Functional alterations of the prefrontal circuit underlying cognitive aging in mice

Executive function is susceptible to aging. How aging impacts the circuit-level computations underlying executive function remains unclear. Using calcium imaging and optogenetic manipulation during memory-guided behavior, we show that working-memory coding and the relevant recurrent connectivity in the mouse medial prefrontal cortex (mPFC) are altered as early as middle age. Population activity in the young adult mPFC exhibits dissociable yet overlapping patterns between tactile and auditory modalities, enabling crossmodal memory coding concurrent with modality-dependent coding. In middle age, however, crossmodal coding remarkably diminishes while modality-dependent coding persists, and both types of coding decay in advanced age. Resting-state functional connectivity, especially among memory-coding neurons, decreases already in middle age, suggesting deteriorated recurrent circuits for memory maintenance. Optogenetic inactivation reveals that the middle-aged mPFC exhibits heightened vulnerability to perturbations. These findings elucidate functional alterations of the prefrontal circuit that unfold in middle age and deteriorate further as a hallmark of cognitive aging.