Instead of testing the changes in expression of each of thousands of genes, a small number of gene co-expression modules are tested in the WGCNA approach. In this study we look for common molecular and neuronal mechanisms for antidepressant action by studying the hippocampi of mice exposed to three different interventions. We compared changes in adult neurogenesis, neuronal plasticity, and gene expression induced by exercise, environmental enrichment, and fluoxetine, a specific serotonin reuptake inhibitor commonly prescribed for major depression. We examined these phenotypes in the hippocampus, because this brain structure has been implicated in the pathophysiology and treatment of mood disorders, and changes in adult neurogenesis in the hippocampus are associated with exercise, environmental enrichment and possibly also with the therapeutic effect of antidepressants. In order to further exclude the possibility of an artefactual explanation for our results we searched for expression data carried out by others on mice treated with any of the antidepressant treatments, fluoxetine or voluntary exercise. For each gene within the modules we also calculated the gene significance – the correlation between the expression profile across samples of each gene and the antidepressant treatment. In addition,Lathyrol for each module, and for each gene, we calculated the module membership, which is the correlation between the gene expression and the module eigengene. The correlation between the gene significance and the module membership score was significant in the four modules, illustrating that genes significantly associated with antidepressant treatments are often also the most important elements in this modules. Out of the four modules, 9-methoxycamptothecine two were positively and two negatively correlated with fluoxetine and exercise. Gene enrichment and functional annotation analyses revealed that the modules are enriched for specific processes. The module showing the most consistent effect in both fluoxetine and exercise was upregulated compared to control, and was enriched for genes belonging to the proteasome. Using a neurogenomics approach to uncover the changes following antidepressant treatments at the molecular, neuronal and behavior levels, we found significant alterations in multiple levels that are common to both exercise and fluoxetine treatments,but are not shared with environmental enrichment. Our results suggest that there is a shared mechanism underlying the antidepressant effect of fluoxetine and exercise. We have identified similar changes in neurogenesis and structural plasticity in the hippocampus of mice following chronic fluoxetine treatment and voluntary exercise. A co-expression network analysis revealed changes of specific groups of genes in the mouse hippocampus in response to antidepressant treatments. Gene expression is subject to a large number of confounds, unrelated to the intervention under examination, but we believe our findings are robust for a number of reasons. Several consistent changes were observed in response to exercise and fluoxetine treatments, which may reveal a core mechanism of antidepressant action. Increase in neurogenesis was observed in both treatments as indicated by staining of immature neurons with DCX. In addition, in both groups there was an increase in spine density. These changes at the cellular levels can be also related to the corresponding changes in gene expression. The most consistent finding at the network level was the upregulation of the light green module, which is enriched for genes involved in the function of the proteasome. The upregulation of proteasome genes might be connected to the increase in dendritic spine density, since this process has very high and dynamic degradative demands.