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

Article https://doi.org/10.1038/s41467-026-73518-x Scg2 drives corticospinal circuit reorganization with spinal premotor interneurons and astrocytes for motor recovery after stroke in mice Received: 21 January 2025 1234567890():,; 1234567890():,; Accepted: 14 May 2026 Check for updates Tokiharu Sato 1,2, Yuka Nakamura Masahiko Takada 3,5, Masato Yano Masaki Ueno 1,2 1,2 , Kana Hoshina1,2, Ken-ichi Inoue , Hitoshi Matsuzawa8,9 & 3,4 , 6,7 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. Stroke is one of the leading causes of neurological deficits resulting in motor and sensory dysfunction1,2. While pharmacological and mechanical treatments are effective for reperfusion in the acute phase, therapeutic options for recovery are limited in the chronic phase, except for rehabilitation3,4. The loss of neurons leads to the disconnection of diverse intrinsic circuits that connect local and distal areas, resulting in functional impairments. Notably, however, patients often exhibit a limited but significant recovery over time. Previous studies have demonstrated that plastic changes in the spared neural networks correlate well with the process of recovery in both human and animal models1,5–9. This raises the possibility that promoting the reorganization process would be a promising therapeutic strategy. 1 Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University, Niigata, Niigata, Japan. 2Department of Systems Neuropathology and Neural Repair, Brain Research Institute, Niigata University, Niigata, Niigata, Japan. 3Institute for the Evolutionary Origins of Human Behavior, Kyoto University, Inuyama, Aichi, Japan. 4Department of Integrative Anatomy, Graduate School of Medical Sciences and Medical School, Nagoya City University, Nagoya, Aichi, Japan. 5Department of Neurology, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan. 6Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan. 7Core Research Facilities for Basic Science Research Center for Medical Science, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan. 8Center for Integrated Human Brain Science, Niigata University, Niigata, Niigata, Japan. 9Center for Advanced Medicine and Clinical Research, Sapporo Hakuyokai Hospital, Sapporo, Hokkaido, Japan. e-mail: Nature Communications | (2026)17:4880 1 Article However, precise targets of neural substrates and molecular mechanisms that drive the reorganization remain largely unknown. Stroke often damages the motor pathways such as the corticospinal tract (CST), the descending pathway that sends commands from the cerebral cortex to the spinal cord for voluntary and skilled movements10–12. In animal models, spared CST axons are often rewired to form compensatory circuits after injuries9,13,14. For example, the axons regrow in the denervated area of the spinal cord and contribute to recovery15–21. Ipsi- or contralesional CST axons are rewired depending on the location and size of the stroke in mice and monkeys19,22. These suggest that reorganization of the corticospinal circuitry would be essential for motor recovery. However, neural and molecular targets to control the reorganization remain to be determined. Specifically, what kind of connections are reformed and what molecular mechanisms control the axon rewiring are largely unknown. The CST comprises multiple projections from the motor and sensory cortical areas, with diverse connections within the spinal cord23–27. For example, we have shown that the axons from the motor cortex project to intermediate to ventral laminae of the spinal cord and primarily connect with motor-related spinal interneurons such as Chx10+ V2a interneurons in mice25. In contrast, the axons from the sensory cortex project dorsally and connect to interneurons involved in sensory functions. Each circuit regulates specific aspects of sensorimotor functions in behaviors25,28. After injuries, spared axons regrow and connect to segmental interneurons and propriospinal neurons that would compensate for lost motor functions in rodents15,29. However, detailed connections of the compensatory circuits contributing to recovery are not comprehensively explored, in contrast to the detailed connection map in intact corticospinal circuits25,26,30. Especially, the types of spinal interneuron targeted by the innervating CST axons, as well as their functional contribution, have not been elucidated yet. Molecular mechanisms that control axon rewiring are also not fully understood. Neural connections, especially in denervated areas, are reorganized in sequential steps after injuries31–33. Injuries degenerate neurons and axons extending to target areas, where they lead to disconnection from target neurons and a reaction of astrocytes and microglia. Spared axons then begin to sprout and grow to appropriate target neurons and reform synaptic connections, while some are eliminated for refinement. Certain molecular mechanisms in growing axons and surrounding cells will cooperatively facilitate the process of reorganization. In this context, previous studies had explored molecules for axon regrowth by focusing on factors putatively secreted in the denervated area. Expression analyses of candidate genes related to axon growth revealed that BDNF and CNTF induce axon innervation of the CST15,34. Transcriptomic analyses using microarrays or RNA-seq in different injury contexts demonstrated diverse gene expressions in the denervated areas21,35–39. However, essential molecules to induce axon rewiring have been limitedly identified, except for GDF10 in the cerebral cortex37,40. Consequently, the cellular and molecular mechanisms that trigger the reorganization are not fully understood. In the present study, we investigated the neural connectivity reformed in the (...truncated)