The process of aging is marked by progressive changes in daily biological timekeeping. these may include fragmentation of the sleep-wake or rest- activity cycle, reduced wake and total activity time, early onsets of activity, reduced amplitude of daily rhythms, and shortening of the underlying circadian period. It is possible that many, if not all, of these changes are related to age-dependent deterioration of pacemaker structure and function. It is the purpose of these studies to elucidate mechanisms by which pacemaker cells communicate with each other and with the rest of the organism, and to understand how these may be altered with age. In the project we consider the circadian system as a discrete behavioral system with a well-defined control center, and ask whether age-related changes are intrinsic properties of the system, or are the properties of the whole organismal environment. Experiments take advantage of the fact that the clock itself, located in the suprachiasmatic nucleus, can be translated to adult hosts and will subsequently express behavioral rhythms. Furthermore, the use of a period mutation in the hamster, tau, allows the direct comparison of donor and host rhythmicity as graft and host tissues age. The mutation shortens the period of the circadian rhythm from 24 hours in wild type to 22 and 20 hours in mutants. Fetal tissue can be transplanted into hosts of different ages and the time course of rhythm deterioration followed. This is made particularly intriguing by the fact that animals carrying the tau mutation have substantially reduced life expectancy and show many characteristics of advanced age. The dual roles of intrinsic cellular processes and of the cellular environment can therefore be assessed. Using the tau mutation in transplant experiments offers the additional advantage of creating animals whose behavior is under the control of two clocks. Animals may express two distinct rhythms or an intermediate rhythm, suggesting that a range of coupling situations is possible. Under these conditions, questions will be asked regarding the strength of communication between pacemakers, the timing of communication, and the time course of age-dependent breakdown in communication. Finally, we will investigate candidate mechanisms that may be involved in pacemaker communication and which may play roles in age-dependent changes in behavior, GABA neurotransmission and chloride conductance have been implicated in rhythm generation pacemaker coupling. Experiments will address the questions of whether these processes have been altered by the tau mutation or by the aging process.
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