Journal of Biological Rhythms

In seasonal mammals, photoperiod change is associated with a suite of alterations in physiology. It has recently been proposed that the immune response is one of the systems regulated by changes in photoperiod, although this hypothesis has not been rigorously challenged by assays of functional immune responses. The aim of this study was to test the hypothesis that photoperiod modulates immune responsiveness in Syrian (Mesocricetus auratus) and Siberian (Phodopus sungorus) hamsters. Consistent with previously reported data, short-day-housed (SD) animals exhibited a significant increase in lymph node cell (LNC) numbers and increased cellular proliferation in response to the polyclonal mitogen concanavalin Acompared to long-day-housed (LD) animals. In contrast, LNC numbers from intact or gonadectomized SD animals that had been sensitized with the antigen dinitrofluorobenzene (DNFB) exhibited a reduced ex vivo proliferative response and reduced production of interleukin-6 (IL-6) compared to LD animals. In vivo studies of the contact hypersensitivity response of animals that had previously been sensitized, and subsequently challenged, with DNFB were similar in SD and LD animals, as was the proliferative activity of LNC recovered from these animals. There were also no photoperiodic differences in the antidinitrophenyl antibody response of animals sensitized with DNFB, or the anti–sheep red blood cell (srbc) response of animals immunized with srbc. Furthermore, no differences could be detected in the activity of natural killer cells from spleens of LD and SD Siberian hamsters, or in lipopolysaccharide-induced IL-6 production by LD and SD Syrian hamsters in vivo. Thus, although photoperiod is able to influence factors regulating the gross number and non-antigen-specific proliferation of lymphocytes in seasonally breeding mammals, day length does not directly influence activation of an effective immune response. The authors conclude, therefore, that expression of the immune response is not directly modified or compromised by photoperiod in these seasonally breeding hamster species.

The authors cloned the period (per) gene from the marine mollusk Bulla gouldiana, a well-characterized circadian model system. This allowed them to examine the characteristics of the per gene in a new phylum, and to make comparisons with the conserved PER domains previously characterized in insects and vertebrates. Only one copy of the per gene is present in the Bulla genome, and it is most similar to PER in two insects: the cockroach, Periplaneta americana, and silkmoth, Antheraea pernyi. Comparison with Drosophila PER (dPER) and murine PER 1 (mPER1) sequence reveals that there is greater sequence homology between Bulla PER (bPER) and dPER in the regions of dPER shown to be important to heterodimerization between dPER and Drosophila timeless. Although the structure suggests conservation between dPER and bPER, expression patterns differ. In all cells and tissues examined that are peripheral to the clock neurons in Bulla, bPer mRNA and protein are expressed constitutively in light:dark (LD) cycles. In the identified clock neurons, the basal retinal neurons (BRNs), a rhythm in bPer expression could be detected in LD cycles with a peak at zeitgeber time (ZT) 5 and trough expression at ZT 13. This temporal profile of expression more closely resembles that of mPER1 than that of dPER. bPer rhythms in the BRNs were not detected in continuous darkness. These analyses suggest that clock genes may be uniquely regulated in different circadian systems, but lead to similar control of rhythms at the cellular, tissue, and organismal levels.

Serotonin (5-HT) can act presynaptically at 5-HT_1B receptors on retinal terminals in the suprachiasmatic nucleus (SCN) to inhibit glutamate release, thereby modulating the effects of light on circadian behavior. 5-HT_1B receptor agonists (1) inhibit light-inducedphase shifts of circadian activity rhythms, (2) attenuate light-induced Fos expression in the SCN, and (3) reduce the amplitude of optic nerve–evoked excitatory postsynaptic currents in SCN neurons in vitro. To determine whether functional disruption of the 5-HT_1B presynaptic receptors would result in an amplified response of the SCN to light, the period ([.tau]) of the circadian rhythm of wheel-running activity was estimated under several different conditions in 5-HT_1B receptor knockout (KO) mice and genetically matched wild- typeanimals. Under constant light (LL) conditions, the [.tau] of 5-HT_1B receptor KO mice was significantly greater than the [.tau] of wild-type mice. Aquantitative analysis of the wheel-running activity revealed no differences between wild-type and KO mice in either total activity or the temporal distribution of activity under LL conditions, suggesting that the observed increase in [.tau] was not a function of reduced activity. Under constant dark conditions, the period of the circadian rhythm of wheel-running activity of wild-type and 5-HT_1B receptor KO mice was similar. In addition, no differences were noted between wild-type and 5-HT_1Breceptor KO mice in the rate of reentrainment toa6h phase advance in the 12:12 light:dark cycle or in phase shifts in response to a 10 min light pulse presented at circadian time 16. The enhanced response of the SCN circadian clock of the 5- HT_1B receptor KO mice to LLconditions is consistent with the hypothesis that the endogenous activation of 5-HT_1B presynaptic receptors modulates circadian behavior by attenuating photic input to the SCN.

