Cognitive impairments are evident in healthy aging as well as, in more extreme form, Alzheimer's disease. This proposal is directed at understanding ways in which these cognitive declines can be ameliorated to inform therapies applicable to the impairments in aging and in associated brain pathologies such as Alzheimer?s disease. Most studies of brain mechanisms responsible for cognitive impairments in aging and Alzheimer's disease consider neuronal changes as the primary mediators. In contrast, this proposal investigates a special role of astrocytes in modulating age-related impairments in learning and memory. In rats, we found a sexually dimorphic trajectory for cognitive changes during aging. Old male rats are impaired at learning hippocampal tasks but enhanced when learning striatal tasks while old females are impaired at striatal learning but have intact hippocampal learning. In rats and mice, astrocytic production of lactate plays a key role in modulating learning and memory. During aging, male rats exhibit diminished lactate responses to training in the hippocampus but retained responses in the striatum, in concert with the behavioral results. Also, lactate infusions directly into the hippocampus can enhance memory scores on a spontaneous alternation task. Other recent findings indicate that beta-2 adrenergic receptors on astrocytes in the hippocampus mediate glycogenolysis in astrocytes and subsequent production of lactate. The proposed research plan probes the cellular locus of age-related deficits in astrocytic lactate provision and evaluates sex as an important biological variable in these deficits. One set of experiments tests the efficacy of norepinephrine and beta- adrenergic receptor agonists that are selective for astrocytes or neurons in enhancing learning and lactate provision in aged male and female rats. A second set of experiments tests whether the loss of lactate production is mediated by decreased release of norepinephrine during training. The findings will identify the extent to which deficient astrocyte provision of lactate vs deficient afferent noradrenergic signaling contributes to age-related cognitive decline in both sexes, lending important insight into the role of specific neuromodulators and energy substrates underlying brain aging in health and in pathological conditions such as Alzheimer's disease.
Aging and age-related brain pathologies like Alzheimer's disease are accompanied by impairments in learning and memory, with women at particular risk. Rats exhibit a significant sexually dimorphic trajectory in cognitive changes with age. This proposal examines age-related changes in norepinephrine activation of astrocytes to provide lactate to neurons, and tests pharmacological treatments that act on astrocytes to ameliorate the learning and memory impairments. ! 1
