ABSTRACT
The functional connectome reflects a network architecture enabling adaptive behavior that becomes vulnerable in advanced age. The cellular mechanisms that contribute to altered functional connectivity in old age, however, are not known. Here we used a multi-scale imaging approach to link age-related changes in the functional connectome to altered expression of the activity-dependent immediate-early gene Arc as a function of training to multi-task on a working memory/bi-conditional association task (WM/BAT). Resting state fMRI data were collected from young and aged rats longitudinally at three different timepoints during cognitive training. After imaging, rats performed the WM/BAT and were immediately sacrificed to examine expression levels of Arc during task performance. Aged behaviorally-impaired, but not young, rats had a subnetwork of increased connectivity between the anterior cingulate cortex (ACC) and dorsal striatum (DS) that was correlated with the use of a suboptimal response-based strategy during cognitive testing. Moreover, while young rats had stable rich club organization across three scanning sessions, the rich club organization of old rats increased with cognitive training. In a control group of young and aged rats that were longitudinally scanned at similar time intervals, but without cognitive training, ACC-DS connectivity and rich club organization did not change between scans in either age group. These findings suggest that aberrant large-scale functional connectivity in aged animals is associated with altered cellular activity patterns within individual brain regions.
SIGNIFICANCE STATEMENT Cognitive decline is frequently observed in advanced age. Although impairments in older adults have been linked to alterations in resting state brain connectivity, how these changes relate to the neurobiology of individual neurons is unknown. The current study reports longitudinal changes in the functional connectome of aged rats with cognitive training that were not observed in young animals with better task performance. These network alterations in old age were associated with poorer task performance and increased Arc expression in the dorsal striatum. This work is significant because it links functional organization of brain networks to behavioral impairments and changes within individual neurons, providing a potential bridge between invasive cell-based analyses in animal models to imaging data from human study participants.
Footnotes
A. Authors report no conflict of interest.
This work was supported by National Institutes of Health National Institute on Aging grants R01 AG049722 and P50 AG047266, and the McKnight Brain Research Foundation. The authors acknowledge the support from the Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) facility (National Science Foundation Cooperative Agreement No. DMR-1157490 and the State of Florida).
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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