Immediate Early Gene Expression in Medial Prefrontal Cortex and Hippocampus as a Function of Aging

Abstract

Normal aging is accompanied by cognitive decline that differs from other aging-related pathological states like Alzheimer's disease. With an increasing proportion of the world population falling in an age group of 65 years and above, a preventive gerontological approach would improve the quality of life in the elderly. Especially important in this regard is the early detection of cognitive decline, so that appropriate measures can be taken to prevent development of cognitive deficits. Impairment in cognitive flexibility, the ability to modify a previously learnt behavior, is one such measure of impairment across species in aged animals. Previous work from our lab has demonstrated that a cognitive flexibility deficit, as measured by extinction of conditioned fear, first emerges in middle-aged animals. Extinction of conditioned fear requires coordinated activity of infralimbic (IL) and prelimbic (PL) subregions of prefrontal cortex, dorsal and ventral hippocampus, and various amygdala sub nuclei. Of these, prefrontal cortex- and hippocampus-dependent behaviors are impaired during aging, indicating that aging-related impairments within these structures could underlie extinction deficits during aging. One way to measure region-specific neuronal activation is through analysis of immediate early gene (IEG) expression. IEG expression at rest is not random but reflects ongoing memory consolidation. The role of IEGs as markers of neuronal plasticity and their critical role in memory consolidation make them ideal markers for investigating early cognitive decline. The current study investigated aging-related changes in the expression of IEGs, Zif-268 and Arc in the IL and PL subregions of the mPFC in addition to dorsal and ventral hippocampus. Specifically, the current study used western blotting and immunohistochemistry to investigate region-specific expression of the IEGs Zif-268 and Arc in naive adult, middle-aged and aged animals. We found that Zif-268 expression was reduced in IL, PL, CA1 and DG of dorsal hippocampus and DG of ventral hippocampus starting middle-age. In addition, Arc expression was reduced in IL but not PL in aged rodents. Within hippocampus, Arc expression was reduced within dorsal but not ventral subregion starting middle age. These data indicate that IEG expression changes are region-specific, can be evident starting middle age and may contribute to behavioral deficits during the aging process.