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Gut microbiota impact on brain development and plasticity.

Periodic Reporting for period 1 - GaMePLAY (Gut microbiota impact on brain development and plasticity.)

Reporting period: 2017-09-01 to 2019-08-31

The gut microbiota has emerged as a novel regulator of system-wide physiology. Intriguingly, the microbiome play an important role in brain related processes: myelination, microglia maturation, neurogenesis, blood-brain-barrier permeability, influencing behavioral outcomes. Despite this evidence, little is known about how intestinal bacteria impinge on neuronal function and especially, nobody has ever explored if there is a link between sensory system development/plasticity and gut microbiota. The new key concept emerging from my project is that changes in the microbiota composition could modulate neural circuit function in sensory systems resulting in altered brain plasticity.
To address this issue, GaMePLAY focused on the visual system. Manipulation of visual inputs results in distinctive behavioral consequences in young and adult subjects. The effect of sensory inputs’ deprivation, obtained via monocular deprivation (MD, the suture of an eye), is highly evident only during the critical period for ocular dominance (OD) plasticity, a postnatal time-window in which neuronal circuits are particularly sensitive to experience. 3 days of MD in juvenile mice are sufficient to cause a plastic phenomenon called OD shift. Visual cortical plasticity and, in general, brain plasticity displays a significant decrease in adulthood.
The paradigm exploited to investigate how changes in gut microbiota composition could affect brain plasticity was the so-called enriched environment (EE). EE consists in a specific animal housing condition characterized by elevated social interactions, cognitive, sensory and motor stimulations. EE has been demonstrated to affect brain plasticity and behaviour, acting during youth, adulthood and aging, and to enhance OD plasticity. Finally, EE has positive effects on a variety of neurological disorder preclinical models (e.g. Alzheimer, Parkinson disease, stroke).

It is becoming clear that the gut microbiota influence brain function and finally behaviour. The data collected by GaMePLAY are helping to understand the microbiota role on brain plasticity. My results show how the faecal transplant of a “pro-plasticity microbiota” enhances brain plasticity in adult rodents, which generally do not display this property. Moreover, the identification of specific bacteria strains might help to discover new probiotics. This is particularly relevant for therapy, with a consequent tremendous impact on society. Indeed, probiotic treatments can be easily applied in humans, opening exciting opportunities for treating neuropsychiatric diseases with microbiota based-therapies.

Objectives:
1)To characterize the gut microbiota at different ages in mice housed in standard (ST) condition or in an EE and to analyse the differences between the two rearing conditions;
2)To investigate the contribution of the gut microbiota to the effects of EE on brain plasticity, studying the visual system;
3)To dissect the mechanisms through which the intestinal microflora affects cortical plasticity.
Objective 1) GaMePLAY aimed at investigating the role of the gut microbiota as a contributor to the effect of EE on brain plasticity. To achieve this primary goal, the composition of the fecal microbiota of WT mice living in ST cages or in an EE was analyzed at different ages: pre-weaning, after weaning and during adulthood. As expected there was an effect of ageing on the bacterial composition both in ST and EE mice. Notably, a strong difference was present in the microbiota of adult EE mice with respect to ST.
Objective 2) EE promotes plasticity in the adult visual cortex, and several mechanisms have been described to explain this effect. However, signals coming from the periphery were never investigated before. To explore the intestinal microflora could be a mediator of EE impact on visual cortical plasticity, the microbiota of EE mice was depleted using an antibiotic cocktail. OD plasticity was evaluated after 3 days of MD. Interestingly, the depletion of the microbiota in EE mice completely prevented the enhancement of visual cortical plasticity observed in adult EE mice with an intact microflora. To further study the involvement of the microbiome in EE-driven plasticity, I performed a fecal transplant experiment. In particular, I transplanted the microflora of EE donors in adult recipient ST mice, which do not show OD plasticity. Strikingly, transferring the microbiota from EE donors to ST recipient enhanced visual cortical plasticity in the recipient animals, suggesting that EE-dependent promotion of brain plasticity could be mediated by signals coming from the gut commensals.
Objective 3) To explore the molecular mechanisms, I performed gene expression analysis in the visual cortex. I found an important modulation of inhibitory-circuit related genes in ST mice transplanted with EE feces, suggesting that remodeling of GABAergic circuits might be implicated in the observed plastic responses.

GaMePLAY highlights the possibility to enhance brain plasticity through the manipulation of gut microbes. The implication of this concept is profoundly wide, and not limited to the visual cortex. I am now dissecting the specific bacteria and derived molecules, aiming at identifying novel probiotics and prebiotics. I will transfer this information to preclinical disease models characterized by plasticity deficits, to discover future therapies for the treatment of neuropsychiatric disorders.
GaMePLAY demonstrated that the gut microbes could modulate plasticity in a sensory system (i.e. the visual system). EE has been used to study how the interaction between gene and environment influences brain structure and function. However, so far nobody has investigated if signals coming from the periphery mediate the impact of EE on the brain. GaMePLAY has discovered that the gut microbiota play a key role in the interaction environment-plasticity, as a mediator of the effect of EE on visual cortical plasticity. I am now working on the identification of the “enriched” bacterial species and signaling molecules responsible for the pro-plastic influence on neural circuits.

From a basic research standpoint, for the first time I demonstrated how EE could impact on microbiota composition, and how these alterations could be important for promoting cortical plasticity. The EE blend of components is extremely complicated. Indeed, the “enrichment derived key feature” through which this “special” environment performs its broad positive effects on brain and body health has not been identified yet. Although, it is extremely difficult and debated how to reproduce the “relevant mechanism” able to replicate such an extensive influence on brain physiology and plasticity, GaMePLAY results are definitely taking a step forward to reach this objective. This is fundamental from a translational point of view. Humans already live in an over-stimulating environment, thus it is hard to recreate the EE effects in real life. The identification of pro-plastic bacteria species and their metabolites will pave the way to the rational use of probiotics/prebiotics for the treatment of neuropsychiatric disorders, hopefully decreasing health-care and typical medicaments economic burden. Finally, since pre- and probiotics are popularly used and easily available, they could become supplements to ameliorate cognitive performance, with paramount implications not only for the clinic but also for the whole society.
Summary of GaMePLAY results