Commensal microbe-derived propionic acid mediates juvenile social isolation-induced social deficits and anxiety-like behaviors

• Juvenile social isolation produces multiple behavioral abnormalities and alters the gut microbiota. • Gut microbiota mediated juvenile social isolation-induced neuropsychiatric behavioral abnormalities. • Juvenile social isolation causes reduction the expression of OXTR in the mPFC. • Juvenile social isolation increases PA that correlated with the expression of OXTR. • Antagonism of OXTR or administration of PA mimics effects of juvenile social isolation on multiple behavioral abnormalities. Social experiences during early life are thought to be critical for proper social and emotional development. Conversely, social insults during development causes long-lasting behavioral abnormalities later in life. However, how juvenile social deprivation influences social and emotional behaviors remains poorly understood. Here, we show that juvenile social isolation induces a shift in microbial ecology that negatively impacts social and emotional behaviors in adulthood. These behavioral changes, which occur during this critical period are transferable to antibiotic pre-treated mice by fecal microbiota transplant. In addition, juvenile social isolation decreases the expression of oxytocin receptor (OXTR) in the medial prefrontal cortex (mPFC), and increases the amounts of fecal propionic acid (PA), a short-chain fatty acid derived from gut micobiota. Accordingly, infusion with an OXTR antagonist (OXTR-A, l -368,899) specifically in the mPFC or supplementation of PA both can cause social deficits and anxiety-like behaviors in group housed mice. Collectively, our findings reveal that juvenile social experience regulates prefrontal cortical OXTR expression through gut microbiota-produced PA and that is essential for normal social and emotional behaviors, thus providing a cellular and molecular context to understand the consequences of juvenile social deprivation.