Declines in episodic memory that accompany normal aging are a growing concern for public health as the average lifespan continues to increase. The hippocampus is a critical structure for long-term episodic and semantic memories and receives major input from the superficial layers of entorhinal cortex (EC). The deep layers of EC in turn receives output following information processing within the hippocampus. Alterations within the hippocampus itself may underlie declines in episodic memory that occur with normal aging, however it is also possible that defects in upstream or downstream structures also contribute to the known behavioral deficits. The medial entorhinal cortex (MEC) appears to process information about self-motion and position while the lateral entorhinal cortex (LEC) processes information about objects in the external environment. This application proposes to investigate the effects of aging on the ability of the EC to encode information about two visually distinct environments in both its superficial and deep layers, as well as to determine if aging has differential effects on the object representations of the LEC compared with the path integrator function of the MEC. Young (6 months) and old (24 months) rats will run on a fixed track in the same room for two sessions. Between sessions the objects on the track will be completely changed. Neurons activated by the first session will be visualized by the expression of the immediate early gene (lEG) Homeria mRNA in their nucleus, while neurons activated by the second session will express the lEG Arc. In situ hybridization will be employed to visualize mRNA, confocal microscopy will be used to image the tissue, and our semi-automated catFISH software will be used to quantify neurons activated by each (or both) behavioral sessions based on which lEG mRNA is present within the nucleus. The results will be analyzed using standard multivariate statistics to determine if aging affects either the relative proportions of activated neurons during each session or the total numbers of neurons activated by experience. The analysis of both the superficial and deep layers of EC will allow age-related changes to be assessed in cells that provide direct input to the hippocampus as well as in cells that receive direct hippocampal output. Detailed understanding of the effects of aging on cognition is of paramount importance as the trend of increasing average lifespan continues. This application proposes to investigate the integrity of brain structures that are critical for memory function during normal aging. The results will assist researchers to minimize the effects of aging on memory function by characterizing how the function of these structures is altered in old age.
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