In a wide range of species and tasks, aging is accompanied by a decreased capacity to remember new information. The major portion of this proposal is based on evidence relating circulating epinephrine and glucose to memory, cholinergic functions and brain 2-deoxyglucose (2-DG) uptake. 1. Epinephrine release after footshock is decreased in aged animals. 2. Epinephrine enhances memory in young animals by increasing circulating glucose levels. 3. Both epinephrine and glucose enhance memory in aged rodents, and glucose enhances memory in elderly humans. 4. Epinephrine and glucose augment a range of cholinergic functions in young animals. 5. Glucose injections increase brain 2-DG uptake in 2-yr-old and scopolamine- treated young mice. Experiments described here will examine the following issues. Expts. a.1- 4: Do decreases in circulating epinephrine and glucose predict the memory deficits observed in individual aged rats? Expts. b.1-4: Most findings suggest that cholinergic agonists readily enhance memory in young but not old animals. Are cholinergic agonists differentially effective in enhancing memory in both aged and young rats and mice? Do treatments (epinephrine, glucose, cholinergic agonists) which enhance memory in aged rodents augment brain 2-DG uptake? Are the effects of cholinergic agonists on memory (whether similar or different across ages) mediated by peripheral release of epinephrine and glucose? An additional recent finding is that age-related memory dysfunctions are most prominent in individual aged rat and human subjects with poor blood glucose control--i.e., a relatively large increase in blood glucose after glucose administration predicts poor memory in individual aged subjects. Comparable relationships are not seen in young adult animals or humans. Expts. c.1-2: In cross-sectional studies, at what age does the relationship between blood glucose control appear in rats and mice? In longitudinal studies, does blood glucose control in individual young rats and mice predict which individual animals will have memory deficits when they are old? In both the cross-sectional and longitudinal studies, similar questions will be asked regarding the relationship of blood glucose control and diminished responsiveness of epinephrine and glucose, as well as decreased brain 2-DG uptake.
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