Investigations into the role of microbiota-gut-brain axis on behaviour and physiology in the mouse

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O'Connor, Rory
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University College Cork
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The growing recognition of the influence of the intestinal microbiota over the brain and behaviour has led to a shift in the world of neuroscience. Recent developments in the understanding of the microbiota-gut-brain axis have highlighted the importance of this bidirectional system of communication as well as its potential as a therapeutic target in psychiatric and neurological disorders. There is therefore growing interest in understanding the mechanisms that underpin the behavioural changes that have been observed and an increased knowledge of these mechanisms will be pivotal in the development of future therapeutic compounds that target the microbiota-gut brain axis. In this thesis we explore the effects of modulation of the gut microbiota in early life through two distinct mechanisms. Firstly we assess the impact of maternal antibiotic administration on behaviour and physiology throughout the lifespan, comparing the effects of a single antibiotic and a cocktail of antibiotics. We observed effects on behaviour both in early life as well as in adulthood including tests of sociability, cognition, and anxiety-like behaviour. As regards to an underlying mechanism, alterations in hippocampal expression of BDNF were also observed following this treatment. Next, we explored behavioural and microbiota alterations following Caesarean section delivery in a mouse model. Behavioural changes were found in anxiety-like behaviour, learning and memory, and antidepressant-sensitive behaviour. We also assessed impact of additional microbiota disruption in these animals through the administration of maternal antibiotics, finding that the further disruption led to exacerbation of behavioural effects as well as additional alterations in microbiota composition. Finally, we assessed whether administration of psychobiotics could reverse these behavioural disruptions, finding that antidepressant-sensitive behaviours were a particularly sensitive to these compounds. In addition to assessing behavioural alterations after early-life modulation of the gut microbiota, we also studied behavioural differences in an aged model of autism spectrum disorder, the BTBR mouse, which is known to have an altered gut microbiota composition. Here we found that many of the behavioural alterations observed in these animals in youth are maintained in ageing, and that these sustained alterations may be linked to an increased immune system activation. Finally, we sought to determine whether exposure of hippocampal slices to various concentrations of the gut microbiota metabolites short-chain fatty acids, can lead to alterations in synaptic signalling, using a multi-electrode array apparatus. It was observed that perfusion with a high concentration of sodium acetate (700µM) lead to a disruption in long-term potentiation (LTP) that is not seen in lower concentrations of the compound. This presents a potential link between gut microbiota metabolites and synaptic function in the brain that may shine a light on a key mechanism underpinning microbiota-gut-brain axis communication. Overall these results highlight the importance of gut microbiota composition throughout the lifespan and particularly during key developmental windows such as early life. Our results also suggest that targeting the microbiota with psychobiotic compounds may be a viable therapeutic tool in cases where disruption of microbiota composition has occurred. Finally, we suggest that alterations in synaptic plasticity may be a key mechanism leading to the observed alterations in behaviour, providing an excellent target for future investigations into the microbiota-gut-brain axis.
Microbiota , Electrophysiology , Microbiota, gut, brain axis , Behavioural neuroscience
O'Connor, R. 2019. Investigations into the role of microbiota-gut-brain axis on behaviour and physiology in the mouse. PhD Thesis, University College Cork.
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