FUNCTIONAL MAPPING OF BRAIN PATHWAYS INVOLVED IN THE GUT MICROBIAL MODULATION OF SOCIAL BEHAVIOURS IN MICE

In our microbial world, we are surrounded by trillions of microbes facilitating food digestion and body homeostasis. Emerging data also suggests a critical influence of the gut microbiota on the brain, impacting behaviour and mental health. For example, microbiota-deficient mice have reduced social interactions. However, the neuronal mechanisms through which the gut microbiota may impact on brain and behaviour remain poorly understood. We hypothesise that vagal signalling through the caudal solitary nucleus (cNTS) and onto the paraventricular hypothalamus (PVN) constitutes a selective neuronal pathway mediating gut microbial influence on social behaviour. Thus our goal is to identify cell-type specific synaptic connections along this selective cNTS-PVN pathway and determine their functional contribution to sociability. To test this hypothesis, we combined antibiotic-mediated gut microbiota depletion with behavioural testing and brain area-specific neuronal activation, and in vivo combinatorial viral labelling followed by multi-channel immunohistochemistry in adult mice of both sexes.
First, we found that microbiota depletion altered the social interactions patterns in a sex dependent manner, accompanied by differential neuronal activation observed in cNTS and PVN. Second, we mapped the populations of PVN-projecting cNTS neurons along the rostro-caudal brainstem. Third, we identified molecularly distinct cNTS projections to PVN including from glutamatergic, GABAergic and catecholaminergic neurons. Notably, many cNTS presynaptic terminals innervated oxytocin-expressing PVN neurons which are key regulators of social behaviour. Together, these findings demonstrate that gut microbial status modulates social behaviour through molecularly diverse brainstem–hypothalamic circuits, highlighting a functional neural pathway linking the gut microbiota to social brain networks.