Major urinary protein 1 acts as a critical molecule in empathy regulation

Abstract Emotional contagion is believed to be the evolutionary basis of empathy. Recently, empathy was also confirmed to exist in rodents. However, the underlying mechanism of empathy remains elusive. Using a social defeat model, we found that depressive emotion can be transmitted between cagemates in mice through odor cues. Odors from defeated mice containing information about danger induced social avoidance, producing a force opposite from social orientation in naïve mice. The medial prefrontal cortex (mPFC) chooses between flight or approach after evaluating these two forces. mPFC activation is stronger in high-empathy (or high-social orientation) mice than in low-empathy (or low-social orientation) mice. Major urinary protein 1 (MUP1), reported as a pheromone, contributes to stronger mPFC activation in higher-empathy mice. MUP1 increases mPFC neuronal excitability by binding with neuronal syntaxin-binding protein 1 (STXBP1) and astrocytic excitatory amino acid transporter 2 (GLT1). Human progestagen–associated endometrial protein (hPAEP), an MUP1 homologous analog in humans, is decreased in children with autistic spectrum disorder (ASD), and reduced hPAEP level in plasma correlates with behavioral abnormity in ASD children. Existing studies have identified MUP1 as a critical molecule in empathy regulation and a potential target for treating disorders characterized by empathy disabilities, such as ASD.