Microbial metabolites regulate social novelty via CaMKII neurons in the BNST

Social novelty is a cognitive process that is essential for animals to interact strategically with conspecifics based on their prior experiences. The commensal microbiome in the gut modulates social behavior through various routes, including microbe-derived metabolite signaling. Short-chain fatty acids (SCFAs), metabolites derived from bacterial fermentation in the gastrointestinal tract, have been previously shown to impact host behavior. Herein, we demonstrate that the delivery of SCFAs directly into the brain disrupts social novelty through distinct neuronal populations. We are the first to observe that infusion of SCFAs into the lateral ventricle disrupted social novelty in microbiome-depleted mice without affecting brain inflammatory responses. The deficit in social novelty can be recapitulated by activating calcium/calmodulin-dependent protein kinase II (CaMKII)-labeled neurons in the bed nucleus of the stria terminalis (BNST). Conversely, chemogenetic silencing of the CaMKIIlabeled neurons and pharmacological inhibition of fatty acid oxidation in the BNST reversed the SCFAsinduced deficit in social novelty. Our findings suggest that microbial metabolites impact social novelty through a distinct neuron population in the BNST.

Automated summary

Social novelty, a cognitive process crucial for strategic interaction among animals based on prior experiences, is modulated by the commensal microbiome in the gut through various routes, including microbe-derived metabolite signaling. Short-chain fatty acids (SCFAs), metabolites produced by bacterial fermentation in the gastrointestinal tract, have been found to affect host behavior. This study demonstrates that the direct delivery of SCFAs into the brain disrupts social novelty through specific neuronal populations, specifically the CaMKII-labeled neurons in the BNST.