Inhibition governs stimulus preference encoding in mPFC pyramidal neurons during a social choice

Social decision-making requires the brain to continuously evaluate competing options and select appropriate actions. The medial prefrontal cortex (mPFC) has been implicated in social cognition and value-based decision-making, yet the neural mechanisms by which it encodes the relative value of competing social choices remain poorly understood. Here, we employed fiber photometry, optogenetics, and projection-specific recordings in mice performing four distinct binary social discrimination tasks to reveal how mPFC pyramidal neurons encode social choice. We found that mPFC pyramidal neurons exhibit profound inhibition during bouts toward the preferred stimulus. This inhibitory response was specific to transitional bouts, when animals switched between stimuli, and was absent during non-transitional bouts, which occurred during continued engagement with the same stimulus. Notably, this differential activity encoded relative rather than absolute stimulus value, such that the same stimulus evoked opposite neural responses depending on its contextual preference. Accordingly, manipulating the subject’s preference between food and social stimuli via food deprivation inverted its inhibition-excitation pattern. Furthermore, negative calcium transients in the mPFC predicted subsequent investigation of the preferred stimulus, suggesting a functional role in guiding behavioral choice. Optogenetic activation of mPFC pyramidal neurons during stimulus investigation produced immediate aversion yet paradoxically biased the stimulated animal to persistently re-engage with the stimulus-associated option through repetitive non-transitional bouts. Finally, projection-specific recordings revealed that mPFC neurons targeting the nucleus accumbens and basolateral amygdala were differentially recruited across tasks, reflecting functional specialization of output pathways. Together, these findings identify inhibition of mPFC pyramidal neurons as a key neural signature for encoding relative stimulus preference, thereby establishing a neural principle by which the mPFC dynamically guides social choice.