Microbes & neurodevelopment - Absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala

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

Research output: Contribution to journalArticlepeer-review

158 Citations (Scopus)

Abstract

The mammalian amygdala is a key emotional brain region for eliciting social behaviour, critically involved in anxiety and fear-related behaviours, and hence a focus of research on neurodevelopmental and stress-related disorders such as autism and anxiety. Recently, increasing evidence implicates host-microbe interactions in the aetiology of these conditions. Germ-free (GF) mice, devoid of any microbiota throughout organismal maturation, are a well-established tool to study the effects of absence of the microbiota on host physiology. A growing body of independently replicated findings confirm that GF animals demonstrate altered anxiety-related behaviour and impaired social behaviour. However, the underlying mechanisms of this interaction and the nature of the pathways involved are only insufficiently understood. To further elucidate the molecular underpinnings of microbe-brain interaction, we therefore exploited unbiased genome-wide transcriptional profiling to determine gene expression in the amygdala of GF and GF mice that have been colonised after weaning. Using RNA-sequencing and a comprehensive downstream analysis pipeline we studied the amygdala transcriptome and found significant differences at the levels of differential gene expression, exon usage and RNA-editing. Most surprisingly, we noticed upregulation of several immediate early response genes such as Fos, Fosb, Egr2 or Nr4a1 in association with increased CREB signalling in GF mice. In addition, we found differential expression and recoding of several genes implicated in brain physiology processes such as neurotransmission, neuronal plasticity, metabolism and morphology.In conclusion, our data suggest altered baseline neuronal activity in the amygdala of germ-free animals, which is established during early life and may have implications for understanding development and treatment of neurodevelopmental disorders.

Original languageEnglish
Pages (from-to)209-220
Number of pages12
JournalBrain, Behavior, and Immunity
Volume50
DOIs
Publication statusPublished - Nov 2015
Externally publishedYes

Bibliographical note

Funding Information:
The authors wish to thank Dr. Lieve Desbonnet, Dr. Gerard M. Moloney, Mr. Patrick Fitzgerald, Ms. Frances O’Brien and Ms. Katie Simpson for technical assistance with animal husbandry, tissue extraction, RNA extraction and qRT-PCR. The Alimentary Pharmabiotic Centre is a research centre funded by Science Foundation Ireland (SFI), through the Irish Government’s National Development Plan (Grant Number 07/CE/B1368 and 12/RC/2273 ). R.M.S. is supported by the Irish Research Council (IRC) through a Government of Ireland Postdoctoral Fellowship (Grant Number GOIPD/2014/355 ). M.J.C. and F.J.R. are also supported by Science Foundation Ireland (Grant Number 11/SIRG/B2162 ). T.G.D. and J.F.C. are also supported by the Irish Health Research Board, the Dept. of Agriculture, Food & Fisheries and Forestry and Enterprise Ireland . GC is supported by a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation (Grant Number 20771 ).

Funding Information:
R.M.S, F.R., and A.E.H. report no biomedical financial interests or potential conflicts of interest. F.S., T.G.D., and J.F.C. are principal investigators in the Alimentary Pharmabiotic Centre, University College Cork. G.C. and M.C. are faculty member or funded investigator, respectively, of the Alimentary Pharmabiotic Centre. The Alimentary Pharmabiotic Centre has conducted research funded by Pfizer, GlaxoSmithKline, Proctor & Gamble, Mead Johnson, Suntory Wellness, and Cremo. T.G.D. has been an invited speaker at meetings organised by Servier, Lundbeck, Janssen, and AstraZeneca. J.F.C. has been an invited speaker at meetings organised by Mead Johnson, Yakult, Alkermes, and Janssen.

Publisher Copyright:
© 2015 Elsevier Inc..

Keywords

  • Activity-induced
  • Differential gene expression
  • Gene regulation
  • Gut-brain axis
  • Hyper-excitability
  • Immediate early gene
  • MAP-kinase pathway
  • Microbiome
  • RNA editing
  • RNA-seq

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