Precise motor control relies on appropriate connections between subcerebral projection neurons (SCPN) in cerebral cortex and targets in brainstem and spinal cord. While cortical innervation of the spinal cord is crucial for skilled movement, input into the brainstem additionally fine-tunes movement and motor planning. The brainstem receives cortical input either through: 1) cortico-brainstem neurons (CBN) innervate brainstem directly without reaching into the spinal cord, 2) corticospinal neurons (CSN) project to the spinal cord while also branching in brainstem. Distinguishing between these two interdigitated cortical subpopulations has been challenging. We recently identified the molecular signature distinguishing CBN from CSN during early SCPN axon extension (Kaiser et al, 2022). Neuropeptide Y (Npy) is specifically expressed by CBN in lateral cortex, providing a novel molecular approach to explore their role in motor control. Assessing brainstem innervation of Npy+ CBN vs. CSN using newly established machine-learning techniques shows a differential topographic organization of projections across brainstem nuclei, suggesting a difference in their contribution to motor control. We are currently investigating the role of direct cortical input into the brainstem by selectively silencing Npy+ CBN within sensorimotor cortex and evaluating their impact on skilled movements. Preliminary data hint at a critical role of CBN in skilled movement, with acute silencing leading to a temporary deficit in grasping success. These findings shed light on cortico-brainstem and cortico-spinal circuit complexity and lay the groundwork for future studies aiming to unravel how these neural networks influence movement control in both healthy and damaged nervous systems.