Spared corticospinal neurons activate an endogenous plasticity program after partial CNS injury
Year: 2026
Type: preprint
Abstract: Functional recovery after incomplete spinal cord injury depends substantially on the capacity of anatomically spared neurons to remodel their connections, yet the molecular programs underlying this endogenous plasticity remain poorly understood. To identify and validate these mechanisms, we combined retrograde labeling, unilateral corticospinal tract injury, and spatial transcriptomics in mice, with an in vitro human neuron model of neurite regeneration. Injured corticospinal neurons (CSNs) exhibited widespread transcriptional downregulation; the few activated pathways included stress, cell death, and degenerative programs. In contrast, spared CSNs activated a coordinated pro-plasticity program characterized by metabolic, immune, and cytoskeletal remodeling together with suppression of axon growth-inhibitory signaling. Computational network and drug perturbation analyses identified, and human neuronal experiments validated, ARHGEF12 suppression and the histone deacetylase inhibitor (HDAC) vorinostat as complementary target- and state-based strategies to enhance neurite regeneration. These findings define key components of endogenous plasticity and provide a framework for discovering neural repair targets.
Institutions: Yale University, Cold Spring Harbor Laboratory
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: Team science approach to integrate machine-learning models and functional genomics to study aging in the context of Alzheimer's disease, Mechanisms that support Raphespinal tract plasticity and regeneration after spinal cord injury, Modeling the interaction of physiological and environmental stressors on common variants to psychiatric traits, High-throughput in vivo and in vitro functional and multi-omics screens of neuropsychiatric and neurodevelopmental disorder risk genes, Neurobiology of Cortical Systems, Defining and exploiting the plasticity transcriptome to repair the damaged spinal cord
OpenAlex ID: W7212817296