of this finding is discussed from an ecological perspective. (Chronobiology International, 18(5), 767– 780, 2001)     

Circadian periods of sensitivity for ramelteon on the onset of running-wheel activity and the peak of suprachiasmatic nucleus neuronal firing rhythms in C3H/HeN mice

Ramelteon, an MT(1)/MT(2) melatonin receptor agonist, is used for the treatment of sleep-onset insomnia and circadian sleep disorders. Ramelteon phase shifts circadian rhythms in rodents and humans when given at the end of the subjective day; however, its efficacy at other circadian times is not known. Here, the authors determined in C3H/HeN mice the maximal circadian sensitivity for ramelteon in vivo on the onset of circadian running-wheel activity rhythms, and in vitro on the peak of circadian rhythm of neuronal firing in suprachiasmatic nucleus (SCN) brain slices. The phase response curve (PRC) for ramelteon (90?μg/mouse, subcutaneous [sc]) on circadian wheel-activity rhythms shows maximal sensitivity during the late mid to end of the subjective day, between CT8 and CT12 (phase advance), and late subjective night and early subjective day, between CT20 and CT2 (phase delay), using a 3-day-pulse treatment regimen in C3H/HeN mice. The PRC for ramelteon resembles that for melatonin in C3H/HeN mice, showing the same magnitude of maximal shifts at CT10 and CT2, except that the range of sensitivity for ramelteon (CT8-CT12) during the subjective day is broader. Furthermore, in SCN brain slices in vitro, ramelteon (10 pM) administered at CT10 phase advances (5.6?±?0.29?h, n?=?3) and at CT2 phase delays (-3.2?±?0.12?h, n?=?6) the peak of circadian rhythm of neuronal firing, with the shifts being significantly larger than those induced by melatonin (10 pM) at the same circadian times (CT10: 2.7?±?0.15?h, n?=?4, p?相似文献   

Serotonergic Actions and Interactions on the SCN Circadian Pacemaker: In Vitro Investigations

The phase of the mammalian circadian pacemaker located in the suprachiasmatic nuclei (SCN) is controlled by a multitude of stimuli. While phase control is undoubtedly dominated by photic input, the serotonergic input from the raphe nuclei also influences SCN clock phase. In this article I review the evidence for serotonergic modulation of the SCN pacemaker, and the cellular mechanisms underlying these effects, obtained from in vitro experiments performed during the past decade. Serotonin can advance the SCN pacemaker when applied during the subjective day, and delay the pacemaker when applied during the subjective night. The daytime advances appear due to stimulation of 5HT₇ receptors, activation of adenylate cyclase and protein kinase A, and opening of K⁺ channels. The synthesis of new proteins may also be critical for these phase shifts. Serotonergic phase advances can be inhibited by a variety of other modulatory inputs to the SCN, including neuropeptide Y, melatonin, and glutamate. Together, these data demonstrate that SCN circadian pacemaker phase is controlled by a complex interplay between multiple afferent stimuli, and that serotonin plays a critical role in this process.     

The effects of the general anaesthetic isoflurane on the honey bee (Apis mellifera) circadian clock

General anaesthesia administered during the day has previously been shown to phase shift the honey bee clock. We describe a phase response curve for honey bees (n=105) to six hour isoflurane anaesthesia. The honey bee isoflurane PRC is “weak” with a delay portion (maximum shift of –1.88 hours, circadian time 0 – 3) but no advance zone. The isoflurane-induced shifts observed here are in direct opposition to those of light. Furthermore, concurrent administration of light and isoflurane abolishes the shifts that occur with isoflurane alone. Light may thus provide a means of reducing isoflurane–induced phase shifts.     

Phase shifts of the circadian locomotor rhythm induced by pigment-dispersing factor in the cricket Gryllus bimaculatus

Pigment-dispersing factors (PDFs) are octadeca-peptides widely distributed in insect optic lobes and brain. In this study, we have purified PDF and determined its amino acid sequence in the cricket Gryllus bimaculatus. Its primary structure was NSEIINSLLGLPKVLNDA-NH(2), homologous to other PDH family members so far reported. When injected into the optic lobe of experimentally blinded adult male crickets, Gryllus-PDF induced phase shifts in their activity rhythms in a phase dependent and dose dependent manner. The resulted phase response curve (PRC) showed delays during the late subjective night to early subjective day and advances during the mid subjective day to mid subjective night. The PRC was different in shape from those for light, serotonin and temperature. These results suggest that PDF plays a role in phase regulation of the circadian clock through a separate pathway from those of other known phase regulating agents.     

