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

Roman M Stilling,Thomaz Fs Bastiaanssen,Marcus J Claesson,Gerard M Moloney,John F Cryan,Gerard Clarke,Fergus Shanahan,Feargal J Ryan,Alan E Hoban,Timothy G Dinan

doi:10.7554/elife.33070

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).

Highlights

The tight association that animals have with the trillions of microbes that colonise them is the result of a long evolutionary history
We subjected conventional mice (CON-SI), germ-free mice (GF-SI), and germ-free mice colonized after weaning to a social stimulus (the three-chamber social interaction test (3CSIT), based on Nadler et al, 2004) and measured the time during which the test mice interacted with a conventional conspecific male mouse or a non-social object (Figure 1A, experimental design and workflow)
As previously reported (Desbonnet et al, 2014; Buffington et al, 2016), on average the group of GF-SI mice showed significantly decreased interaction with a conspecific compared with controls and colonized animals, while interaction with the non-social object was similar among the three groups (Figure 1B–C)

Summary

Introduction

The tight association that animals have with the trillions of microbes that colonise them is the result of a long evolutionary history. We only very recently started to understand the intimate relationship between microbes and host physiology, including brain function, it is well accepted that host neurodevelopment, brain function and behaviour are regulated by presence and activity of the host-associated microbiota (Collins et al, 2012; Cryan and Dinan, 2012; Foster et al, 2017; Lyte, 2013; Mayer et al, 2014a; Sampson and Mazmanian, 2015; Sharon et al, 2016). A growing body of data in healthy volunteers and patient populations is emerging, indicating microbial influences translate to human emotional behaviours (Tillisch et al, 2013) and have been suggested to play a role in neurodevelopmental disorders such as autism spectrum disorders (ASDs)

Methods

Results

Conclusion