MICROBIAL METABOLITES REGULATE SOCIAL NOVELTY VIA CAMKII NEURONS IN THE BNST

Abstract Background 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. Aims & Objectives Short-chain fatty acids (SCFAs), metabolites derived from bacterial fermentation in the gastrointestinal tract, have been previously shown to impact host behavior. Method We interrogate the functional role of SCFAs in the brain and social behavior via intracerebroventricular infusion of SCFAs in freely moving mice. Electrophysiology, chemogenetic manipulation, and Cre- dependent cell ablation were employed to unravel the neural circuit by which SCFAs alter social behavior. Results Herein, we demonstrate that the delivery of SCFAs directly into the brain disrupts social novelty through distinct neuronal populations. We observed 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 CaMKII-labeled neurons and pharmacological inhibition of fatty acid oxidation in the BNST reversed the SCFAs-induced deficit in social novelty. Discussion & Conclusion Our findings suggest that microbial metabolites impact social novelty through a distinct neuron population in the BNST. References Liou CW, Cheng SJ, Yao TH, Lai TT, Tsai YH, Chien CW, Kuo YL, Chou SH, Hsu CC, Wu WL. Microbial metabolites regulate social novelty via CaMKII neurons in the BNST. Brain Behav Immun. 2023 Oct;113:104-123. doi: 10.1016/j.bbi.2023.06.029. Epub 2023 Jun 29. PMID: 37393058.