Serotonergic Actions and Interactions on the SCN Circadian Pacemaker: In Vitro Investigations

The phase of the mammalian circadian pacemaker located in the suprachiasmatic nuclei (SCN) is controlled by a multitude of stimuli. While phase control is undoubtedly dominated by photic input, the serotonergic input from the raphe nuclei also influences SCN clock phase. In this article I review the evidence for serotonergic modulation of the SCN pacemaker, and the cellular mechanisms underlying these effects, obtained from in vitro experiments performed during the past decade. Serotonin can advance the SCN pacemaker when applied during the subjective day, and delay the pacemaker when applied during the subjective night. The daytime advances appear due to stimulation of 5HT₇ receptors, activation of adenylate cyclase and protein kinase A, and opening of K⁺ channels. The synthesis of new proteins may also be critical for these phase shifts. Serotonergic phase advances can be inhibited by a variety of other modulatory inputs to the SCN, including neuropeptide Y, melatonin, and glutamate. Together, these data demonstrate that SCN circadian pacemaker phase is controlled by a complex interplay between multiple afferent stimuli, and that serotonin plays a critical role in this process.     

Photic and nonphotic responses of the circadian clock in serotonin-deficient Pet-1 knockout mice

The neurotransmitter serotonin plays an important role in the regulation of the circadian clock. To gain further insight into the mechanisms by which serotonin regulates rhythmicity, the authors investigated photic and nonphotic effects on the circadian clock in Pet-1 knockout mice. In these mice, the serotonergic system suffers a developmental loss of 70% of serotonin neurons, with the remaining neurons being deficient in serotonergic function as well. Pet-1 knockout mice show significantly decreased phase delays of the circadian clock in response to light pulses in the early night; however, this difference was not reflected in a difference in the expression of Fos protein in the suprachiasmatic nucleus. There were no genotypic differences detected in the phase-shifting response to injection of the 5-HT_1A/7 (serotonin 1A and 7) agonist 8-OH-DPAT ((±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide); however, there were small but significant differences in the phase-shifting responses to cages between genotypes and sexes. Several different patterns of wheel-running activity were observed in knockout mice that differed from those in wild-type mice, suggesting that normal serotonergic function is necessary for the proper consolidation of nocturnal activity. Overall, these data are consistent with other pharmacological and genetic studies demonstrating a significant role for serotonin in circadian clock function.     

Interactions of GABA A receptor activation and light on period mRNA expression in the suprachiasmatic nucleus

Activation of gamma-aminobutyric acid (GABA) A receptors in the suprachiasmatic nucleus (SCN) resets the circadian clock during the day and inhibits the ability of light to reset the clock at night. Light in turn acts during the day to inhibit the phase-resetting effects of GABA. Some evidence suggests that Period mRNA changes in the SCN are responsible for these interactions between light and GABA. Here, the hypothesis that light and the GABA A receptor interact by altering the expression of Period 1 and/or Period 2 mRNA in the SCN is tested. The GABA A agonist muscimol was injected near the SCN just prior to a light pulse, during the mid-subjective day and the early and late subjective night. Changes in Period 1 and Period 2 mRNA were measured in the SCN by in situ hybridization. Light-induced Period 1 mRNA was inhibited by GABA A receptor activation in the early and late subjective night, while Period 2 mRNA was only inhibited during the late night. During the subjective day, light had no effect on the ability of muscimol to suppress Period 1 mRNA hybridization signal. Thus, light and GABA A receptor activation inhibit each other's ability to induce behavioral phase shifts throughout the subjective day and night. However, only in the late night are these behavioral effects correlated with changes in Period gene expression. Together, our data support the hypothesis that the interacting effects of light and GABA are the result of the opposing actions of these stimuli on Period mRNA, but only during the subjective night.     

Serotonin phase-shifts the circadian rhythm of locomotor activity in the cockroach

Serotonin, a putative neurotransmitter in insects, was found to cause consistent phase shifts of the circadian rhythm of locomotor activity of the cockroach Leucophaea maderae when administered during the early subjective night as a series of 4-microliters pulses (one every 15 min) for either 3 or 6 hr. Six-hour treatments with dopamine also caused significant phase shifts during the early subjective night, but 3-hr treatments with dopamine had no phase-shifting effect. Other substances tested in early subjective night (norepinephrine, octopamine, gamma-aminobutyric acid, glutamate, carbachol, histamine, tryptophan, tryptamine, N-acetyl serotonin, or 5-hydroxyindole-3-acetic acid) did not consistently cause phase shifts. The phase-shifting effect of serotonin was found to be phase-dependent. The phase response curve (PRC) for serotonin treatments was different from the PRC for light. Like light, serotonin caused phase delays in the late subjective day and early subjective night, but serotonin did not phase-shift rhythms when tested at phases where light causes phase advances.     

