Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. After TBI, neurons undergo various phenotypic changes in response to multiple stimuli, and these changes may either facilitate recovery or exacerbate neuronal damage. Our study aimed to explore the potential impact of such phenotypic alterations on TBI outcomes. We obtained publicly available single-cell and bulk RNA-sequencing datasets of mouse cortical tissue from the GEO database. These datasets were used to identify genes associated with neuronal phenotypic changes following TBI. Using stereotactic intracranial injections of AAV vectors, we modulated the expression of candidate genes in neurons and evaluated their biological functions in TBI recovery through behavioral tests, including the modified Garcia score, rotarod test, and balance beam test. Finally, we employed molecular docking analyses to assess the binding capacity of various small-molecule compounds to the identified target gene. Our scRNA-Seq analyses identified a population of neurons that displayed significant mRNA expression changes after TBI. Enrichment analyses, pseudotime trajectory studies, and cell-to-cell pathway communication analyses highlighted distinct gene expression and signaling pathway alterations within this neuronal cluster post-TBI. Among these genes, Anxa2 emerged as a potentially important factor in neuronal repair following injury. Behavioral experiments indicated that overexpression of Anxa2 led to improved outcomes, whereas Anxa2 knockdown worsened recovery. Furthermore, molecular docking analysis revealed several small-molecule compounds that may interact with Anxa2, suggesting potential therapeutic candidates for TBI treatment. Neurons exhibit extensive gene expression and signaling pathway modifications after TBI, and neuronal Anxa2 plays a beneficial role in behavioral recovery. Moreover, our findings suggest that multiple small-molecule compounds may serve as potential therapeutic agents targeting Anxa2, providing new insights for the development of TBI therapeutics. • scRNA-Seq identifies a distinct neuronal state after traumatic brain injury. • Neuronal Anxa2 upregulation enhances functional recovery after TBI. • Anxa2-targeting small molecules identified as potential therapeutic candidates.
Hu et al. (Sun,) studied this question.