Survey of the Arc Epigenetic Landscape in Normal Cognitive Aging

Aging is accompanied by aberrant gene expression that ultimately affects brain plasticity and the capacity to form long-term memories. Immediate-early genes (IEGs) play an active role in these processes. Using a rat model of normal cognitive aging, we found that the expression of Egr1 and c-Fos was associated with chronological age, whereas Arc was more tightly linked to cognitive outcomes in aging. More specifically, constitutive Arc expression was significantly elevated in aged rats with memory impairment compared to cognitively intact aged rats and young adult animals. Since alterations in the neuroepigenetic mechanisms that gate hippocampal gene expression are also associated with cognitive outcome in aging, we narrowed our focus on examining potential epigenetic mechanisms that may lead to aberrant Arc expression. Employing a multilevel analytical approach using bisulfite sequencing, chromatin immunoprecipitations, and micrococcal nuclease digestion, we identified CpG sites in the Arc promoter that were coupled to poor cognitive outcomes in aging, histone marks that were similarly coupled to spatial memory deficits, and nucleosome positioning that also varied depending on cognitive status. Together, these findings paint a diverse and complex picture of the Arc epigenetic landscape in cognitive aging and bolster a body of work, indicating that dysfunctional epigenetic regulation is associated with memory impairment in the aged brain.