Scg2 drives corticospinal circuit reorganization with spinal premotor interneurons and astrocytes for motor recovery after stroke in mice.

Brain injuries such as stroke damage neural circuitry and lead to functional deficits. Spared motor pathways are often reorganized for recovery; however, the connectivity and mechanisms that drive the reorganization are largely unknown. Here, we demonstrate structural and functional connectivity reformed by corticospinal axons after stroke in male mice and determine a secretory protein that drives the reorganization. We first find that corticospinal axons innervate the denervated cervical cord and reconnect to premotor V2a interneurons after stroke. Kinematic analyses and chemogenetic silencing reveal their contribution to motor recovery. Translated mRNA expression analyses identify a secretory protein secretogranin II (Scg2), which is upregulated in astrocytes by injury-induced ATP and in V2a neurons by rehabilitation-induced neural activity. Scg2 promotes axon growth via cAMP and S6 and enhances axon rewiring, while its knockdown attenuates it. Our data reveal the neural substrate and molecular mechanism to induce reorganization and recovery, providing therapeutic targets for central nervous system (CNS) injuries.