At least two major physiological systems are involved in the adaptation of the organism to environmental challenges: the circadian system and the stress reaction. This study addressed thepossibility that interindividual differences in stress sensitivity and in the functioning of the circadian system are related. At 2 months of age, corticosterone secretion in response to a 20-min restraint stress was assessed in 9 Sprague-Dawley rats for which running wheel activity was recorded as a rhythmic behavioral marker of the circadian clock. Two weeks later, the adaptive response of the circadian system to an abrupt shift in the light:dark (LD) cycle was assessed in those rats using a jet-lag paradigm. Finally, after resynchronization to the new LD cycle,rats were transferred to constant darkness to assess the free-running period of their circadianrhythm of running-wheel activity. Results indicate that stress-induced corticosterone secretionwas (1) positively correlated with the number of days to resynchronize the circadian activity rhythm to the new LD cycle, and with the value of its free-running period, and (2) negatively correlated with the intensity of daily locomotor activity. Those data, emphasizing the interactions between the stress response of an organism and the functioning of its circadian system, could explain interindividual differences in humans' susceptibility to shift work or other circadian-related disorders.

Both recumbency and sleep affect core body temperature (CBT). To characterize their circadian effects and interactions, the authors examined the bedtime temperature drops (TDs) of nine men and eight women (aged 20 to 30) who repeated 90-min sleep-wake cycles over 2.5 days. While awake, subjects were exposed to 50 to 250 lux; while asleep, lights were off. Electroencephalogram-monitored time in bed lasted 30 min during each cycle. Cosinor nonlinear mixedeffects regressions modeled the circadian rhythm of TDs. The circadian maximum of TDs occurred approximately 4 h before the time of circadian CBTminimum, in a model that included the effects of baseline expected CBT, deviations from baseline CBT, time in study, and gender-dependent 24- and 12-h adjustments. Rates of temperature drops were faster during initial periods of lying awake than during periods of initially sleeping. Both rates followed separate circadian rhythms. The circadian maximum of TDs was located near customary nocturnal bedtimes, suggesting its role in fostering sleep during a normal bedtime routine. The apparent deceleration of temperature dropping at sleep onset supports the notion that the sleep onset period has complicated circadian neuroregulatory dynamics. These findings confirm the need for nonlinear models of temperature responses to postural changes and sleep that incorporate circadian variability in these masking effects.

The circadian pacemaker is an endogenous clock that regulates oscillations in most physiological and psychological processes with a near 24-h period. In many species, this pacemaker triggers seasonal changes in behavior. The seasonality of symptoms and the efficacy of light therapy suggest involvement of the circadian pacemaker in seasonal affective disorder (SAD), winter type. In this study, circadian pacemaker characteristics of SAD patients were compared with those of controls. Seven SAD patients and matched controls were subjected to a 120-h forced desynchrony protocol, in which core body temperature and melatonin secretion profiles were measured for the characterization of circadian pacemaker parameters. During this protocol, which enables the study of unmasked circadian pacemaker characteristics, subjects were exposed to six 20-h days in time isolation. Patients participated twice in winter (while depressed and while remitted after light therapy) and once in summer. Controls participated once in winter and once in summer. Between the SAD patients and controls, no significant differences were observed in the melatonin-derived period or in the phase of the endogenous circadian temperature rhythm. The amplitude of this rhythm was significantly smaller in depressed and remitted SAD patients than in controls. No abnormalities of the circadian pacemaker were observed in SAD patients. Adisturbance in thermoregulatory processes might explain the smaller circadian temperature amplitude in SAD patients during winter.

Nonphotic entrainment of an overt sleep-wake rhythm and a circadian pacemaker–driving temperature/melatonin rhythm suggests existence of feedback mechanisms in the human circadian system. In this study, the authors constructed a phase dynamics model that consisted of two oscillators driving temperature/melatonin and sleep-wake rhythms, and an additional oscillator generating an overt sleep-wake rhythm. The feedback mechanism was implemented by modifying couplings between the constituent oscillators according to the history of correlations between them. The model successfully simulated the behavior of human circadian rhythms in response to forced rest-activity schedules under free-run situations: the sleep-wake rhythm is reentrained with the circadian pacemaker after release from the schedule, there is a critical period for the schedule to fully entrain the sleep-wake rhythm, and the forced rest-activity schedule can entrain the circadian pacemaker with the aid of exercise. The behavior of human circadian rhythms was reproduced with variations in only a few model parameters. Because conventional models are unable to reproduce the experimental results concerned here, it was suggested that the feedback mechanisms included in this model underlie nonphotic entrainment of human circadian rhythms.