Bruce D. Goldman - US grants

It is well-established that a wide variety of organisms, including humans, have internal, biological clocks that are instrumental in allowing them to maintain synchrony to both daily (i.e. circadian) and annual cycles of environmental change. Most mammals are exposed, on a daily basis, to environmental cues such as sunrise and sunset or day/night temperature fluctuations. These cues are used to synchronize their internal clocks to local environmental time. To understand the biological time keeping systems used by mammals, Dr. Goldman examines animals in hibernation. He will determine the hormonal and neural mechanisms that these animals use to time and coordinate the end of hibernation. Dr. Goldman's work will provide significant insights into understanding how the internal clocks continue to function in an environment where the animals remain sheltered for a significant period from most environmental cues. These results will increase our understanding of the physiological mechanisms regulating the maintenance of internal clocks and, therefore, may contribute to the development of treatments which would reduce the detrimental consequences associated with jetlag.

Thirty years ago, the pineal was known only as a tissue that contains a compound--melatonin--that has a potent skin lightening effect in certain amphibians and reptiles, via its effect on dermal melanophores. The physiology of the mammalian pineal was completely unknown, and it was often considered to be a "rudimentary" tissue in this group of vertebrates. Research accomplished since that time has clearly established that the pineal hormone, melatonin, has an essential role in the photoperiodic mechanism of mammals. In this role, melatonin has potent effects on a wide variety of seasonal, photoperiod-influenced traits; these include reproduction, pelage, thermoregulatory behavior, body mass, and lipid content. There is also some evidence for a role of melatonin in the circadian system of mammals. Through much is known about the overt actions of melatonin, little is known about he specific sites of action of this hormone. Using high specific activity radiolabeled melatonin, several sites of uptake have recently been identified, but there is no firm evidence for the specific role of any of these sites with respect to the actions of melatonin. This proposal is a plan to investigate the action of melatonin at three of these uptake sties--the suprachiasmatic nuclei, the nucleus reuniens, and the paraventricular nuclei of the thalamus, and also in the anterior hypothalamus, and the mediobasal hypothalamus, which have been suggested as melatonin target sites. Melatonin will be administered locally at each of these CNS nuclei via microdialysis, and photoperiodic and circadian responses will be monitored. Siberian hamsters will be used in these studies. A good deal of useful background information exists for this species, and my laboratory is experienced in studying photoperiodic and circadian mechanisms in Siberian hamsters.

The objective of this project is to investigate circadian rhythm biology in naked mole-rats. Naked mole-rats are highly social rodents that live in large colonies (60-80 individuals). They are among the most exclusively subterranean of mammals; many individuals may never leave their underground burrows. Circadian (daily) rhythms of locomotor activity, body temperature, and metabolic rate will be examined to determine whether mole-rats, like more 'typical' mammals exhibit rhythmic daily variations that are regulated by an internal biological clock. The project will also examine whether mole-rat rhythms (and the clock that controls them) are influenced by light, as is the case for other organisms. Finally, the possibility of influence of circadian rhythms by social interactions will also be examined in mole-rat colonies. Rhythms of locomotor activity will be studied by continuous monitoring of activity of individuals both within a colony setting and when animals are isolated from their colonies. Body temperature variations will be measured by use of implanted telemeters, and metabolic rate will be assessed by continuous measurements of oxygen consumption.

In all organisms that have been carefully studied, the biological clocks that regulate circadian rhythms are synchronized primarily by light cues, but there is evidence that under certain circumstances these clocks can also be synchronized by social cues. Yet, the most intensely studied species (rats, mice, hamsters) are relatively non-social, and few studies have been performed with social mammals. Humans clearly organize many of their daily activities in relation to social interactions, and in its most extreme form this extends to areas such as shift work and non-24 hour work schedules in certain situations. Despite some research in these areas---particularly with regard to sleep/wake rhythms, body temperature rhythms, and rhythms of hormone secretion---it is not clear how the human circadian system is involved in social aspects of human daily rhythms. By examining a mammal recently discovered to have evolved an unusually high degree of social organization, it will be possible to assess the potential of the mammalian circadian system for functioning in the context of social cues. This will provide valuable cues in the effort to understand the human circadian system. In addition to their extreme sociality, naked mole-rats live in burrows where they are very rarely exposed to light and may thus be unable to make use of the light:dark cycle for synchronization of biological rhythms. Naked mole-rats are also relatively unique in exhibiting a very low body temperature and metabolic rate as compared to other mammals. Therefore, studies of the circadian regulation of metabolism and body temperature in naked mole-rats will extend our understanding of the physiology of mammalian energetics.