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Gut microbiota impact on brain development and plasticity.

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A deeper understanding of the gut-brain axis

The microbiota play a fundamental role in the development and maintenance of immune system function and the regulation of body weight. Emerging evidence suggests that the intestinal microbiota could be involved in the gut-brain axis communication route, modulating brain functions and behaviour.

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The intestinal microbiota, or more commonly microflora, is a complex ecosystem of microorganisms, principally bacteria, which populate the gut living in symbiosis with our body. To take a closer look at the connection between the brain and the microbiome, Paola Tognini, principal investigator of the GaMePLAY project looked into how gut microbiota modulates brain development and plasticity. Based at the Scuola Normale Superiore in Pisa, she used the established method of assessing the development of the visual cortex in mice. Neural or brain plasticity is the capability of our brain to modify its circuits in response to external stimuli and/or experience. Tognini focused on adult brain plasticity. The property of being ‘modifiable’ is particularly high in young brains and decreases with age. As Tognini explains: “Our brain contains some areas that show plasticity only in specific temporal windows of postnatal development. When this special time of youth is over, the circuits become stable and are not mutable anymore.” The GaMePLAY project, which received support from the Marie Skłodowska-Curie programme, asked if signals coming from the intestinal microbiota could favour the re-activation of plasticity in the brain of adult mice. “To achieve this objective, I exploited the visual system as a model, because the adult animals do not normally display plasticity. Importantly, I observed that specific changes in the composition of the gut microbes could actually promote plasticity in the visual area of the brain of adult mice. The brains of these animals behaved like the brain of a young mouse, changing in response to specific stimuli,” Tognini adds.

The role of enriched cages on the microbiota of mice

GaMePLAY found that the gut microbiota composition changed with the age of the animals and also with the type of environment the mouse was raised in. “Mice living in environments able to promote brain plasticity, (I would call it: ‘pro-plasticity’), contain different microbes compared to mice living in an environment that is not stimulative,” says Tognini. The same animals were analysed at different ages: before weaning, as weaned juveniles, and in adulthood. Interestingly, the biggest differences in the bacterial composition remained into adulthood. “I think this must be caused by the fact that the adult mice can fully and better experience the variety of stimuli presented to them in the cages,” Tognini explains. To assess plasticity in the brain the researcher recorded the responses of neurons in the visual cortex, which correspond to the occipital part of the brain. In particular, she studied ocular dominance plasticity. Ocular dominance refers to the property of visual cortical neurons that respond preferentially to the input coming from one eye over the other. In the juvenile mouse it is possible to induce a plastic phenomenon, which corresponds to the shift in the neuron’s preference for the visual input from one eye to the other one. This plastic phenomenon is not present in the adult, unless they are raised in particular environmental conditions. “In our study we found that raising the mice in a stimulating, ‘special environment’ promotes ocular dominance plasticity and that the intestinal bacteria contribute to this pro-plasticity effect,” Tognini explains. GaMePLAY managed to demonstrate the possibility of re-activating brain plasticity through the manipulation of gut microbes. The implication of this concept is extensive, and not limited to sensory systems and the visual cortex. “Indeed, I am now dissecting the specific bacteria and their derived molecules with the aim of identifying novel probiotics and prebiotics. At the moment I am transferring this information to preclinical disease models characterised by plasticity deficits. I’m focusing in particular on neurodevelopmental disorders to discover future therapies for their treatment,” Tognini concludes.

Keywords

GaMePLAY, brain plasticity, microbiome, intestinal microbiota, gut-brain axis, visual cortex

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