NAS research objectives rely heavily on a rat model of cognitive aging validated over the course of many earlier studies. Important features of the model are that outbred, Specific-Pathogen-Free Long-Evans rats are tested using a sparse training protocol in a hidden platform version of the Morris water maze. This protocol reveals prominent and reliable individual differences in spatial learning and memory at 24+ months of age, with impairment qualitatively similar to the effects of hippocampal damage in young subjects. Excluding subjects with sensorimotor deficits that confound the interpretation, spatial learning capacities among the aged rats are continuously distributed across a broad range from substantial deficits to fully intact performance on par with young adults. In this way the model enables comparisons across subjects matched according to chronological age but distinguished by differences in the cognitive outcome of aging. Previous studies confirm that behavioral outcome in this setting provides a valuable framework for exploring the neurobiology of cognitive aging, and for developing potential therapeutic interventions. Progress during the project period includes studies aimed at documenting the role of the key plasticity immediate-early gene, Arc (also known as Arg3.1;Fletcher et al., Soc. Neurosci. Abstr., 2012). Arc mRNA expression is necessary for multiple forms of synaptic plasticity and long-term memory. Although experience dependent Arc transcription is reportedly reduced in the hippocampus of aged rats, it has not been clear whether this effect is an invariant consequence of growing older or a specific correlate of age-related memory impairment. Taking advantage of our rat model of cognitive aging we have found that experience dependent Arc mRNA expression in the hippocampus fails selectively among aged rats with spatial memory deficits. Although these findings are consistent with earlier work concluding that blunted Arc transcription contributes to cognitive aging, we also found that increases in Arc protein levels induced by water maze training remain entirely intact in the aged hippocampus. Additional analyses revealed that behavioral training potently modulates multiple regulators of Arc translation, and that blunted translation dependent decay mechanisms may contribute to the Arc protein sparing noted in memory impaired aged rats. A manuscript describing these findings is currently in revision for publication. Other recent work utilizing this model has identified additional hippocampal signatures of cognitive aging, including changes in inhibitory neural networks that are both coupled with impaired memory and that are sensitive to pharmacological treatment that rescues age-related impairment (e.g., Speigel et al., J. Comp. Neurol., 2013). A new project direction, launched recently in collaboration with investigators from the Neuroimaging Research Branch of the National Institute on Drug Abuse IRP, is taking advantage of in vivo magnetic resonance imaging to test the proposal that age-related changes in brain resting state activity and functional connectivity are coupled with individual differences in the cognitive outcome of aging (Ash et al., Soc. Neurosci. Abstr., 2013). Ultimately, studies of this sort will establish the foundation for longitudinal analyses testing preclinical intervention strategies, as well as a translational bridge to related human research in other LBN and IRP projects.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Institute on Aging
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Hsu, Li-Ming; Liang, Xia; Gu, Hong et al. (2016) Constituents and functional implications of the rat default mode network. Proc Natl Acad Sci U S A 113:E4541-7
Tomás Pereira, Inês; Gallagher, Michela; Rapp, Peter R (2015) Head west or left, east or right: interactions between memory systems in neurocognitive aging. Neurobiol Aging 36:3067-78
Sewal, Angila S; Patzke, Holger; Perez, Evelyn J et al. (2015) Experience Modulates the Effects of Histone Deacetylase Inhibitors on Gene and Protein Expression in the Hippocampus: Impaired Plasticity in Aging. J Neurosci 35:11729-42
Zhu, Min; Allard, Joanne S; Zhang, Yongqing et al. (2014) Age-related brain expression and regulation of the chemokine CCL4/MIP-1β in APP/PS1 double-transgenic mice. J Neuropathol Exp Neurol 73:362-74
Ash, Jessica A; Rapp, Peter R (2014) A quantitative neural network approach to understanding aging phenotypes. Ageing Res Rev 15:44-50
Castellano, James F; Fletcher, Bonnie R; Patzke, Holger et al. (2014) Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging. Hippocampus 24:1006-16
Fletcher, Bonnie R; Hill, Gordon S; Long, Jeffrey M et al. (2014) A fine balance: Regulation of hippocampal Arc/Arg3.1 transcription, translation and degradation in a rat model of normal cognitive aging. Neurobiol Learn Mem 115:58-67
Spiegel, Amy M; Sewal, Angila S; Rapp, Peter R (2014) Epigenetic contributions to cognitive aging: disentangling mindspan and lifespan. Learn Mem 21:569-74
Koh, Ming Teng; Spiegel, Amy M; Gallagher, Michela (2014) Age-associated changes in hippocampal-dependent cognition in Diversity Outbred mice. Hippocampus 24:1300-7
Tweedie, David; Rachmany, Lital; Rubovitch, Vardit et al. (2013) Changes in mouse cognition and hippocampal gene expression observed in a mild physical- and blast-traumatic brain injury. Neurobiol Dis 54:1-11

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