Neurobiological substrates of the aging primate brain
01 / 1997 - 03 / 2004
Aging is associated with a deterioration of cognitive function, loss of memory, or decreased ability to learn new information. The pattern of memory deficits seen following hippocampal damage in rats, non-human primates and humans is similar to that seen during normal aging, indicating that the hippocampal formation plays a critical role in memory processes and that the hippocampus is affected during normal aging. Glucocorticoids play an important role during normal aging. Increased activity of the hypothalamus-pituitary-adrenal (HPA) axis results in elevated circulating levels of glucocorticoids, and has been shown in rats, non-human primates and humans. Low levels of glucocorticoids play a role in maintaining hippocampal neuronal integrity, whereas high levels have deleterious consequences for hippocampal neurons. Among rats and humans, and (due to different social status) probably in monkeys as well, some individuals do and other do not exhibit increased HPA axis activity during aging. This might underlie individual differences in cognitive functioning during aging, as demonstrated in rats, monkeys and humans. Therefore, cognitive impairment is not an inevitable consequence of normal aging. However, increased HPA axis activity accounts only partially for individual differences in the occurrence of age-related hippocampal pathology and cognitive deficits. The existence of such differences is a valuable strategy for the study of the neurobiological correlates of cognitive aging. A major finding of non-human primate and human aging is atrophy of the brain. Cortisol levels during human aging have been shown to predict hippocampal atrophy and memory deficits. Since the central nervous system comprises three major cellular domains (being vascular cells, glial cells, and neurons), all these cells types may be involved in age-related cognitive impairment and hippocampal pathology. Normal cerebral performance requires not only adequate functioning of all three of these components separately, but also a proper interaction between the three is necessary. Aging-related changes have been demonstrated in all of these three cell types. Nevertheless, very few studies on neuronal, glial and microvascular integrity have been carried out on non-human primates. Furthermore, to get a better understanding of how these cell types may differentially be affected in aging, it is important to perform such studies in the same animals. The aim of this project is to investigate structural and functional changes in the aging non-human primate brain, and thereby to obtain better insights into differences in cognitive impairment that occur during normal aging. Although many brain regions are involved in memory processes and cognitive impairment during normal aging, this project will confine to investigate the hippocampal formation. A series of hippocampi of 21 male rhesus monkeys (Macaca mulatta) was obtained from the Wisconsin Regional Primate Research Center (WRPRC, Madison, USA), and form the study material of this project. The age of the rhesus monkeys varied between 1 day to 31 years for the males. Since the collection is very valuable, is was important to carry out pilot studies in order to investigate the possibilities and limitations of the material. Immersion fixation of the brains, as well as long storage in fixative caused limitations for some immunocytochemical stainings. From additional pilot studies it became clear that immunocytochemical stainings for the calcium binding proteins parvalbumin and calbindin (each staining a sub-population of GABA-ergic interneurons) and immunocytochemistry for GFAP (indicative for reactive astrocytes) will be successful. Furthermore, using the electron microscope, it was possible to conduct and complete a study on the microvascular integrity in a male subgroup of the collection. This study demonstrated that microvessels in the CA1 and CA3 areas (substantial regions in the perforant pathway) of the hippocampus show increasing occurrence of depositions in the basement membrane during aging. These depositions have recently been proven to correlate with cognitive impairment. The current experiments deal with possible aging-related change or preservation of neuron numbers of all areas of the hippocampus in the male rhesus monkeys. Recent advances in the field of stereology have made it possible to determine with greater precision the magnitude of neuronal degeneration in the aged hippocampus. Stereological tools have been used before to prove that human hippocampal neuronal degeneration is not an inevitable consequence of normal aging. Before these experiments are carried out, it is important to complete a study that will show whether the pyramidal neurons of the cornu ammonis and the granule cells of the dentate gyrus are evenly distributed along the anterior-posterior axis. The rhesus monkey hippocampi that are used for establishing neuron numbers will be included in the stereological investigation of age-related effects on the number of parvalbumin and calbindin immunoreactive interneurons, as well as changes in the number of GFAP-immunopositive astrocytes during aging.