Mapping prefrontal afferents along development

The medial prefrontal cortex (mPFC) acts as a hub for cognitive, emotional, and social processes, integrating neuronal inputs from numerous brain regions. Knowledge on the processes underlying formation and myelination of prefrontal afferents is essential for a comprehensive understanding of the emergence, maturation, and refinement of mPFC-dependent behaviors. However, despite detailed investigation of long-range projections to the mPFC in the adult brain, little is known about their maturation. Here, we use retrograde labeling, light-sheet imaging, and automatic cell segmentation to quantify afferent projections to the mPFC from neonatal to adult age. We show that densities of ipsi- and contralateral prefrontal afferents change along development from a widespread bilateral distribution at neonatal age to a predominantly ipsilateral organization. Furthermore, myelination of interhemispheric prefrontal afferents starts only after the decline of neonatal contralateral projections and is followed by temporally elevated projection densities from limbic brain regions. Overall, these distinct developmental dynamics of prefrontal afferents might have major implications for the maturation of mPFC-dependent functional and behavioral outputs.