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Link to original content: https://pubmed.ncbi.nlm.nih.gov/15102909
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. 2004 Apr 21;24(16):3933-43.
doi: 10.1523/JNEUROSCI.5646-03.2004.

A bioinformatics analysis of memory consolidation reveals involvement of the transcription factor c-rel

Jonathan M Levenson  1 , Sangdun Choi, Sun-Young Lee, Yun Anna Cao, Hyung Jin Ahn, Kim C Worley, Marina Pizzi, Hsiou-Chi Liou, J David Sweatt
Affiliations

A bioinformatics analysis of memory consolidation reveals involvement of the transcription factor c-rel

Jonathan M Levenson et al. J Neurosci. .

Abstract

Consolidation of long-term memory (LTM) is a complex process requiring synthesis of new mRNAs and proteins. Many studies have characterized the requirement for de novo mRNA and protein synthesis; however, few studies have comprehensively identified genes regulated during LTM consolidation. We show that consolidation of long-term contextual memory in the hippocampus triggers altered expression of numerous genes encompassing many aspects of neuronal function. Like contextual memory formation, this altered gene expression required NMDA receptor activation and was specific for situations in which the animal formed an association between a physical context and a sensory stimulus. Using a bioinformatics approach, we found that regulatory elements for several transcription factors are over-represented in the upstream region of genes regulated during consolidation of LTM. Using a knock-out mouse, we found that c-rel, one of the transcription factors identified in our bioinformatics study, is necessary for hippocampus-dependent long-term memory formation.

