1. Determine if loss of SARM1 activity promotes axonal survival following ischemic injury.

2. Identify molecular targets of SARM1 in mediating axonal degeneration in stroke.

Functional preservation of axons after ischemic stroke is limited yet critical to post-stroke recovery. Genetic deletion of SARM1 gene has previously been shown to prevent axonal degeneration after traumatic nerve injuries. However, whether similar mechanism mediates axonal loss in ischemic injury is unclear. We sought to understand whether SARM1 activity directly regulates axonal as well as neuronal survival in ischemic stroke.

We utilized an in vivo model of subcortical white matter stroke to compare the degree of axonal and neuronal survival between wildtype (WT) and SARM1 null (SARM1-/-) mice after ischemic injury. Furthermore, using cell capture and RNA-seq analysis, we profiled the molecular signature of SARM1-/- neurons after stroke to elucidate the downstream targets of SARM1-dependent regulation of axonal survival following ischemic injury.

We found that genetic deletion of SARM1 robustly attenuated both axonal and neuronal degeneration for up to 28 days after focal ischemic injuries to the subcortical white matter. Thus, inhibiting SARM1 activity is sufficient to promote axonal and neuronal survival after ischemic stroke. Moreover, transcriptional profiling of stroke-injured wildtype and SARM1-/- neurons revealed a restricted subset of differentially expressed genes that drive neuronal differentiation, axonogenesis and synaptogenesis. Functional genomic analysis of candidate genes further uncovered novel cell signaling pathways that regulate axonal and neuronal survival after stroke injuries.