title: Regulation of prefrontal cortex myelination by the microbiota.
abstract: The prefrontal cortex (PFC) is a key region implicated in a range of neuropsychiatric disorders such as depression, schizophrenia and autism. In parallel, the role of the gut microbiota in contributing to these disorders is emerging. Germ-free (GF) animals, microbiota-deficient throughout life, have been instrumental in elucidating the role of the microbiota in many aspects of physiology, especially the role of the microbiota in anxiety-related behaviours, impaired social cognition and stress responsivity. Here we aim to further elucidate the mechanisms of the microbial influence by investigating changes in the homeostatic regulation of neuronal transcription of GF mice within the PFC using a genome-wide transcriptome profiling approach. Our results reveal a marked, concerted upregulation of genes linked to myelination and myelin plasticity. This coincided with upregulation of neural activity-induced pathways, potentially driving myelin plasticity. Subsequent investigation at the ultrastructural level demonstrated the presence of hypermyelinated axons within the PFC of GF mice. Notably, these changes in myelin and activity-related gene expression could be reversed by colonization with a conventional microbiota following weaning. In summary, we believe we demonstrate for the first time that the microbiome is necessary for appropriate and dynamic regulation of myelin-related genes with clear implications for cortical myelination at an ultrastructural level. The microbiota is therefore a potential therapeutic target for psychiatric disorders involving dynamic myelination in the PFC.
authors.affiliation: APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
authors.forename: A E
authors.initials: AE
authors.lastname: Hoban
authors.affiliation: APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
authors.forename: R M
authors.initials: RM
authors.lastname: Stilling
authors.affiliation: APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Microbiology, University College Cork, Cork, Ireland.
authors.forename: F J
authors.initials: FJ
authors.lastname: Ryan
authors.affiliation: APC Microbiome Institute, University College Cork, Cork, Ireland.
authors.forename: F
authors.initials: F
authors.lastname: Shanahan
authors.affiliation: APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.
authors.forename: T G
authors.initials: TG
authors.lastname: Dinan
authors.affiliation: APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Microbiology, University College Cork, Cork, Ireland.
authors.forename: M J
authors.initials: MJ
authors.lastname: Claesson
authors.affiliation: APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.
authors.forename: G
authors.initials: G
authors.lastname: Clarke
authors.affiliation: APC Microbiome Institute, University College Cork, Cork, Ireland.|Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
authors.forename: J F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D020869:Gene Expression Profiling / Q000379:methods; D051379:Mice; D064307:Microbiota / Q000235:genetics / Q000502:physiology*; D046529:Microscopy, Electron, Transmission; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000382:microbiology; D060888:Real-Time Polymerase Chain Reaction; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology; D059467:Transcriptome / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology