CORTICO-BRAINSTEM PATHWAY COMPENSATES FOR LOSS OF CORTICOSPINAL OUTPUT AFTER STROKE AND SPINAL CORD INJURY

* co-corresponding authors
Descending cortical projections are essential for skilled motor control, and injury to these pathways results in substantial motor impairments. We recently identified parallel descending pathways arising from distinct subsets of subcerebral projection neurons (SCPN) that diverge during development: cortico-brainstem neurons (CBN), which limit axon extension to the brainstem, and corticospinal neurons (CSN), whose axons extend into the spinal cord while also innervating the brainstem. While compensatory sprouting of CSN has been linked to functional recovery after stroke and spinal cord injury (SCI), whether CBN undergo structural plasticity or contribute to recovery after such injuries remains unclear. Here, we investigated CBN axonal plasticity and their role in functional recovery following stroke and SCI. Specifically, we asked how spared CBN axons remodel their brainstem collateralization in response to two anatomically distinct insults: a cortical lesion caused by unilateral loss of SCPNs after stroke, and a spinal injury that disrupts corticospinal connectivity. Using StARQ, a machine learning-based pipeline for quantifying axonal collateralization across the entire rostro-caudal extent of the brainstem, we find that CBN axons exhibit increased collateralization in caudal brainstem regions in both injury models, regions that are usually dominated by corticospinal collaterals. Ongoing work will assess the functional relevance of this reorganization using skilled forelimb behavior combined with chemogenetic silencing of CBN. Overall, our results indicate that spared cortico-brainstem pathways are consistently recruited when direct corticospinal access to downstream motor circuits is compromised, positioning CBN as a flexible relay for cortical output after central nervous system injuries.