Aging and lesion-induced changes of frontotemporal integrity in the macaque monkey

The overall aim of this dissertation was to investigate changes in frontotemporal integrity as a result of both normal aging and experimental brain lesions in the macaque monkey. Traditionally, neurobiological assessment of the effects of either normal aging or medial temporal lobe damage has been limited to discrete brain regions in the prefrontal or medial temporal cortices. Far less is known about changes distributed across these regions. It was hypothesized that aging and experimental brain damage induce a coordinated pattern of degenerative and reactive alterations across both the prefrontal and medial temporal lobe regions. To test this hypothesis, we first used in vivo imaging and measured hippocampal volume to determine whether age-related atrophy occurs in the hippocampus, and if it was predictive of recognition memory deficits. The results of this assessment revealed that although hippocampal volume was not correlated with recognition memory, cerebral volume was correlated with recognition accuracy. We expanded the study to include additional aged subjects and further assessed volumetric changes across both the prefrontal and medial temporal lobes to determine whether the correlation between cerebral atrophy and recognition memory could be accounted for by atrophic changes across the frontotemporal system. Our results demonstrated that hippocampal volume was predictive of spatiotemporal memory deficits, whereas prefrontal volumes were predictive of recognition memory impairments. As a starting point to investigate lesion-induced effects on the brain, we used post-mortem histological techniques to determine whether the nonhuman primate brain has the capacity for structural reorganization following entorhinal lesion-induced medial temporal lobe dysfunction. Volumetric assessment demonstrated that atrophy occurred in the terminal zone of the entorhinal projections, the outer molecular layer of the dentate gyrus and an expansion rostral region of the inner molecular layer. Using stereological methods to define fiber length, we also revealed sprouting of the cholinergic system in the rostral portion of the inner molecular layer. This data suggests that the macaque dentate gyrus has the capacity for reactive transsynaptic plasticity following entorhinal cortex damage. This dissertation focused on the structural changes in the macaque brain. Therefore, an important next step is to assess functional reorganization across memory-related networks.