Developmental molecular signatures define de novo cortico-brainstem circuit for skilled forelimb movement

Skilled movement relies on descending cortical projections to the brainstem and spinal cord. The brainstem integrates cortical inputs from subcerebral projection neurons (SCPN). Here, we identify a previously unrecognized direct cortico-brainstem circuit that emerges early in development and persists into adulthood. A subset of SCPN project exclusively to the brainstem from the earliest stages of axon extension, never extending to the spinal cord. We find that during development, these cortico-brainstem neurons (CBN) can be prospectively identified by Neuropeptide Y (Npy) expression. In adulthood, Npy+ CBN project preferentially to rostral brainstem motor regions. Silencing Npy+ CBN impairs the precision and targeting of forelimb movement in a skilled reaching task. Together, these results outline how molecular programs lay the foundation for adult cortico-brainstem circuits underlying skilled movement. Our findings reveal the developmental logic diversifying descending cortical circuits and enable investigation of specific descending projection neuron subsets in motor control. Here authors show cortico-brainstem neurons are molecularly specified in early development to restrict axon growth to the brainstem without extending to spinal cord. This developmentally defined circuit persists into adulthood and supports skilled forelimb movement.