Laboratory of Experimental Gerontology |
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Peter Rapp, Ph.D., Senior Investigator Chief, Laboratory of Experimental Gerontology and Chief, Neurocognitive Aging Section |
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Models of Neurocognitive Aging: Age-related deficits in cognitive function compromise the quality of life and are among the most troubling consequences of growing older. A major line of research in the Neurocognitive Aging Section (NAS) is aimed at establishing a nonhuman primate model for defining the basis of normal cognitive aging, and for developing effective interventions. Early studies succeeded in revealing the basic neuropsychological profile of aging, and we have now turned attention to the specific nature of decline, with the aim of defining the effects of aging on the component processes of declarative/episodic memory. Young and aged monkeys are tested across a battery of novel assessments that manipulate demands on key operating characteristics of memory: 1) the contributions of recollection and familiarity to visual recognition, 2) memory for spatial and non-spatial context, 3) the temporal structure of experience, and 4) the relational organization of memory. An important goal of these studies is to develop a detailed and sensitive framework for testing the working hypothesis that age-related decline results from large-scale restructuring of the neural networks that support normal memory. Toward this end, subjects receive periodic high resolution, structural MRI and corresponding [18F]fluorodeoxyglucose PET scans, over the course of neuropsychological testing. Metabolic activity in the prefrontal cortex and medial temporal lobe system is then evaluated in relation to individual variability in the cognitive outcome of aging. The incidence of menstruation and urinary hormone profiles are also tracked, enabling evaluation of the behavioral and imaging results in relation to naturally occurring ovarian failure. |
Enabled by collaborations with Dr. Michela Gallagher at Johns Hopkins University, John Morrison at the Mount Sinai School of Medicine, Howard Eichenbaum at Boston University, and others, NAS has configured additional basic research efforts around several integrated themes. Age-associated cognitive decline in humans prominently involves disrupted interactions between multiple memory-related brain systems. Ongoing studies in NAS are among the first to address this issue in an aged rat model, using a plus-maze procedure and quantitative in situ hybridization for the plasticity-related gene Arc to test the possibility that deficits in cognitive flexibility are coupled with functional network reorganization across the prefrontal cortex, dorsal striatum and hippocampus. Current perspectives implicate alterations in plasticity mechanisms as a basis for cognitive aging, and accordingly, our effort toward the development of effective interventions focus on this target from multiple levels of analysis. It is noteworthy in this context that histone deacetlylase inhibitor administration in young subjects promotes chromatin rearrangement permissive for normal gene transcription, enhances hippocampal long-term potentiation, and benefits memory. These results predict that, even in the absence of underlying defects in chromatin remodeling, treatments targeting epigenetic transcriptional control may improve the neurocognitive outcome of aging. NAS is testing this proposal in both rats and nonhuman primates, coordinating behavioral assessment with the analysis of pharmacological effects on relevant molecular signatures of successful aging. We will also pursue a systematic examination of chromatin remodeling contributions to normal cognitive aging, focusing on both the resting basal status of epigenetic transcriptional control, and the dynamic regulation of these mechanisms under learning activated conditions. |
Ovarian Hormone Influences on Neurocognitive Health: Additional collaborative studies in nonhuman primates take advantage of the uniquely valuable translational potential of this animal model. Although available evidence indicates that aging modulates the cognitive and neurobiological effects of ovarian hormone manipulation, this proposal has proved difficult to test in women. Studies currently underway in young and aged monkeys are therefore designed to compare the cognitive effects of multiple hormone replacement strategies, modeled on regimens available for clinical use in women. Our strategy for neuropsychological assessment takes advantage of a battery of extensively standardized tasks with sensitivity to both aging and ovarian hormone manipulation, and that facilitates the development of testable predictions about the neural systems that might mediate the effects of hormone administration. Behavioral testing also includes systematic manipulations of interference and distraction, aimed at illuminating the specific information processing capacities responsible for the cognitive benefits of treatment. These studies will establish a unique framework of behavioral data for related collaborative initiatives focusing on the neurobiological effects of ovarian hormone manipulation. Taken together, the results can be expected to inform a number of pressing issues in the clinical use of hormone replacement, and to substantially advance research on women's neurocognitive health. |
Structure and Organization of Memory: Progress in research on neurocognitive aging is critically supported by advances in understanding the fundamental structure and organization of memory in brain. Based on this perspective, another line of investigation in NAS brings into convergence research on the neurology and cognitive psychology of memory. Guided by the consensus that the medial temporal lobe system is critical for normal episodic memory, a key aim is to identify the information processing functions of the primate hippocampus that mediate this capacity. Although a variety of tasks are used, the underlying strategy throughout is to incorporate "probe" tests that go beyond task accuracy to reveal the nature of representations established during training. Taken together, these investigations are expected to substantially advance our understanding of the structure and organization of medial temporal lobe memory in primates and, ultimately, fuel research on a variety of conditions in which memory is prominently affected. |
Contact Information: Laboratory of Experimental Gerontology Biomedical Research Center, room 09C222 251 Bayview Boulevard, Suite 100 Baltimore, MD 21224 Phone 410-558-8195 Fax 410-558-8302 E mail rappp@mail.nih.gov For more information about the Laboratory: http://www.grc.nia.nih.gov/branches/leg/leg.htm |
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