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

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).

Decoding the role of the microbiome on amygdala function and social behaviour

“…Moreover, social stimulus evoked an increase in transcripts of genes involved in neuronal activity, which includes induction of several well established immediate early genes such as Fos or Arc, the MAP-K pathway and neurotrophic signalling via Bdnf. Moreover, we find upregulation of complement components, which have lately been established to be necessary for synaptic rearrangements and plasticity upon neuronal activity [6].…”

“…Transcriptomic analysis demonstrated an upregulation of several immediate early response genes such as Fos, Fosb, Egr2 or Nr4a1 in association with increased CREB signalling in GF mice (see [5] for full details). Moreover, when a germ-free mouse is introduced to a social stimulus the normal transcriptional pathway recruitment is absent but instead genes involved in alternative splicing are enriched (see [6] for full details of genes affected)…”

“…However, GF mice displayed a strikingly different pattern of amygdala gene activity in response to social interaction [6] (Fig. 1).…”

Annual Research Review: Critical windows – the microbiota–gut–brain axis in neurocognitive development

“…Perhaps the strongest evidence for microbial modulation of cognition and behavior in animal models comes from studies of social interactions (Sherwin et al, 2019). Germ-free rodents typically exhibit deficits in both sociability and memory for social stimuli (indexed by preference for a novel social partner; Buffington et al, 2016;Desbonnet et al, 2014;Sgritta et al, 2019;Stilling et al, 2018; but see also Arentsen et al, 2015). Similar effects are observed following antibiotic depletion of the microbiota during development (Degroote et al, 2016;Desbonnet et al, 2015), while administration of certain probiotic species can enhance social behavior in various murine models of autism (Buffington et al, 2016;Hsiao et al, 2013;Sgritta et al, 2019) and inflammation-induced social withdrawal (D'Mello et al, 2015).…”

Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice

“…Early studies showed that germ-free mice (i.e. mice that are raised completely sterile with no internal or external microbiome) have marked deficits in social behaviors and in gene expression profiles in multiple brain regions related to regulation of these behaviors [12][13][14] . Additionally, mice who have had their microbiomes depleted with antibiotics show deficits in social behavior, cognitive flexibility, and multiple other ASD-like behaviors 6,15,16 .…”