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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M2))
Program Officer
Wagster, Molly V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Schools of Medicine
United States
Zip Code
Hargis, Kendra E; Blalock, Eric M (2017) Transcriptional signatures of brain aging and Alzheimer's disease: What are our rodent models telling us? Behav Brain Res 322:311-328
Latimer, Caitlin S; Brewer, Lawrence D; Searcy, James L et al. (2014) Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats. Proc Natl Acad Sci U S A 111:E4359-66
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
Pancani, Tristano; Anderson, Katie L; Brewer, Lawrence D et al. (2013) Effect of high-fat diet on metabolic indices, cognition, and neuronal physiology in aging F344 rats. Neurobiol Aging 34:1977-87
Keeney, Jeriel T R; Förster, Sarah; Sultana, Rukhsana et al. (2013) Dietary vitamin D deficiency in rats from middle to old age leads to elevated tyrosine nitration and proteomics changes in levels of key proteins in brain: implications for low vitamin D-dependent age-related cognitive decline. Free Radic Biol Med 65:324-34
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
Craft, Suzanne; Foster, Thomas C; Landfield, Philip W et al. (2012) Session III: Mechanisms of age-related cognitive change and targets for intervention: inflammatory, oxidative, and metabolic processes. J Gerontol A Biol Sci Med Sci 67:754-9
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
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