Developmentally distinct architectures in top-down pathways controlling threat avoidance

The medial prefrontal cortex (mPFC) is critical for learning and decision-making processes, including responding to threats. The protracted maturation of the mPFC extends into early adulthood. Although prominent models suggest that increasing top-down control by the mPFC eventually allows adult behavioral repertoires to emerge, it is unclear how progressive strengthening can produce nonlinear behavioral changes observed across development. We use fiber photometry and optogenetics to establish causal links between frontolimbic pathway activity and threat avoidance strategies in juvenile, adolescent and adult mice. We uncover multiple developmental switches in the roles of mPFC pathways targeting the nucleus accumbens and basolateral amygdala. These changes are accompanied by axonal pruning, strengthening of synaptic connectivity and altered functional connectivity with downstream cell types, which occur in the mPFC-basolateral amygdala and mPFC-nucleus accumbens pathways at different rates. Our results reveal how developing mPFC pathways pass through distinct architectures that may make them optimally adapted to age-specific challenges.