Memory-specific temporal profiles of gene expression in the hippocampus

Abstract

Many experiments in the past have demonstrated the requirement of de novo gene expression during the long-term retention of learning and memory. Although previous studies implicated individual genes or genetic pathways in learning and memory, they did not uncover the collective behaviors or patterns of the genes. We have used genome-scale screening to analyze gene expression during spatial learning of rats in the Morris water maze. Our results show distinct temporal gene expression profiles associated with learning and memory. Exogenous administration of one peptide whose sustained increase during memory retention was implicated by microarray analysis, fibroblast growth factor (FGF)-18, improved spatial learning behavior, suggesting that pharmacological modulation of pathways and targets identified may allow new therapeutic approaches for improving learning and memory. Results of this study also suggest that while learning and physical activity involve common groups of genes, the behavior of learning and memory emerges from unique patterns of gene expression across time.

Fig. 1.

Differential gene expression during water maze learning. (A and B) Venn diagrams of differentially expressed hippocampal genes. Genes differentially expressed in naive and swimming control animals 1, 6, and 24 h after training were operationally defined as “physical activity-related genes” (PARGs), whereas genes differentially expressed in water maze-trained animals compared with swimming controls were operationally defined as “memory-related genes” (MRGs) (A). Among these, 91 genes were down-regulated (B), whereas 55 genes were up-regulated (C) in at least one of three time points examined. (D) Hierarchical clustering of memory-related genes. A hierarchical clustering algorithm (Pearson correlation, separation ratio 0.5, minimum distance 0.001) was used to order memory-related genes in a dendrogram in which the pattern and length of the branches reflect the relatedness of the samples. Data are presented in a matrix format. Each row represent a single gene and each column represents an experimental condition. The averaged normalized intensity from two replicates is represented by the color of the corresponding cell in the matrix. Blue, yellow, and red cells, respectively, represent transcript levels below, equal to, or above the median abundance across all conditions. Color intensity reflects the magnitude of the deviation from the median (see scale at the bottom). (E–L) Differentially expressed genes in swimming control (SC) vs. water maze (WM)-trained animals at 1, 6, and 24 h after training.