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High-throughput gene expression profiling measures individual gene expression across conditions. However, genes are regulated in complex networks, not as individual entities, limiting the interpretability of gene expression data. Machine learning models that incorporate prior biological knowledge are a powerful tool to extract meaningful biology from gene expression data. Pathway-level information extractor (PLIER) is an unsupervised machine learning method that defines biological pathways by leveraging the vast amount of published transcriptomic data. PLIER converts gene expression data into known pathway gene sets, termed latent variables (LVs), to substantially reduce data dimensionality and improve interpretability. In the current study, we trained the first mouse PLIER model on 190,111 mouse brain RNA-sequencing samples, the greatest amount of training data ever used by PLIER. We then validated the mousiPLIER approach in a study of microglia and astrocyte gene expression across mouse brain aging. mousiPLIER identified biological pathways that are significantly associated with aging, including one latent variable (LV41) corresponding to striatal signal. To gain further insight into the genes contained in LV41, we performed k -means clustering on the training data to identify studies that respond strongly to LV41. We found that the variable was relevant to striatum and aging across the scientific literature. Finally, we built a Web server (http://mousiplier.greenelab.com/) for users to easily explore the learned latent variables. Taken together, this study defines mousiPLIER as a method to uncover meaningful biological processes in mouse brain transcriptomic studies., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Zhang et al.)