| New mothers exhibit enhanced aspects of sociability in the postpartum period, such as heightened empathy and bonding, which is critical to the survival and development of offspring. To assess neural alterations associated with the emergence of the maternal phenotype, large-scale gene expression in lactating mice was measured relative to nulliparous controls in two behaviorally relevant brain regions, the lateral septum (LS) and medial prefrontal cortex (mPFC). In LS, it was found that the extra-synaptic, alpha4/delta-containing GABAA receptor subtype is downregulated in the transition to motherhood, while the synaptic population remains static. In both LS and mPFC, pathway analysis provided evidence that developmental processes are invoked in the postpartum period, suggesting that the establishment of the maternal brain involves long-lasting, structural changes. It is possible that genes and pathways involved in shaping the healthy maternal phenotype could also put individuals at risk for pathological disorders such as autism, bipolar disorder, and schizophrenia, when regulated inappropriately. To overcome limitations of existing software and assess enrichment of mental health related genes within the expression profile of the maternal brain, we developed the open source Modular Single-set Enrichment Test (MSET). Using MSET, a striking consensus of enrichment for mood and social disorders was found within maternal expression data for multiple, independently curated disease-linked gene modules extracted from association databases and recent publications. MSET was validated as a versatile enrichment analysis tool using thirty gene sets representing six diseases, ranging from schizophrenia to arthritis, within five publicly available expression datasets from independent experiments including knockout mouse models and drug treatments. This work demonstrates for the first time a shared genetic basis between the maternal brain and mental health, highlighting the translational value of the maternal mouse as a natural model for adult neuroplasticity and the genetics of neurodevelopment disorders. Additionally, MSET provides a powerful tool with extensive potential applications to the biomedical community by facilitating the simple integration of public genetic resources in the performance of robust enrichment testing and gene identification with any conceivable gene set of interest. |
