Date

11-2013

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Behavioral Neuroscience

Institution

Oregon Health & Science University

Abstract

Recent changes in demographics resulting in a drastically increased aging population have sparked significant interest in research combating deficits and diseases occurring in late life. While the treatment of age-related diseases is of utmost importance, improving quality of life by maintaining normal healthy aging shows promise in preventing the development of chronic disease. For example, MCI is an early risk factor for AD, and thus addressing sub-pathological deficits in memory may prevent or delay the onset of dementia. Gonadal and adrenal steroids play major roles in many cognitive processes, including the formation and maintenance of memory, and these hormones decline markedly with age in humans. The gonadal steroids E2 and T improve cognitive performance in both rodent models as well as in human studies of memory; however, recent research in the effects of hormone therapy in advanced age raise questions as to the safety and efficacy of these treatments. The adrenal hormone DHEA, however, shows promise in rodent models of age-related cognitive decline, and endogenous levels of this hormone are associated with preserved cognitive performance in the elderly. As a result, treatment with exogenous DHEA may serve as a safer form of HT with the potential to slow cognitive decline. Despite this, trials of DHEA supplementation in the aged find little or no impact on memory. This dissertation seeks to explore this dissociation between the effects of DHEA on rodent and human cognitive aging using the rhesus macaque (Macaca mulatta), a large diurnal primate with gonadal and adrenal endocrine systems similar to those of the human. Using hormone supplementation paradigms including physiological E2, P4, DHEA, and T, I have investigated effects of E2 and DHEA treatment on memory performance in postmenopausal rhesus macaques, as well as effects of hormone supplementation paradigms on peripheral and 14 central hormone pathways. Additionally, investigation of the intracrine conversion of DHEA to E2 has shown the potential for this metabolism within the brain, suggesting DHEA administration could possibly improve cognition via local synthesis of E2 in cognitive areas such as the HPC and PFC. The enzymes responsible for this conversion, however, decline significantly with age. Thus, DHEA supplementation in the elderly may be ineffective due to a decreased ability to synthesize E2 within the brain itself. In addition to the interactions of gonadal and adrenal hormones within the brain itself, I show a significant sex-dependent interaction of the two endocrine systems in the periphery. Human and macaque research has previously shown a compensatory interaction between peripheral DHEA and E2 in females, an effect which I have found also occurs in steroidogenesis in the central nervous system. Moreover, a novel finding in this research is a positive interaction between T and DHEA in male rhesus macaques. Additional data support a mechanism by which adrenal and gonadal systems interact to maintain the hormonal milieu in youth, how and why these mechanisms differ between males and females, and suggest a hormone supplementation paradigm that seeks to restore hormone balance in aged male rhesus macaques. In summary, the classical approach of hormone therapy for the aged in which a single hormone that is deemed “deficient” is replaced may not be the most physiologically relevant approach to recreate a youthful endocrine composition. Due to the significant compensatory and facilitatory interactions between the adrenal and gonadal axes, a multi-level approach is needed to fully address the impact of the changing hormone environment on cognitive function in the aged.

Identifier

doi:10.6083/M4319T64

School

School of Medicine

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