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Social interactions among animals mediate essential behaviours, including mating, nurturing, and defence1,2. The gut microbiota contribute to social activity in mice3,4, but the gut-brain connections that regulate this complex behaviour and its underlying neural basis are unclear5,6. Here we show that the microbiome modulates neuronal activity in specific brain regions of male mice to regulate canonical stress responses and social behaviours. Social deviation in germ-free and antibiotic-treated mice is associated with elevated levels of the stress hormone corticosterone, which is primarily produced by activation of the hypothalamus-pituitary-adrenal (HPA) axis. Adrenalectomy, antagonism ofglucocorticoid receptors, or pharmacological inhibition of corticosterone synthesis effectively corrects social deficits following microbiome depletion. Genetic ablation of glucocorticoid receptors in specific brain regions or chemogenetic inactivation of neurons in the paraventricular nucleus of the hypothalamus that produce corticotrophin-releasing hormone (CRH) reverse social impairments in antibiotic-treated mice. Conversely, specific activation of CRH-expressing neurons in the paraventricular nucleus induces social deficits in mice with a normal microbiome. Via microbiome profiling and in vivo selection, we identify a bacterial species, Enterococcus faecalis, that promotes social activity and reduces corticosterone levels in mice following social stress. These studies suggest that specific gut bacteria can restrain the activation of the HPA axis, and show that the microbiome can affect social behaviours through discrete neuronal circuits that mediate stress responses in the brain.
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Bidirectional communication between the gut and the brain affects health and disease5,7. Various environmental and/or peripheral factors influence gut-brain interactions, including the intestinal microbiota. Changes in stress responses, anxiety, locomotion, and social behaviour have shown that the microbiota contribute to brain development and function and to behaviour4,6,8-13. Specific gut bacterial species contribute to each of these behavioural domains in mice3,14. The influence of host-microorganism interactions on complex behaviours may extend beyond preclinical studies, as the human microbiome is altered in several neuropsychiatric disorders that are associated with changes in sociability5.
Sensory processing, internal states, and decision-making are crucial for the control of social behaviour2. An animal perceives visual, olfactory, pheromonal, auditory, and/or tactile cues from another animal, which may modulate the internal state of the first animal towards a decision that will guide a specific response. In addition, past experiences, emotions, motivation, and physiological inputs shape the internal state and...