Social Interaction-induced Activation of RNA Splicing in the Amygdala of Microbiome-Deficient Mice

Social behaviour is regulated by activity of host-associated microbiota across multiple species. However, the molecular mechanisms mediating this relationship remain elusive. We therefore determined the dynamic, stimulus-dependent transcriptional regulation of germ-free (GF) and GF mice colonised post weaning (exGF) in the amygdala, a brain region critically involved in regulating social interaction. In GF mice the dynamic response seen in controls was attenuated and replaced by a marked increase in expression of splicing factors and alternative exon usage in GF mice upon stimulation, which was even more pronounced in exGF mice. In conclusion, we demonstrate a molecular basis for how the host microbiome is crucial for a normal behavioural response during social interaction. Our data further suggest that social behaviour is correlated with the gene-expression response in the amygdala, established during neurodevelopment as a result of host-microbe interactions. Our findings may help toward understanding neurodevelopmental events leading to social behaviour dysregulation. Equal amounts of RNA from two to three animals were pooled to yield 4 samples per group for naive animals (CON, GF, and exGF). Sample for social-interaction samples were sequenced infividually (n=8-12). Comparisons for all relevant pairwise combinations were performed using DESeq2 and DEXSeq.