Although a variety of stimuli have been identified which can alter the circadian clock system of young animals, little is known about how aging alters the response of the clock to external or internal environmental stimuli. Preliminary data in the golden hamster demonstrate that the response of the circadian clock system to light and feedback signals from the activity-rest cycle are dramatically altered in old age (i.e. >15 months of age). The overall objectives of the proposed studies are: 1) to more fully delineate the effects of age on the circadian clock system, 2) to determine the role of monoamines in age-related changes in the characteristics and response of the circadian clock to environmental stimuli, and 3) to determine the extent to which circadian properties can be restored in advanced age. To examine the effects of aging on the response of the circadian system to various stimuli, the circadian rhythm of locomotor activity in golden hamsters will be used in all studies as a marker rhythm for the state of the circadian clock located in the suprachiasmatic nucleus (SCN) that underlies most behavioral and physiological rhythms in this species. One series of studies will examine the effects of age on 1) entrainment to various light-dark cycles, 2) the response to various activity-inducing stimuli, and 3) the feedback effects of endogenous activity on the clock. In examining the role of monoamines in age-related changes in the circadian system, the effects of age on monoaminergic inputs and neurotransmission in the region of the SCN and intergeniculate leaflet (IGL) of the thalamus will be determined using immunohistochemical and in vivo microdialysis techniques. The hypothesis that age-related changes in the circadian clock system can be reversed by pharmacologically-induced changes in brain monoaminergic neurotransmission will also be tested. Preliminary studies indicate that transplantation of fetal SCN tissue into the brains of old animals can reverse age-related changes in the response of the clock to some environmental stimuli, and further studies will be carried out to determine the extent of this restored function. In addition, the hypothesis that age-related changes in the circadian clock can be prevented or reversed by increasing the strength of the entraining light- dark cycle will also be tested. The rhythms of drinking behavior and body temperature will also be monitored in those studies that seek to reverse the effects of aging on the circadian clock system. It is anticipated that the elucidation of the physiological basis for age-related changes in the responsiveness of the clock, and the mechanisms which underlie the ability of various experimental manipulations to restore normal circadian function to old animals, will lead to new insight into the mechanisms by which environmental stimuli alter clock function. Furthermore, determining how the response of the circadian clock system to external and internal stimuli is altered with age, may lead to new clinical approaches for treating disorders in the elderly that are associated with a disruption of circadian rhythmicity.
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