An Investigation of the Locus Coeruleus and Noradrenergic System in Cognitively Impaired Aged Macaques

Abstract

The locus coeruleus (LC) is a small brainstem nucleus best known for being the primary central nervous system site of noradrenaline (NA) production and is integral for the modulation and optimization of behavioral performance in mammals. Some recent evidence posits that the LC is the first location in the brain to show Alzheimer’s disease pathology and decreases in LC functional integrity have drastic consequences for multiple cognitive processes. The extent to which changes in the LC and its projections are exclusive features of neurodegenerative disease remains unclear due to gaps in the literature regarding LC integrity in normal aging. The purpose of this thesis is to examine the cellular, molecular and connectivity differences in the LC and its cortically projecting axons in aging. This thesis utilizes tissue from two colonies of behaviorally categorized aged and adult bonnet and rhesus macaques, which provide excellent models of normative human brain aging as there is strong evidence that these animals do not spontaneously develop Alzheimer’s disease. The experiments and analyses in this thesis were designed to examine the locus coeruleus - noradrenergic system in normal aging at multiple levels. First, volumes, cell numbers, and vascular and glial densities are assessed within the LC nucleus itself with respect to age and cognitive performance of the rhesus macaque cohort. Then, in the bonnet cohort, the microstructural composition of the LC nucleus itself as well as its ascending projections to the cortex are examined using a high-resolution ex vivo magnetic resonance imaging (MRI) protocol to determine the extent of age-related changes. Finally, noradrenergic axons and adrenergic receptors are analyzed within the hippocampus in the rhesus macaque cohort with respect to age and cognitive status. Aged macaques had smaller LC volumes than did adults but did not differ in the number of cells in the LC or in the vascular or glial densities. Volumetric changes were not associated with performance on the behavioral tasks administered. MRI analyses of theLC nucleus revealed age-related increases in metrics indicative of water diffusion restriction, which is consistent with the histological findings of decreased volume but not cell counts (and thus increased density of cells). LC ascending projections across age groups were correlated with changes in metrics associated with gliosis but not axon loss. In the hippocampus, aged and adult rhesus macaques did not differ in density of NA axons, but older macaques had higher densities of excitatory NA receptors in CA3. In the aged macaques, higher densities of NA axons were associated with poorer performance on the tasks administered. Taken together, the comprehensive results from this thesis suggest stability in the LC nucleus and its hippocampal projections with age and posits that alterations in the volume of the nucleus itself and in the density of receptors for NA may reflect changes characteristic of in normal nonpathological aging.