The DOI matches its Crossref record; 105 of the 106 references it cites were found in a registry or an index.
Microbes & neurodevelopment – Absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala
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.
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In the citing paper
“GF mice display heightened expression of transcription factors related to neuronal activation (e.g., fos) in the amygdala relative to conventional controls (Stilling et al., 2015).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Stilling et al., 2015
In the citing paper
“GF animals have altered expression of genes implicated in neurophysiology in the amygdala (Stilling et al., 2015) and hippocampus (Chen et al., 2017a) (see Table 2).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Stilling et al., 2015
In the citing paper
“These findings suggest that gut microbes not only regulate gene expression in the mouse brain (Hoban et al., 2016; Neufeld et al., 2011; Stilling et al., 2015), but also affect alternative splicing (Stilling et al., 2018), and can regulate the production of specific isoforms of genes that have been implicated in ASD.”
From Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice (2019) · cites this paper as Stilling et al., 2015
In the citing paper
“Indeed, the gut microbiota is reported to modulate structural and functional changes in the amygdala, a critical brain area for social and fear-related behaviors, which are associated with a variety of neuropsychiatric disorders [165].”
From Autism, Gastrointestinal Symptoms and Modulation of Gut Microbiota by Nutritional Interventions (2019) · cites this paper as [165]
Citations
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Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286
Kelly, J. R., Borre, Y., O' Brien, C., Patterson, E., El Aidy, S., Deane, J., Kennedy, P. J., Beers, S., Scott, K., Moloney, G., et al. (2016) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.07.019 · Cited by 1,683
The central nervous system and the gut microbiome
Sharon, G., Sampson, T. R., Geschwind, D. H., & Mazmanian, S. K. (2016) · Cell · doi:10.1016/j.cell.2016.10.027 · Cited by 1,513
The gut microbiome in neurological disorders
Cryan, J. F., O'Riordan, K. J., Sandhu, K., Peterson, V., & Dinan, T. G. (2020) · The Lancet Neurology · doi:10.1016/s1474-4422(19)30356-4 · Cited by 1,336
Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice
Sharon, G., Cruz, N. J., Kang, D.-W., Gandal, M. J., Wang, B., Kim, Y.-M., Zink, E. M., Casey, C. P., Taylor, B. C., Lane, C. J., et al. (2019) · Cell · doi:10.1016/j.cell.2019.05.004 · Cited by 1,182
Metadata
- Authors
- Stilling, R. M., Ryan, F. J., Hoban, A. E., Shanahan, F., Clarke, G., Claesson, M. J., Dinan, T. G., & Cryan, J. F.
- Affiliations
- University College Cork (IE)
- Corresponding author
- Stilling, Roman M.
- Cryan, John F.
- ORCID
- Venue
- Brain Behavior and Immunity
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 50
- Pages
- 209-220
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W889536224
- Cited by
- 233
- References
- 106
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 20 · 2023: 15 · 2022: 17 · 2021: 27 · 2020: 30 · 2019: 27 · 2018: 26 · 2017: 19 · 2016: 26 · 2015: 3
- FWCI
- 10.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Science Foundation Ireland (07/CE/B1368, 12/RC/2273, 11/SIRG/B2162)
- Irish Research Council (GOIPD/2014/355)
- Dept. of Agriculture, Food & Fisheries and Forestry and Enterprise Ireland
- Brain and Behavior Research Foundation (20771)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- gut microbiota, germ-free mice, amygdala, brain development, host-microbe interactions, anxiety-like behavior, social behavior, immediate early genes, gene expression, exon usage, RNA editing, neuronal activity, neurodevelopmental disorders
- MeSH terms
- Amygdala, Animals, Interpersonal Relations, Male, Neurons, Signal Transduction, Genes, Immediate-Early, Gene Expression Profiling, Mice, Microbiota
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