Social hierarchy modulates cognitive flexibility through basal forebrain-prefrontal cholinergic projections

Social hierarchy is closely linked to individual cognitive flexibility; however, the causal mechanisms underlying this relationship remain incompletely understood. In the present study, we found that dominant mice exhibited significantly enhanced cognitive flexibility compared to subordinate mice, as demonstrated by superior performance in the Y-maze and Novel Object Recognition (NOR) tests. Notably, dominant mice showed increased levels of acetylcholine (ACh) in the medial prefrontal cortex (mPFC) and elevated firing rates of cholinergic neurons in the horizontal diagonal band (HDB) of the basal forebrain compared to subordinate mice. Moreover, chemogenetic activation of cholinergic neurons in subordinate mice led to improved cognitive performance, confirming the critical role of cholinergic signaling in cognitive function. Activation of cholinergic projections from the HDB to the mPFC similarly enhanced cognitive flexibility in subordinate mice. These findings indicate that social dominance influences cognitive flexibility through cholinergic pathways, suggesting potential therapeutic targets for cognitive enhancement in individuals with lower social status.