As a first, critical step toward achieving the project aims, considerable start-up effort has been directed at establishing an 'in-house'colony that will yield a steady supply of behaviorally characterized young adult and aged rats appropriate for investigation. Capitalizing on collaborative support from colleagues at Johns Hopkins University, studies conducted during the current reporting period utilized a standardized model in which aged male Long-Evans rats were classified as aged impaired (AI, n = 7) or unimpaired (AU, n = 10) on a test of spatial memory. Animals were sacrificed two hours after training on a second water maze task, and the hippocampus was microdissected for regional histone deacetylase (HDAC) determinations. Although overall class I and II HDAC activity appeared elevated in behaviorally trained rats relative to untrained controls in region CA1, there was no difference across the young, AU and AI groups in any hippocampal subfield. We next determined levels of individual HDAC proteins by quantitative Western blot. Nuclear HDAC2 levels were significantly decreased in AI animals relative to young selectively in regions CA1 and CA3, whereas values in AU and young rats were comparable. This effect was HDAC specific because HDAC1 levels were equivalent across groups. Immunohistochemical localization extended these findings, demonstrating that whereas HDAC2 is abundant in hippocampal neurons, HDAC1 is predominantly localized to astrocytes. Finally, HDAC2 levels in CA3 were significantly coupled with individual variability in spatial memory across all animals. Taken together, the results establish HDAC regulation as a potentially critical epigenetic component of normal cognitive aging.
Showing the most recent 10 out of 20 publications
