Cellular and molecular interactions of corticosterone and the serotonin neuronal system in the aging brain.

摘要

As individuals age, they become more vulnerable to and less able to learn under stress, such as a changing living environment. The central serotonergic system has been shown to undergo significant alterations with aging. Therefore, the work encompassed in this thesis addresses changes with aging in the 5-HT neurotransmitter system, as regulated by various concentrations of corticosterone. The corticosterone replacement model was used throughout and consisted of adrenalectomized female Fischer 344 rats, ages 3, 13 and 18 mo, supplemented with subcutaneously implanted placebo- or corticosterone-containing pellets that delivered either low, moderate or stressed levels of circulating plasma corticosterone (LC, MC and HC, respectively) for a three week period. Cresyl violet revealed no changes in hippocampal cell number or gross morphology across age and hormone treatment. Glial fibrillary acidic protein (GFAP) immunoreactivity was assessed and revealed an age-related decline in GFAP level responsiveness to hormone treatment in the oldest group. Equilibrium binding assays demonstrated significant regulation of 5-HT1A binding by varied corticosterone in young and middle-aged animalsnot present in the old group, showing a decline in regulation with aging. In contrast, hypothalamic 5-HT1A receptors maintained corticosterone regulation across age. Quantitative autoradiography confirmed these results and showed the dentate gyrus exhibited the largest degree of regulation within the hippocampus. Autoradiographic analysis of 5-HT transporter binding revealed regulation in the 3 mo, group not present in 13 or 18 mo groups. The 5-HT2A receptor showed no age- or corticosterone-related changes. Basal Gi protein levels in both the hippocampus and frontal cortex did not vary across age. Hippocampal Gi protein levels increased following moderate and high corticosterone administration in the 3 mo animals but not in the 18 mo animals showing an age-dependent decline in regulation. Complementary studies showed no changes in the coupling of the 5-HT1A receptor to G proteins with aging and differential corticosterone exposure. These experiments will add to the knowledge of the regulation of centrally located physiological players in the stress response, specifically the serotonin 5-HT1A receptor, and how this modulation differs with aging.