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Figures

Figure 2.
Figure 2.
Verification of microarray results. Six genes whose expression was regulated during consolidation of LTM (transthyretin, c-fos, sgk, prostaglandin D2 synthase, ectonucleotide pyrophosphatase/phosphodiesterase 2, and isopentenyl-diphosphate δ isomerase) were selected for independent verification via real-time RT-QPCR. Changes in gene expression measured using micro arrays were virtually identical to changes measured using RT-QPCR. Open bars represent data obtained using oligonucleotide arrays, and filled bars represent data obtained using RT-QPCR.
Figure 1.
Figure 1.
Requirements for formation of contextual fear memory. A, Diagram illustrating the various behavior paradigms used in these studies. For a complete description, see Material and Methods. B, Animals exposed to the paired fear conditioning training paradigm (Context + Shock) exhibited a high degree of freezing behavior when placed into the training context 24 hr later. Animals exposed to the latent inhibition paradigm (Latent Inhibition) exhibited no significant freezing behavior when tested 24 hr later. **p < 0.01 indicates that means were significantly different. C, Animals were injected with either saline or MK-801 1 hr before exposure to the paired fear conditioning paradigm. MK-801 significantly inhibited display offreezing behavior in a dose-dependent manner when animals were placed into the context 24 hr after training. ***p < 0.001 indicates that means were significantly different. In all graphs, bars represent mean data from six animals; error bars indicate SEM.
Figure 3.
Figure 3.
Changes in gene expression overtime and lack of correlation with changes induced by stimuli that do not induce LTM. A, B, Changes in gene expression are grouped by time. Bars represent number of genes that were either upregulated (open) or downregulated (filled) at each time point. Note the initial surge in upregulation of gene expression (1 hr), followed by a decrease in gene expression (2-4 hr).Data are plotted for CA1 (A) and dentate gyrus (B). C, Bar chart of changes in mRNA expression in area CA1 for genes in which data were collected for all three experimental conditions. Note that changes in gene expression observed in the paired training paradigm were not seen in either the unpaired or MK-801 control groups. D, Bar chart of changes in mRNA expression in the dentate gyrus for genes in which data were collected for all three experimental conditions. Note that changes in gene expression observed in the paired training paradigm were not seen in either the unpaired or MK-801 control groups except for decorin.
Figure 4.
Figure 4.
Regulation of gene expression is grouped by chromosome. Analysis of the changes in gene expression revealed a significant grouping of gene regulation by chromosome. A, In the murine genome, significant grouping of consolidation-associated changes in gene expression was observed. The dotted lines indicate lower and upper 95% confidence intervals of the mean proportion of observed/expected changes in gene expression. Significant grouping was seen at chromosomes 10, 12, 16, 18, and 19. B, Consolidation-associated genes were mapped from the murine genome to the human genome. Human homologs for 66 of the 69 murine genes were found. Significant grouping of consolidation-associated genes was observed in the human genome. The dotted lines indicate lower and upper 95% confidence intervals of the mean proportion of observed/expected changes in gene expression. Significant grouping was seen on chromosomes 2, 3, 9, 12, 14, 15, and 18. C, Human homologs of the consolidation-associated genes were mapped to the human genome. Arrows indicate positions of genes. Red arrows indicate genes implicated in derangements of human memory or cognition. Green arrows indicate genes that have not yet been implicated in human cognitive disease. Blue circles indicate groups of genes that were present in the same chromosome in the mouse and the human.
Figure 5.
Figure 5.
Presence of regulatory elements in the upstream region of genes involved in LTM consolidation. Upstream regions (1 kb) of consolidation-associated genes were analyzed for the presence of potential regulatory elements. Plotted are the number of different regulatory elements versus the number of genes containing the respective regulatory elements. Numerous regulatory elements were identified; however, few regulatory elements were found in most or all genes analyzed in each group. For example, the first bar in A indicates that 27 different regulatory elements were found exclusively upstream of only one gene, and the last bar in A indicates that only one regulatory element (octamer binding protein 1) (supplementary Table 4) was present in 13 different genes (of a total of 15). A, CA1, Upregulation; B, CA1, downregulation; C, dentate gyrus, upregulation; D, dentate gyrus, downregulation. Numbers in graphs indicate total number of genes in each group in which genomic upstream sequence data were available. E, Promoter region of MKP-3 (GenBank accession number AI845584). MKP-3 was upregulated in area CA1 1 hr after fear conditioning. The upstream region of MKP-3 contains 92 potential regulatory elements, and 10 of the 11 regulatory elements over-represented in the upstream regulatory regions of genes whose expression was upregulated during consolidation of LTM in area CA1. * indicates a regulatory element that was found to be significantly over-represented in genes upregulated in area CA1 during consolidation of LTM (supplementary Table 4).
Figure 6.
Figure 6.
Behavioral characterization of c-rel-/- mice. Basal behavioral characteristics of c-rel-/- mice were quantified. A, c-rel-/- animals (n = 9) were significantly hypoactive relative to WT animals (n = 9) during a 15 min session in the open-field task. B, No significant difference in the ratio of distance traveled in the center/total was seen, indicating that c-rel-/- mice have similar levels of basal anxiety relative to WT mice. C, No significant difference was seen in thermal sensitivity between WT (n = 9) and c-rel-/- (n = 9) animals, indicating that nociception is comparable between the two groups of mice. These results indicate that disruption of the c-rel gene does not cause gross changes in basal behavioral characteristics of C57BL/6 mice.
Figure 7.
Figure 7.
c-rel-/- animals have impaired contextual, but not associative, fear memory. WT and c-rel-/- animals were exposed to either an associative (A, B) or contextual (C, D) fear conditioning paradigm. Freezing behavior was assessed during (A, C) or 24 hr after (B, D) training. A, No significant difference was seen in freezing behavior between WT (n = 4) or c-rel-/- (n = 3) mice during associative fear conditioning training. B, No significant differences were seen in freezing behavior when mice were tested 24 hr later in the absence and presence of the auditory cue. C, No significant difference was seen between WT (n = 5) or c-rel-/- (n = 6) animals during contextual fear conditioning training. D, c-rel-/- animals had a significant deficit in freezing behavior assessed 24 hr after training in the training context. These results indicate that c-rel-/- animals have a specific deficit in hippocampus-dependent long-term memory formation.
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