Shared and unique transcriptomic signatures of antidepressant and probiotics action in the mammalian brain
To comprehensively characterize the intrinsic molecular effects of ADs independently of the specifics of particular disease models, we generated 300 transcriptomic profiles from 10 brain regions in naive rats. Three classical tricyclic antidepressants, Bupropion, desipramine, fluoxetine, and a probiotic formulation (Lacidofil®) can massively alter gene expression in most regions [>1,500 differentially expressed genes (DEGs)], suggesting that traditional single-gene or single-pathway analyses may under-represent the complexity of molecular responses. Using spatial transcriptomics in the prefrontal cortex from an independent set of animals, we further delineated DEGs and molecular pathways that exhibited layer-specific differential regulation by probiotics and fluoxetine. Overall design: To complement our multi-regional epigenome and transcriptome map of chronic fluoxetine action (Rayan et al. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01725-1), we used bulk RNA-seq to profile the Bupropion-, Desipramine-, Fluoxetine-, Maltodextrin- and Probiotic-  induced genome-wide transcriptome changes (post 3 week treatment) in 10 brain regions. Here we deposit these RNA-seq profiles (10 regions, 6 treatment groups, 5 replicates; 10*6*5= 300 profiles, GSE222756). To reduce the effects of inter-animal biological variation, each RNA-seq sample was pooled from 2 animals (60 animals in total). We complemented the bulk RNA-seq with 10x Visium spatial omics assay, focusing on the ILC and PLC. Although these two adjacent brain regions are often studied as a whole, they showed distinct treatment responses in our analyses. We treated an independent cohort of rats with FT (n=4) vs Sham (n=4), Pro (n=4) vs Mal (n=2). We then extracted cortical slices and generated 10x Genomics Visium spatial transcriptomics profiles comprising ~33,000 spatially localized spots, with a median of 2,100 detected genes per spot.