NEUROCHEMICAL AND NEUROENDOCRINE ALTERATIONS IN THE AGED RHESUS BRAIN: A REVIEW.
Steven G. Kohama*
Division of Neuroscience, Oregon Regional Primate Research Center/Oregon Health Sciences University, 505 N.W. 185th Ave, Beaverton, Oregon 97006.
Age-related changes in behavior are believed to reflect functional and structural modifications in the brain, which also serve as a permissive environment for the emergence of human neurodegenerative diseases. In order to mimic clinical aspects of brain aging, the rhesus monkey has emerged as an important experimental model in which to explore and manipulate relevant neural systems at a mechanistic level. The monkey is advantageous for these types of studies due to its similar physiology, genetics, sophisticated brain structure, rich behavioral repertoire and relatively long lifespan. Of great interest has been the use of the aged rhesus macaque to mimic human neurodegenerative diseases, particularly Alzheimer's (AD) and Parkinson's disease (PD). Studies have revealed similar types of pathology in the aged rhesus brain, documented as an accumulation of amyloid plaques and the loss of midbrain dopaminergic and basal forebrain cholinergic neurons. However, recent data suggests the possibility that the aged rhesus is an incomplete model due to relatively mild deficits in behavior, brain weight, volumetric brain change documented by in vivo imaging, neuronal number, synaptic integrity and the lack of correlation of behavioral deficits with pathological markers. In addition, reports of neuronal loss in diffusely projecting subcortical neurotransmitter systems of the aged rhesus monkeys may actually reflect a down-regulation of phenotypic markers as a result of declining neurotrophic stimuli. Therefore, the nonhuman primate may actually represent an ideal situation in which to study aspects of normative brain aging, without the interference of neurodegenerative disease processes. But, if the overall structural integrity of the aged rhesus brain is relatively intact this suggests much more subtle changes are ultimately responsible for known behavioral deficits. Because many of the fundamental cellular pathways responsible for specific aspects of neuronal function are still being defined, little has been explored in this regard in the aged rhesus brain. However, the underlying neurobiology behind age-related deficits in behavior, for example, cognition, reproduction and stress have been examined recently. In particular, neurochemical changes reflected in the ligands and receptors of major neurotransmitter and peptidergic systems have been explored and offer targets for pharmacological intervention and amelioration of aging effects. Similarly, reports of subtle neurochemical changes in myelination may disrupt functional aspects of neuronal communication resulting in behavioral deficits. Some of these age-related modifications of central nervous function may ultimately have long-term and far-reaching physiological effects, manifested through dysregulation of neuroendocrine systems. The hypothalamic-pituitary-adrenal axis and hypothalamic-pituitary-gonadal axis, for example, are both highly dependent upon central nervous system regulation and integration of peripheral signaling for normal function. The loss of estrogenic feedback due to menopause may in fact be detrimental for other aspects of brain function. Thus, understanding brain senescence and the development of appropriate models remains a critical issue for the field of aging research.
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