This application proposes to address a fundamental unresolved question in the field of cognitive aging, the nature of the neurobiological factors that distinguish individuals with healthy cognitive aging (HCA) from those with unhealthy cognitive aging (UCA). The focus of the studies will be on biomarkers developing near the age of divergence of unhealthy from healthy cognitive aging, as these appear particularly likely to provide important insights into causal mechanisms. A major emphasis of the project will also be testing the hypothesis that midlife activation of myelinogenic programs in the hippocampus is an important factor in converting HCA to UCA. This view derives from our recent work with both microarray and immunohistochemical techniques showing that myelinogenesis is increased around midlife in rats, the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological correlates of cognitive aging in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in hippocampal slices, concomitant Ca2+ imaging in recorded neurons, extensive immunohistochemistry with a battery of stains, diffusion tensor imaging (MRI/DTI), separate microarray analysis of each individual rat, and substantial behavioral testing of each animal. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of cognitive aging in the same animals and will relate cognitive function to myelin structure and density in cross-sectional and longitudinal analyses. Further, the course of myelinogenesis will be altered in long-term studies that manipulate dietary iron and/or treat with cuprizone. Animals subjected to altered myelinogenesis will be tested on a battery of behavioral, electrophysiological, microarray and immunohistochemical analyses, to test the proposition that conversion to UCA has been slowed and, if it has, to determine through which hippocampal pathways this occurred. Overall, these studies should substantially elucidate neurobiological markers distinguishing UCA from HCA, and should importantly determine the role of myelinogenic programs in cognitive aging. Further, the proposed longitudinal studies should have direct translational relevance.

Public Health Relevance

This proposed research will be conducted in an established rat model of aging, which shows demonstrated relevance to human aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy cognitive aging. Therefore, the proposed studies should have both predictive and therapeutic value in determining the course of human cognitive aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034605-05
Application #
8520138
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M2))
Program Officer
Wagster, Molly V
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$517,910
Indirect Cost
$132,908
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Chen, Kuey-Chu; Blalock, Eric M; Curran-Rauhut, Meredith A et al. (2013) Glucocorticoid-dependent hippocampal transcriptome in male rats: pathway-specific alterations with aging. Endocrinology 154:2807-20
Searcy, James L; Phelps, Jeremiah T; Pancani, Tristano et al. (2012) Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of Alzheimer's disease. J Alzheimers Dis 30:943-61
Latimer, Caitlin S; Searcy, James L; Bridges, Michael T et al. (2011) Reversal of glial and neurovascular markers of unhealthy brain aging by exercise in middle-aged female mice. PLoS One 6:e26812
Blalock, Eric M; Buechel, Heather M; Popovic, Jelena et al. (2011) Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease. J Chem Neuroanat 42:118-26