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.

Microbes, Immunity, and Behavior: Psychoneuroimmunology Meets the Microbiome

“…An increasing body of evidence suggests a link between microglia and the microbiota-gut-brain axis which has implications for many stress-related and neurodegenerative disorders There is a close link between HPA axis activation and the regulation of the peripheral and central immune responses, leading to monocyte priming and trafficking, subsequent alterations in microglia phenotype and, ultimately resulting in neuroinflammation. Indeed such neuroinflammatory responses are implicated in a number of psychiatric disorders, including anxiety and depression (Hodes et al, 2015;Miller and Raison, 2015). Microglia activation and subsequent release of cytokines plays a causal role in the manifestation of behavioral phenotypes in a variety of rodent stress models (Kreisel et al, 2014).…”

Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling

“…It receives sensory inputs from the thalamus and cortical areas as well as extensive inputs from other regions in the limbic system, including the prefrontal cortex and hippocampus, [15] both of which are markedly altered in germ-free (GF) animals. [10,12,16] In fact, the connectivity between these three major regions, not just the function of the individual structures, is fundamental to appropriate emotional responses. [17] Although tracer studies have shown afferents reaching all amygdala nuclei, sensory inputs often reach the amygdala through the LA while inputs from other brain regions target primarily the LA and BLA.…”

“…[7] Thus far, the use of microbial manipulations to test for brain region-specific effects has largely focused on the hippocampus and the prefrontal cortex. [8][9][10][11][12] However, we are now beginning to understand that the same microbial manipulations may also have implications for the amygdala.…”

Probiotics drive gut microbiome triggering emotional brain signatures

“…1 , 2 The ‘gut-brain axis‘ had already been studied before this field of research gained new momentum a decade ago with the characterization of the gut microbiome. 3 Although the underlying molecular mechanisms remain elusive, the gut microbiota has been shown to modulate behavior and brain processes, including pain perception, 2 stress responsiveness, 4 prefrontal myelination, 5 and brain biochemistry. 1 Experimental manipulation of the gut microbial community composition was shown to be able to modify the host's neural function.…”

“…1 The gut microbiota was found to influence the process of myelination in frontal brain regions, suggesting a role of gut microbiota in higher-order cognitive functions, in addition to emotional processing. 5 …”