Photic phase response curve in Octodon degus: assessment as a function of activity phase preference

Light exposure during the early and late subjective night generally phase delays and advances circadian rhythms, respectively. However, this generality was recently questioned in a photic entrainment study in Octodon degus. Because degus can invert their activity phase preference from diurnal to nocturnal as a function of activity level, assessment of phase preference is critical for computations of phase reference [circadian time (CT) 0] toward the development of a photic phase response curve. After determining activity phase preference in a 24-h light-dark cycle (LD 12:12), degus were released in constant darkness. In this study, diurnal (n = 5) and nocturnal (n = 7) degus were randomly subjected to 1-h light pulses (30-35 lx) at many circadian phases (CT 1-6: n = 7; CT 7-12: n = 8; CT 13-18: n = 8; and CT 19-24: n = 7). The circadian phase of body temperature (Tb) onset was defined as CT 12 in nocturnal animals. In diurnal animals, CT 0 was determined as Tb onset + 1 h. Light phase delayed and advanced circadian rhythms when delivered during the early (CT 13-16) and late (CT 20-23) subjective night, respectively. No significant phase shifts were observed during the middle of the subjective day (CT 3-10). Thus, regardless of activity phase preference, photic entrainment of the circadian pacemaker in Octodon degus is similar to most other diurnal and nocturnal species, suggesting that entrainment mechanisms do not determine overt diurnal and nocturnal behavior.     

A Compromise Phase Position for Permanent Night Shift Workers: Circadian Phase after Two Night Shifts with Scheduled Sleep and Light/Dark Exposure

Night shift work is associated with a myriad of health and safety risks. Phase‐shifting the circadian clock such that it is more aligned with night work and day sleep is one way to attenuate these risks. However, workers will not be satisfied with complete adaptation to night work if it leaves them misaligned during days off. Therefore, the goal of this set of studies is to produce a compromise phase position in which individuals working night shifts delay their circadian clocks to a position that is more compatible with nighttime work and daytime sleep yet is not incompatible with late nighttime sleep on days off. This is the first in the set of studies describing the magnitude of circadian phase delays that occurs on progressively later days within a series of night shifts interspersed with days off. The series will be ended on various days in order to take a “snapshot” of circadian phase. In this set of studies, subjects sleep from 23:00 to 7:00 h for three weeks. Following this baseline period, there is a series of night shifts (23:00 to 07:00 h) and days off. Experimental subjects receive five 15 min intermittent bright light pulses (～3500 lux; ～1100 µW/cm²) once per hour during the night shifts, wear sunglasses that attenuate all visible wavelengths—especially short wavelengths (“blue‐blockers”)—while traveling home after the shifts, and sleep in the dark (08:30–15:30 h) after each night shift. Control subjects remain in typical dim room light (<50 lux) throughout the night shift, wear sunglasses that do not attenuate as much light, and sleep whenever they want after the night shifts. Circadian phase is determined from the circadian rhythm of melatonin collected during a dim light phase assessment at the beginning and end of each study. The sleepiest time of day, approximated by the body temperature minimum (T_min), is estimated by adding 7 h to the dim light melatonin onset. In this first study, circadian phase was measured after two night shifts and day sleep periods. The T_min of the experimental subjects (n=11) was 04:24±0.8 h (mean±SD) at baseline and 7:36±1.4 h after the night shifts. Thus, after two night shifts, the T_min had not yet delayed into the daytime sleep period, which began at 08:30 h. The T_min of the control subjects (n=12) was 04:00±1.2 h at baseline and drifted to 4:36±1.4 h after the night shifts. Thus, two night shifts with a practical pattern of intermittent bright light, the wearing of sunglasses on the way home from night shifts, and a regular sleep period early in the daytime, phase delayed the circadian clock toward the desired compromise phase position for permanent night shift workers. Additional night shifts with bright light pulses and daytime sleep in the dark are expected to displace the sleepiest time of day into the daytime sleep period, improving both nighttime alertness and daytime sleep but not precluding adequate sleep on days off.     

Neuropeptide Y in the mammalian circadian system: effects on light-induced circadian responses

The present review examine the role of neuropeptide (NPY) in the circadian system, focusing on the interactions between light and NPY, especially during the subjective night. NPY has two different effects on the circadian system of mammals. On one hand, NPY, similar to behavioral stimulation, can change the phase of the clock by itself during the subjective day. On the other hand, NPY, again similar to behavioral stimulation, can inhibit the phase-shifting effect of light during the night. These effects of NPY may occur through different receptor subtypes, the Y2 receptor mediating day-time effects and the Y5 receptor mediating night-time effects of NPY. Our results also indicate that there are differences between in vivo and in vitro studies: NPY inhibition of in vivo light-induced phase shifts was observed only late in the subjective night; however, NPY applied in vitro could block light-induced phase shifts early in the subjective night as well. Contrasting these in vivo and in vitro results led us to suggest that the time of day of maximal effect of NPY in the intact animal may be a time when exogenous administration of NPY has little effect, due to saturation of the system. This situation could be an example of how the measurable output of the clock can be affected by the behavioral state in a different way at different time points, depending not only on the clock itself but also on behavior. If verified in human beings, the ability of NPY to modulate the circadian-clock responses to light may be of clinical importance.