Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient mice

  • Stilling R
  • Moloney G
  • Ryan F
  • et al.
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Abstract

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, such as those found in autism spectrum disorders (ASDs).In our bodies, there are at least as many microbial cells as human cells. These microbes, known collectively as the microbiome, influence the activity of our brain and also our behaviour. Studies in species from insects to primates have shown that the microbiome affects social behaviour in particular. For example, germ-free mice, which grow up in a sterile environment and thus have no bacteria in or on their bodies, are less sociable than normal mice.For animals to show behaviours such as social interaction, cells in specific regions of the brain must change the activity of their genes. These brain regions include the amygdala, which is part of the brain’s emotion processing network, and also contributes to fear and anxiety responses. Stilling et al. set out to determine whether gene activity in the amygdala during social interaction differs between germ-free mice and those with a normal microbiome.Stilling et al. placed each mouse into a box with three chambers. One chamber contained an unfamiliar mouse while another contained an inanimate object. Germ-free mice were less sociable and spent less time than control animals interacting with the unfamiliar mouse. Before entering either test chamber, the germ-free animals showed signs of excessive activity in the amygdala. During social interaction, they displayed a strikingly different pattern of gene activity in this brain region compared to controls. In particular, they had increased levels of a process called alternative splicing. This process enables cells to produce many different proteins from a single gene.These results reveal one of the steps leading from absence of bacteria during brain development to reduced sociability in adulthood in mice. Increases in gene activity in the amygdala may provide clues to the processes underlying reduced sociability in people with autism spectrum disorders. This new study thus deepens our understanding of the link between the microbiome and brain health.

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Stilling, R. M., Moloney, G. M., Ryan, F. J., Hoban, A. E., Bastiaanssen, T. F., Shanahan, F., … Cryan, J. F. (2018). Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient mice. ELife, 7. https://doi.org/10.7554/elife.33070

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