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Objective: Retrospective assessments of negative mood have predicted coronary artery disease development and progression. Using momentary assessment, we evaluated associations between average positive and negative mood states and diurnal mood patterns, with prevalent and incident coronary artery calcification (CAC), a measure of calcified atherosclerosis., Methods: In a prospective cohort study of 669 white and African American men and women, aged 33 to 45 years, from the Coronary Artery Risk Development in Young Adults Study, mood was assessed at Year 15 examination, six times over a weekday. Prevalent, progressive, and 5-year incident CAC (any detectable CAC [score >0]) and substantial CAC (CAC score ≥ 20) were assessed at examinations at Years 15 and 20 by electron-beam tomographic scans. We employed a modified Poisson regression approach for binary data with robust error estimation to quantify relative risk., Results: In multivariate-adjusted analyses, those with high-average positive mood that improved over a day had a lower risk of prevalent CAC higher than 0 (relative risk [RR] = 0.17 [95% confidence interval {CI} = 0.04-0.67]) and substantial CAC (RR = 0.25 [95% CI = 0.06-0.95]). In contrast, those with high-average, increasingly negative mood over a day had a higher risk of prevalent CAC (RR = 1.85 [95% CI = 0.86-3.99]) and substantial CAC (RR = 3.11 [95% CI = 1.29-7.49]). Findings were similar for progressive CAC at Year 20. This pattern of high/worsening negative mood (not positive mood) during the day was also predictive of 5-year incident CAC (RR = 2.99 [95% CI = 1.00-8.93])., Conclusions: Diurnal mood patterns were associated with the progression of calcified atherosclerosis, with negative mood predicting greater progression and positive mood predicting lower progression.

To explore the multioscillator nature of the neurohumoral circuitry controlling the expression of circadian rhythmicity, rats' wheel running circadian activity rhythms were compared following sagittal knife cuts in the region of the suprachiasmatic nucleus (SSCN), following pinealectomy (PX) and following the combination of SSCN and PX. 25% of animals with knife cuts that passed through one SCN had disturbed running activity under constant illumination; rhythmic disturbances were seen neither in animals with sham knife cuts nor in rats with knife cuts on the midline or lateral to the SCN. Animals with both SSCN and PX were twice as likely to show severe rhythmic disruptions under free-running conditions as rats with SSCN and sham PX. Rats with PX and sham SSCN did not display disrupted activity rhythms. When animals with PX alone or SSCN alone were first observed under free-running conditions and then subjected to a second surgical procedure so that all animals underwent both PX and SSCN, all PX and most SSCN animals demonstrated coherent activity rhythms after the first operation, but 35% showed disruptions in circadian activity patterns only following the second surgery. The activity rhythms of rats with knife cuts placed either on the midline or lateral to the SCN did not deteriorate when combined with PX. Rats with coherent rhythms following knife cuts damaging one SCN had rhythm disruptions after the addition of PX. The effects of pinealectomy may indicate that the pineal gland plays a role in maintaining the coupling relationships in the multioscillator system controlling circadian activity rhythms. The results of this study also suggest that neither the direct commissural connection of the SCNs nor the humoral output of the pineal gland is indispensable for the expression of coherent circadian activity rhythms in the rat.

Rats were exposed to repeated sessions of inescapable footshock, and behavioral depression was subsequently assessed by measuring escape performance during exposure to escapable shock in a different testing environment. Free-running circadian activity rhythms were assessed using running wheels for approximately three weeks before and after administration of inescapable shock. Several animals showed lengthening of free-running period and decreases in activity level following shock. Similar effects were also seen in rats that were removed from their running wheels, placed within the shock apparatus, and not given shock, but not in nonhandled control animals. Furthermore, period lengthening in shocked and handled rats was positively correlated with escape performance, suggesting that circadian rhythm alterations occurred in those animals that were best able to cope with shock or handling-related stressors. In contrast, individual differences in circadian period and activity level during baseline conditions were not predictive of either escape performance or circadian rhythm alterations. These results suggest that successful behavioral adaptation to stress may be associated with alterations of circadian rhythmicity.

