Martin C. Moore-Ede

Circadian timekeeping in health and disease. Part 1. Basic properties of circadian pacemakers

THE study of circadian (approximately 24-hour) rhythms has within the past decade evolved from a biologic curiosity to a science with enormous implications for clinical medicine. The concurrent mat...

ENTRAINMENT OF HUMAN ORCADIAN RHYTHMS BY LIGHT‐DARK CYCLES: A REASSESSMENT

Abstract— Man is the only eukaryotic organism in which it has been reported that the circadian system cannot be entrained to a 24‐h period by a simple light‐dark (LD) cycle. In this paper, we reexamine the evidence for that claim and demonstrate that there were some fundamental flaws in the experimental design of the previous studies on which this conclusion was based. We report new studies in which we tested the efficacy of LD cycles in entraining the circadian rhythms of human subjects living in isolation from environmental time cues. We found that the cyclic alternation of light and dark, when applied to human subjects in a comparable way to experiments in other species, was an effective entraining agent. Our results and a critical review of the literature indicate that a LD cycle alone can be an effective environmental synchronizer of the human circadian timing system. Other factors, such as the knowledge of time of day, social contacts, the feeding schedule, and the imposed rest‐activity schedule may contribute to stable entrainment, although their relative strengths as synchronizers have yet to be determined.

In vivo metabolic activity of the suprachiasmatic nuclei: a comparative study.

In vivo glucose utilization was measured in the suprachiasmatic nuclei (SCN) of the rat, monkey, and cat using the 14C-labeled deoxyglucose technique. SCN metabolic activity in all species was endogenously rhythmic with high levels during the subjective daylight portion of the 24 h day. Such phase conservation across night-, day-, and randomly-active species is in agreement with formal analyses of the properties of entrainable circadian oscillators, and our data suggest that the biochemical processes which underlie the activity of this circadian clock are similar in mammals with differing patterns of expressed circadian rhythmicity.

Feeding time synchronizes primate circadian rhythms

Abstract Circadian rhythms of squirrel monkeys maintained in constant light and temperature can be entrained by 24 hr cycles of food availability with eating for 3 hr and fasting for 21 hr (EF 3:21). Rhythms of drinking, body temperature and urinary potassium and water excretion exhibited periods which matched the 24 hr period of the EF 3:21 cycle. These results suggest that temporal patterns of food intake are capable of synchronizing the circadian timekeeping system which underlies the observed rhythms.

Role of the suprachiasmatic nuclei in the circadian timing system of the squirrel monkey. I. The generation of rhythmicity

The circadian organization of squirrel monkey (Saimiri sciureus) drinking behavior was evaluated before and after the placement of radiofrequency lesions which completely destroyed the suprachiasmatic nuclei (SCN) in 4 monkeys and partially ablated the SCN in another 4 animals. In continuous illumination (LL: 600 lux) prior to surgery, each monkey had a precise free-running circadian rhythm of drinking behavior with a period of 25.31 +/- 0.21 h (means +/- S.E.M.). By 4-6 weeks following the lesions, the temporal organization of drinking behavior had become disrupted, but a statistically significant free-running circadian rhythm was still detectable by time series analyses. Subsequently, the circadian organization of drinking behavior in 7 out of 8 monkeys gradually decayed with either no statistically significant rhythmicity or only weak circadian and/or ultradian rhythmicity detected by time series analyses by 10-92 weeks post-lesion. The remaining animal which maintained a statistically reliable free-running rhythm in drinking behavior received the least damage (less than 50%) to the SCN. Despite the major alterations in the temporal patterning of behavior, the overall amount of drinking behavior per 24 h was unchanged. The SCN are thus essential for maintaining the circadian organization of squirrel monkey drinking behavior. However, the existence of residual circadian rhythmicity following SCN lesions and the gradual decay of circadian organization thereafter suggest that the SCN may coordinate the activity of circadian oscillators which lie outside its borders.

Lithium lengthens circadian period in a diurnal primate, Saimiri sciureus.

