CNS genomic profiling in the mouse chronic social stress model implicates a novel category of candidate genes...

Despite high prevalence, medical impact and societal burden, anxiety, depression and other affective disorders remain poorly understood and treated. Clinical complexity and polygenic nature complicate their analyses, often revealing genetic overlap and cross-disorder heritability. However, the interplay or overlaps between disordered phenotypes can also be based on shared molecular pathways and 'crosstalk' mechanisms, which themselves may be genetically determined. We have earlier predicted (Kalueff et al., 2014) a new class of 'interlinking' brain genes that do not affect the disordered phenotypes per se, but can instead specifically determine their interrelatedness. To test this hypothesis experimentally, here we applied a well-established rodent chronic social defeat stress model, known to progress in C57BL/6J mice from the Anxiety-like stage on Day 10 to Depression-like stage on Day 20. The present study analyzed mouse whole-genome expression in the prefrontal cortex and hippocampus during the Day 10, the Transitional (Day 15) and Day 20 stages in this model. Our main question here was whether a putative the Transitional stage (Day 15) would reveal distinct characteristic genomic responses from Days 10 and 20 of the model, thus reflecting unique molecular events underlining the transformation or switch from anxiety to depression pathogenesis. Overall, while in the Day 10 (Anxiety) group both brain regions showed major genomic alterations in various neurotransmitter signaling pathways, the Day 15 (Transitional) group revealed uniquely downregulated astrocyte-related genes, and the Day 20 (Depression) group demonstrated multiple downregulated genes of cell adhesion, inflammation and ion transport pathways. Together, these results reveal a complex temporal dynamics of mouse affective phenotypes as they develop. Our genomic profiling findings provide first experimental support to the idea that novel brain genes (activated here only during the Transitional stage) may uniquely integrate anxiety and depression pathogenesis and, hence, determine the progression from one pathological state to another. This concept can potentially be extended to other brain conditions as well. This preclinical study also further implicates cilial and astrocytal mechanisms in the pathogenesis of affective disorders.