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 (i.e., aged-unimpaired;AU versus aged-impaired;AI). Previous studies confirm that behavioral outcome in this setting provides a valuable framework for exploring the neurobiology of cognitive aging, and establishing a stable, in-house colony of behaviorally characterized young and aged rats has been a high priority. The founder source comprises male Long-Evans rats obtained as retired breeders from Charles River Laboratories. Animals are maintained on-site, typically until 24 months of age (depending on experimental aims), when they receive standard behavioral characterization and are made available for further cognitive and neurobiological investigation. Our multi-year effort to establish a stable, replenishing animal resource for NAS research on neurocognitive aging reached a key milestone in development during the current reporting period, and the colony is now yielding substantial numbers of behaviorally characterized young adult and aged rats on a continuing basis. Encouraged by this progress, we are now in a position to consider requests to provide animals or material for a range of collaborative efforts in addition to the immediate needs of NAS projects. Consistent with a substantial body of earlier work in this model (reviewed in Fletcher and Rapp, in press;Rapp and Bachevalier, in press) these efforts are expected to significantly leverage investment in this initiative. Progress on this project during the current reporting period had focused on the role of epigenetics and chromatin modification dynamics to neurocognitive aging. In one study, for example, we used a combination of low- and higher-resolution microscopy, a multi-purpose image classifier algorithm, and quantitative western blotting, to examine the effects of aging on hippocampal cAMP response element binding (CREB)-binding protein (CBP). CBP is a transcriptional coactivator with innate histone acetyltransferase (HAT) activity, and blocking CBP mediated HAT activity, independent of transcriptional coactivator effects, disrupts performance on multiple tests of memory. Results of our recent experiments confirmed that training on a single session variant of the water maze dynamically regulates CBP protein levels in the young and aged hippocampus (Castellano et al., 2012). Both baseline and experience-dependent regulation of CBP, however, failed to differ as a function of either chronological age or the integrity of hippocampal memory (Pereira et al., 2012). A related series of experiments examined both resting and experience-dependent chromatin regulation in the hippocampus of young, AU and AI rats, including multiple histone modifications implicated in memory-related synaptic plasticity, and factors responsible for the bidirectional control of histone acetylation. Whereas current research in the area of cognitive neuroepigenetics has emphasized that chromatin regulation permissive for gene expression broadly benefits memory, our findings suggest that experience engages a more complex, dynamic pattern of bidirectional modification. Regarding our primary focus of cognitive aging, the main finding was that whereas no individual epigenetic abnormality was uniquely coupled with impairment, poor memory in aging was associated with a broad failure in the coordinated epigenetic regulation observed in young subjects in response to recent behavioral training (Castellano et al., 2012). By comparison with current preclinical research promoting treatments that broadly enable gene transcription (e.g., histone deacetylase inhibitor, HDACi, administration), our findings imply that efficacy may instead hinge on reestablishing the coordinated orchestration of epigenetic control in the aged brain. Consistent with this prediction, in a recent we found that non-specific, long-lasting pharmacological enhancement of histone acetylation in the aged hippocampus produces, at most, a modest benefit on memory (Castellano et al., in preparation). Ongoing experiments are addressing a number of related issues in neurocognitive aging, including the contribution of learning-induced gene transcriptional profiles to successful cognitive outcomes (Haberman et al., 2012, Soc. Neurosci. Abstr.);the potential role of altered transcription and translation of the plasticity related Arc gene (Fletcher et al., 2012, Soc Neurosci Abstr);the mechanisms of HDACi treatment effects on synaptic connectivity (Sewal et al., 2012, Soc Neurosci Abstr);and the network distribution of neuronal activations that mediates cognitive flexibility in young and aged rats (Pereira et al., 2012, Soc Neurosci Abstr).

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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Ash, Jessica A; Lu, Hanbing; Taxier, Lisa R et al. (2016) Functional connectivity with the retrosplenial cortex predicts cognitive aging in rats. Proc Natl Acad Sci U S A 113:12286-12291
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
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
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 36:3067-3078
Ash, Jessica A; Rapp, Peter R (2014) A quantitative neural network approach to understanding aging phenotypes. Ageing Res Rev 15:44-50
Zhu, Min; Allard, Joanne S; Zhang, Yongqing et al. (2014) Age-related brain expression and regulation of the chemokine CCL4/MIP-1? in APP/PS1 double-transgenic mice. J Neuropathol Exp Neurol 73:362-74
Spiegel, Amy M; Sewal, Angila S; Rapp, Peter R (2014) Epigenetic contributions to cognitive aging: disentangling mindspan and lifespan. Learn Mem 21:569-74
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
Koh, Ming Teng; Spiegel, Amy M; Gallagher, Michela (2014) Age-associated changes in hippocampal-dependent cognition in Diversity Outbred mice. Hippocampus 24:1300-7

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