Lithium lengthens the period of free-running circadian rhythms in a variety of species, but this effect has not been demonstrated unequivocally in primates. Because of the possible link between lithiums action on the circadian clock and its therapeutic action in human mood disorders, we tested the ability of lithium to lengthen circadian period in a diurnal primate with circadian properties similar to those of humans. Lithium carbonate was administered in food pellets to 8 adult male squirrel monkeys (Saimiri sciureus) for at least 27 consecutive days. Serum lithium levels on the last day of lithium administration ranged from 0.76 to 2.02 mEq/liter, comparable to the therapeutic range for treatment of bipolar disorder in humans (0.6-1.2 mEq/liter). Circadian periods of perch-hopping activity were longer during lithium treatment than during baseline in 7 of the 8 monkeys (changes of -0.08 to +1.41 hr, mean +0.55 hr, p = 0.01), and returned toward baseline values when lithium was discontinued. In most cases, the period change was evident within a few days after beginning full lithium dose, and was not accompanied by changes in level or pattern of activity, nor in amplitude of the circadian rhythm. Food consumption and body weight were reduced during lithium treatment, and rebounded on return to lithium-free diet. Period change was related to lithium dose (p less than 0.05), but did not correlate with food consumption, body weight, or baseline circadian period. These results, by establishing that lithium lengthens circadian period in primates, suggest that studying the cellular mechanisms of this circadian effect may be relevant to understanding lithiums therapeutic effect on mood in humans.

Internal Temporal Order

The temporal organization of physiological events within an animal may often be as important as their spatial organization. Mutually interdependent events must not only occur at precise spatial locations but must also occur with appropriate timing. Similarly, incompatible processes, which may require different physicochemical conditions for their completion, can be separated just as effectively in time as in space.

Tonic effects of light on the circadian system of the squirrel monkey

SummaryThe tonic effects of constant light were examined on the organization of the circadian time-keeping system of squirrel monkeys. The rhythms of feeding, colonic temperature and urinary potassium excretion were measured in chair-restrained animals maintained in 1 lux, 60 lux or 600 lux in isolation chambers at constant temperature with food availablead lib. When compared to previous results from monkeys synchronized by light-dark cycles, there was a reduction in the ranges (R) of all 3 rhythms in constant light. As the intensity of light increased, the computedα/ρ ratio increased for the feeding and temperature rhythms but not for the renal potassium rhythm. The average free-running period (τ) for all three rhythms was approximately 25 h, and long term experiments with unrestrained monkeys showed a small lengthening ofτ with brighter light. There was a much broader distribution ofτ for the urinary potassium rhythm than for the feeding and temperature rhythms. Spontaneous internal desynchronization between the potassium rhythm and the feeding and temperature rhythms occurred in approximately one-quarter of the experiments, with the light intensity having no influence on the incidence of desynchronization.

Food-Anticipatory Rhythms under 24-Hour Schedules of Limited Access to Single Macronutrients

Food-restricted rats anticipate a fixed daily mealtime by entrainment of a circadian timekeeping mechanism separate from that which generates daily light-entrainable activity rhythms. The entrainment pathways and rhythm-generating substrates for food-anticipatory rhythms are unknown. In this study, we attempted to define minimal food-related stimuli necessary or sufficient for food anticipation by employing schedules of restricted macronutrient availability, with or without free access to a complementary diet. Rats did not anticipate a daily meal of protein, carbohydrate, or fat, as measured by tilt-cage, running-wheel, or food-bin activity, when they had free access to other nutrients. However, rats did anticipate single-macronutrient meals when they were limited to only two, larger, complementary meals each day (protein-fat, protein-carbohydrate) providing a reduced total number of calories. Previous work has shown that caloric restriction per se is not a prerequisite for food anticipation. In combination with that study, the present results indicate that the size of a nutrient meal, in absolute terms or relative to total daily nutrient intake, is of pre-eminent importance in determining its value as a synchronizer of anticipatory rhythms. The results further suggest that physiological responses unique to the ingestion and absorption of any particular macronutrient are not necessary components of the entrainment pathway.

Spontaneous internal desynchronization of circadian rhythms in the squirrel monkey

Abstract 1. 1. The circadian rhythms of feeding, colonic temperature, and urinary potassium and water excretion persisted with free-running periods in chair-acclimatized squirrel monkeys (Saimiri sciureus) maintained in isolation in constant bright light. 2. 2. Spontaneous internal desynchronization, i.e. separate rhythmic variables oscillating with different periods, was shown to occur between the rhythms of feeding and colonie temperature (τ ⋍ 25 hr) and the urinary rhythms (τ ⋍ 21 hr). 3. 3. This evidence indicates that the circadian timing system in squirrel monkeys is composed of multiple potentially-independent oscillators.