Project 467218

Spinal Cord Injury (SCI) is one of the leading causes of disability, and although rehabilitation strategies are common, there is a need for new treatment options that focus on the regeneration of cells lost during injury. The type-2 diabetes drug, metformin, has shown potential in promoting regeneration and functional recovery in different central nervous system (CNS) injuries, including SCI. At the cellular level, recent work has shown that metformin has profound effects on neural stem/progenitor cells (NPCs), enhancing their activity, promoting their proliferation, and maturation into neurons and oligodendrocytes (the crucial cell types lost during injury). Moreover, metformin also affects inflammation in the CNS post-injury by acting on immune cell populations, like microglia and astrocytes. Therefore, the cellular mechanism behind metformin-mediated recovery after injury is still unclear. Here, we seek to validate a knock-out NPC mouse model, in which NPCs are absent, to ask whether activated NPCs are necessary for the metformin-mediated recovery following SCI. To achieve this, we will use the Sox2-TK mouse model, treating mice with the antiviral agent ganciclovir results in the ablation of proliferating Sox2+ cells, the same NPCs that become activated following SCI. After confirming the absence of NPCs, we will induce SCI in the Sox2-TK mice, administer metformin, and assess motor recovery across treatment and control groups. We hypothesize that these mice will not recover motor function following treatment with metformin due to the absence of activated NPCs. Overall, this work will provide valuable insights into the cellular basis for metformin-mediated recovery and highlight new targets for novel therapeutic strategies to regenerate the injured CNS.