Schizophrenia is a functionally disabling neurodevelopmental disorder involving host genetics and environmental risk factors and it has high prevalence in Ireland. Due to the lack of efficacious long-term treatments, there is an unmet clinical need for new therapeutic interventions. Improving treatments requires the identification of novel targetable biological indicators of cognitive impairments as core symptoms of schizophrenia. Evidence is mounting for alterations in the gut microbiome as additional environmental factors associated with schizophrenia. Gut microbes through interactions with the vagus nerve provide sensory signals to the brainstem but the mechanisms of how memory-related brain regions such as hippocampus and prefrontal cortex are affected remain to be defined. How can we unravel whether different cognitive impairments in schizophrenia could result from vagus nerve-mediated reciprocal microbiota-host interactions? Genetically altered mouse models of schizophrenia are excellent tools allowing mechanistic studies not feasible in humans. Based on novel preliminary results, I hypothesize that gut microbiota-vagal projections can modulate hippocampus and prefrontal cortex via at least three specialised central nervous system pathways arising from the brainstem. I propose ground-breaking interdisciplinary investigations by combining state-of-the-art viral optogenetic tracing, microbiome-vagal manipulations, in vivo electrophysiology, behavioural testing and high-resolution neuroanatomy in a human chromosome 22 (22q11.2) deletion genetic mouse model recapitulating schizophrenia pathophysiology including working memory impairment and altered hippocampal and prefrontal-cortical neuronal dynamics. First, I will determine the contributions of host genetic variation and the microbiome to hippocampal-cortical-dependent contextual, social and spatial working memory, sex-dependently. Second, I will establish an integrative functional definition of the distinct brain pathways likely mediating these effects. Third, I will exploit these newly defined pathways for potential therapeutic interventions targeting memory improvement, sex-dependently. My strategy could pave the way for refined, intelligent vagal nerve stimulation and/or novel gut microbiome-based brain therapeutics for people living with schizophrenia, addressing a global public health priority.