Two studies explore the relationship between rhythmicity and behavioral depression. Behavioral depression was induced using inescapable footshock, and assessed by measuring subsequent responses to escapable shock, in rats housed under different light-dark conditions. Experiment 1 compared escape performance in free-running and entrained animals following inescapable shock. Free-running and entrained animals did not exhibit differential vulnerability to the effects of inescapable shock. In addition, there were no systematic effects on phase following shock. However, several free-running animals showed increased circadian period following shock, and lengthening of period was significantly correlated with escape performance. Individual differences in baseline period or phase were not predictive of escape performance. In Experiment 2, "aftereffects" of entrainment to long or short light-dark cycles were utilized to create groups of animals with long or short free-running periods. After the administration of inescapable shock, escape performance was tested. There were no significant differences among experimental groups in escape performance. These results suggest that plasticity of circadian period, but not baseline period per se, may be associated with the ability to adapt to environmental challenges.

The experiments described here demonstrate that TPX and TX male rats display shorter free-running activity rhythms and higher activity levels compared to intact males. Neither effect could be duplicated in TPX females. The patterns in activity period, range of entrainment, and levels of activity observed in TPX males closely resembles that reported in intact females or OVX females treated with estradiol. These data suggest the possibility of a common mechanism linking circadian alterations produced by estradiol and thyroid state. This hypothesis needs to be tested, as does the question of whether thyroid hormones or calcitonin are responsible for the TPX and TX results. If thyroid hormones prove to be the causal agents, opposing effects of thyroid hormones and estradiol on adrenergic receptors provide a possible common mode of action for these agents on the circadian system. Disparate results from rat and hamster studies concerning the influence of thyroid state on activity rhythms suggest the possibility of species differences in this level of circadian organization. Thus, caution should be exercised in extrapolating results to other species, including humans.

The purpose of this experiment was to investigate the relationship between daily patterns of wheel running activity and feeding behavior. Wheel running and bar pressing for food were continuously recorded from rats which had concurrent access to both wheels and food. In a second condition, wheel running and (non-reinforced) bar pressing were recorded during food deprivation. In a third condition, bar pressing for food was recorded while wheel running was prevented. During ad lib access to wheels and food, both behaviors occurred primarily during the dark phase of the light-dark cycle. However, the nocturnal distribution of these responses differed: the early dark hours were primarily devoted to running, while feeding occurred in small, frequent meals. Maximal food intake occurred during the late dark hours, when meals were larger and less frequent, and there was little running. During three days of complete food deprivation, both wheel running and meal initiation attempts (as indicated by nonreinforced bar pressing) maintained their normal daily patterns. However, during wheel deprivation, changes occurred in the temporal distribution of meals which equalized early and late dark food intake. These results show that the availability of an alternative activity, like wheel running, can be an important determinant of daily feeding patterns. However, the daily pattern of wheel running is not influenced by food availability. Different behaviors may show differential plasticity in the coordination of an overall daily behavioral program.

Two temporal variables have been implicated in the timing of postpartum heat in Norway rats: time of day and time since parturition. The nature of the interaction between these variables is not clearly understood. We extend previous observations on this problem to freely behaving animals continuously videotaped during parturition and postpartum mating in a seminatural habitat. The timing of postpartum mating is best described by a model in which an interval timer is coupled to a circadian gating mechanism. Interactions between circadian and interval timing mechanisms may be widespread in the neuroendocrine control of behavior.

Schedules of limited daily access to food result in 'anticipatory' activity preceding each daily feeding. It is well-established that such food-anticipatory activity depends on a food-entrainable circadian timing mechanism. In the present study, we sought to extend the generality of these results by maintaining rats in running wheels under schedules which provided access to salt solutions or to salty food for 2 hr each day. The animals were subjected to dietary, pharmacological and surgical treatments that promote salt appetite. However, we found no evidence for daily salt-anticipatory wheel running activity in any condition.

Considerable progress has been made in elucidating the mechanisms underlying the generation of circadian rhythmicity. This review describes several distinct lines of evidence which converge on the general hypothesis that circadian timing systems consist of multiple circadian oscillators, coordinated by both hierarchical and non-hierarchical coupling relationships. Such a view is supported by the complex phenomenology of circadian systems, as well as by physiological considerations. We have attempted wherever possible to integrate these two sources of evidence, in order to define the current "state of the art" in bridging the gap between structure and function in the analysis of circadian timing systems. While we concentrate mainly on the mammalian, and particularly the rodent, circadian system, we also incorporate comparative evidence obtained from a variety of vertebrate and invertebrate species.

