Hippocampal gene expression patterns underlying the enhancement of memory by running in aged mice
Introduction
The aging brain retains its responsiveness to the environment. Studies have shown that environmental enrichment can influence a number of factors relevant to brain aging, including synaptic plasticity and neuronal morphology (van Praag et al., 2000). Enriched environments typically afford increased opportunities for social and cognitive stimulation, as well as physical activity. Among these components of the enrichment paradigm, physical activity in the form of wheel running has emerged as a potent modulator of central neuroplasticity. Wheel running preserves learning and memory, and enhances adult neurogenesis in the hippocampus of aging mice (van Praag et al., 2005). These effects of voluntary wheel running on learning and memory are associated with changes in genes expression. For example, learning (Cavallaro et al., 2002) and environmental complexity (Rampon et al., 2000) alter gene transcription in young animals. Pathways influenced by these experiences include cell-survival associated genes and genes involved in synaptic plasticity. The gene expression profile to learning has also been shown to differ between young and aged animals (Rowe et al., 2007).
The hippocampus plays a critical role in learning and memory, and is susceptible to dysfunction and degeneration in aging and Alzheimer's disease (Mattson and Magnus, 2006). Several studies have now shown that running in a wheel influences gene transcription in the hippocampus of young adult mice and rats (Molteni et al., 2002, Tong et al., 2001, Hunsberger et al., 2007). The transcripts upregulated by running overlap considerably with those influenced by enrichment and learning. In addition, the pathways influenced by running oppose the effects of aging at multiple levels. However, it remains unknown whether exercise influences the transcriptome in aging animals. Moreover, it is uncertain what changes in gene transcription might underlie the established ability of exercise to preserve learning and memory in aging animals (van Praag et al., 2005).
In these studies, we characterized the effects of lifelong running on learning-induced transcriptional modifications in aged animals. Under basal, unstimulated conditions, the differences between runners and controls were restricted to a small pool of genes. In contrast, when we compare the regulation of gene expression by learning across runners and sedentary animals, a large number of gene transcripts are differentially regulated. Running enhanced hippocampus-dependent learning in aged mice, and the enhancement of spatial memory was accompanied by differential expression of genes important for learning and synaptic plasticity, as well as genes involved in energy metabolism, and insulin and Wnt signaling. These studies suggest that aged runners differentially express certain gene transcripts in the hippocampus, and may recruit an entirely different transcriptional profile following learning.
Section snippets
Animals and activity monitoring
Animal care and experimental procedures followed NIH guidelines and were approved by the National Institute on Aging Animal Care and Use Committee. Male C57BL/6 mice were housed individually with (n = 24) or without (n = 18) running wheels (Campden Instruments), beginning at 2–4 months of age. The number of wheel turns was collected automatically with custom software, and the room was maintained on a 12 h light/dark schedule with food and water available ad libitum.
Experimental design
After 16 months in their
Running enhances hippocampus-dependent learning in aged mice
All mice housed with running wheels ran extensively (mean distance = 1.54 ± 0.32 km/day) and there was a significant decrease in running activity with age (Pearson's correlation, time × distance; r2 = 0.76, p = 0.0005). In concurrence with previous reports (van Praag et al., 2005) running was associated with reduced escape latency in the maze (F1,48 = 6.81, p = 0.02; Fig. 1A). Runners also took a more direct path to the platform (F1,48 = 5.76, p = 0.003; Fig. 1B). In the probe trial, animals that had engaged in
Discussion
Running enhances hippocampus-dependent learning in aged mice. Improvements in learning were not attributable to changes in a small number of genes, but instead involved changes in the number and diversity of the molecular pathways influenced by water maze training. Runners recruited a more varied set of transcriptional categories following learning. These categories included transcripts involved in dendritic and synaptic plasticity, as well as genes implicated in learning and memory. Mice
Acknowledgements
This research was supported by the Intramural Research Program of the National Institute on Aging. We would like to thank Xiangru Xu for valuable discussions. The authors have no actual or potential conflicts of interest.
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