NON-LINEAR MATURATION OF WORKING MEMORY AND PREFRONTAL CORTEX CONTRIBUTION ACROSS DEVELOPMENT IN MICE

Working memory (WM), a core component of cognitive flexibility, continues to mature into adulthood alongside prolonged circuit remodeling of the prefrontal cortex (PFC). Recent findings indicate that functional maturation of the PFC during late development follows a non-linear trajectory, yet it remains unclear whether this is reflected at the behavioral level. To address this question, we assessed spatial WM performance across development in mice using a delayed non-match to sample task. Behavioral performance was compared across four age groups: pre-juvenile (postnatal day (P)20-25), early adolescent (P30-35), late adolescent (P40-45), and adult (P55-60). While all groups were capable of solving the task, detailed analysis revealed age-dependent differences in learning rate, overall performance, and behavioral strategy. Notably, late adolescent mice required more training and exhibited reduced performance compared to the other age groups. These behavioral dynamics are in line with our findings on functional changes of prefrontal circuitry at this age. To probe the contribution of the PFC to the WM dynamics along development, we performed bilateral chemogenetic inhibition of prefrontal activity in adult and pre-juvenile mice. In adults, PFC inhibition resulted in a mild but measurable impairment in task performance. Preliminary data further suggest that pre-juvenile performance is also impaired by prefrontal inhibition, despite evidence for minimal functional PFC recruitment at this age. Together, these findings support a non-linear dynamic of spatial WM development that mirrors the functional maturation of PFC.