The locus of rise of the rate-frequency function was determined for rats at many times of day to ascertain whether the circadian fluctuations in the frequency of bar pressing for electrical stimulation of the medial forebrain bundle could be accounted for by alterations in the perceived magnitude of the reward. No evidence of circadian changes in the value of the locus of rise were detectable. These findings suggest that for self-stimulation, the endogenous circadian rhythm generating apparatus affects behavior through neural mechanisms similar to those through which motivational and arousal variables act. The animal's requirement for verity of memorial representations may underlie the lack of a circadian rhythm in the locus of rise.

The paraventricular nucleus of the hypothalamus (PVN) is thought to be a part of the neural circuit comprising the melatonin rhythm generating system (MRGS). Electrical stimulation of the PVN during the early lights-on period significantly elevated urinary 6-hydroxymelatonin content to nearly 50% of night levels; stimulation during the lights-off period did not produce significant changes. In contrast to the effects of PVN stimulation, stimulation of surrounding brain areas was without effect at either time. This observation confirms the participation of the PVN in the MRGS.

Rats maintained on limited-access daily feeding schedules develop food-anticipatory activity rhythms which coexist with the photic circadian activity rhythm. These food anticipatory rhythms appear to depend upon a food-entrainable circadian oscillator which is separate and distinct from the light-entrainable circadian oscillator system. This study explored the long-term behavior of the putative food-entrainable oscillator in the presence and in the absence of a feeding schedule, and under light-dark cycles and constant light. The results suggest that a food-entrainable oscillator can show persisting self-sustained oscillations in the absence of a feeding schedule, and that the food- and light-entrainable circadian oscillators may show varying degrees of coupling, depending upon feeding conditions. Such a flexible coupling arrangement may allow the oscillator system to function as a "continuously consulted clock" in the adaptive temporal coordination of behavior with stable and unstable environmental periodicities.

The dorsal and median mesencephalic raphe nuclei provide a robust projection to the hypothalamic suprachiasmatic nucleus, the site of a putative neuronal circadian pacemaker. Although it has been suggested that the raphe may play a role in the circadian timing system, this role has not yet been specified. In the present report, we examined the circadian activity patterns of rats with large mid-brain lesions aimed at the median and dorsal raphe nuclei under conditions of light-dark entrainment, and while free-running in constant light and constant darkness. The results indicate that midbrain raphe lesions may interfere with the expression of free-running circadian activity rhythms.

Circadian rhythms and levels of wheelrunning were studied in thyroidectomized, parathyroidectomized, thyro-parathyroidectomized, and sham-operated male rats. Animals were entrained to a 12:12 light:dark schedule, then exposed to constant dim red illumination, and then given a diet containing lithium. Under constant conditions, free-running circadian activity rhythms were shorter, and levels of activity were greater, in thyroidectomized and thyroparathyroidectomized animals. Lithium reversed these effects, lengthening free-running circadian periods in all groups, with a greater reduction of activity observed in animals with thyroids removed. Parathyroidectomy had no clear effects. Since lithium slowed circadian rhythms and reduced activity even in the absence of intact thyroid or parathyroid glands, these effects may have been due to the action of lithium at some other site. The same may be true of other thyroid suppressors reported to affect circadian rhythms. These findings may be relevant to the biological substrates of major affective disorders in humans, which have been associated with abnormalities of thyroid function, abnormally short circadian rhythms, abnormal activity levels, and responsiveness to lithium therapy.

Previous studies using 2-deoxyglucose (2-DG) autoradiography have demonstrated that the suprachiasmatic nucleus (SCN) of the hypothalamus, a putative neural circadian pacemaker, displays circadian rhythmicity in its metabolic activity. In the present study, we show that distinct circadian variations in 2-DG uptake occur not only in the suprachiasmatic, but also in the supraoptic and median raphe nuclei of the rat brain. On the other hand, several other brain areas failed to display systematic circadian variations in 2-DG uptake. These results indicate that circadian metabolic rhythms are not unique to the SCN. Further studies are required to precisely define the extent of such phenomena.

Alterations in circadian rhythms have previously been associated with estrous and seasonal changes in reproductive state. In the present study we explored the effects of the reproductive events of pregnancy and parturition on free-running circadian activity rhythms in the rat. Free-running rhythms were monitored before mating, during pregnancy, and following parturition and removal of pups. Systematic and long-lasting alterations of the period of the free-running activity rhythm were seen following parturition. The effects of estrous, seasonal, and gestational reproductive states on circadian rhythms may be mediated by the endocrine events which accompany these states.