Aging disrupts the link between network centrality and functional properties of prefrontal neurons during memory-guided behavior

The prefrontal cortex (PFC) is vital for higher cognitive functions and displays neuronal heterogeneity, with neuronal activity varying significantly across individual neurons. Using calcium imaging in the medial PFC (mPFC) of mice, we investigate whether differences in degree centrality-a measure of connectivity strength within local circuits-could explain this neuronal diversity and its functional implications. In young adults, neurons with high degree centrality, inferred from resting-state activity, exhibit reliable and stable action-plan selectivity during memory-guided tasks, suggesting that connectivity strength is closely linked to functional heterogeneity. This relationship, however, deteriorates in middle-aged and older mice. A computational model simulating age-related declines in synaptic plasticity reproduces these results. In young adults, degree centrality also predicts cross-modal action-plan selectivity, but this predictive power diminishes with age. Furthermore, neurons with high action-plan selectivity are spatially clustered, a pattern that fades with aging. These findings reveal the significant aging impact on the network properties in parallel with the functional and spatial organization of the mPFC.