NAS research on neurocognitive aging utilizes a rat model validated over the course of many earlier studies. This model has enabled productive collaborations with both intra- and extramural investigators, including laboratories at Johns Hopkins University, University of California Irvine, the Mount Sinai School of Medicine, and the University of Washington. Important features of the model are that genetically outbred, Long-Evans rats are tested on the hidden platform version of a standardized water maze procedure using a sparse training protocol. This approach reveals reliable individual differences in spatial learning and memory at 24 months of age relative to young, mature adults at 6 months, with impairments qualitatively resembling the effects of hippocampal damage. Subjects with sensorimotor deficits that might be misinterpreted as cognitive in origin are excluded on the basis of performance on a cue-guided, non-hippocampal variant of testing. Spatial learning capacities among aged rats are continuously distributed across a broad range, with some performing on par with normal young adults, and other aged animals displaying impairment outside this normative range. In this way the model enables comparisons across subjects matched according to chronological age but distinguished by differences in the status of hippocampal memory. Previous work confirms that behavioral testing in this setting provides a valuable framework for exploring the neurobiology of cognitive aging, and for developing potential therapeutic interventions. Earlier progress in this area has cut across multiple levels of analysis, from molecular studies on the epigenetic regulation of gene expression, to neural systems analysis testing whether cognitive aging arises from disrupted interactions between multiple memory systems. The most recent line of investigation in NAS has begun to directly examine neural network dynamics in relation to cognitive aging in animal models by functional magnetic resonance imaging (fMRI). In a recent study, for example, we aimed to define the effects of aging on the integrity of network resting state functional connectivity (rs-FC). In a previous study our collaborators at NIDA demonstrated that young rats maintained under twilight anesthesia, via a custom-designed regimen of dexmedetomidine and 0.5% isoflurane, exhibit a regional distribution of temporally correlated BOLD activity overlapping, but anatomically more extensive than, the default mode network (DMN) in humans and monkeys. Adopting a parallel approach in our aged rat model, we recently completed an analysis of resting state fMRI data collected on a Bruker Biospin 9.4T small animal scanner. Aged subjects with impaired memory exhibited a distinct network signature relative to both young and age-matched animals with normal memory, characterized by marked reductions in resting state activity correlated with a seed region in the retrosplenial cortex, including frontal and cingulate areas overlapping the DMN. By comparison, successful cognitive aging, in aged rats with preserved spatial memory, was associated with a qualitatively different pattern, involving reduced connectivity in a network that showed anti-correlated activity in young adults. These latter findings add to growing evidence that successful aging reflects a qualitatively distinct neuroadaptive outcome, not simply the endurance of a youth phenotype or slower rate of aging. A full-length report of these novel findings is currently under consideration for publication.
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