Abstract Body: Ischemic stroke is a leading cause of death and disability in the US, occurring when the blood supply to an area of the brain is disrupted. Such vascular insults may impact different brain areas responsible for neurologic functions ranging from the generation of movement to language, executive cognitive performance, and mood. Clinicians consider strokes as macroscopic events affecting structures such as cortex, basal ganglia, thalamus, or brainstem. However, each of these is comprised of circuitry involving multiple neuronal cell types, each with stratified metabolic requirements and distinct firing patterns that impact susceptibility to ischemia. Many strokes affect neocortex, a 6-layered cellular sheet containing excitatory glutamatergic pyramidal projection neurons (~80%) and inhibitory local GABAergic interneurons (~18%) assembled into circuits that are elaborated across different cortical areas..

In the weeks following a stroke many patients experience unanticipated neurologic issues that disrupt their recovery and lead to additional suffering. These secondary complications fall into the categories of mood disorders (occurring in 31% of stroke survivors), seizure (3-7%), movement disorders (4%), and cognitive decline (11%). While some therapies exist, complications are often inadequately treated and the causes remain poorly understood as they relate to specific pathologic changes in local cortical circuits. Using a combination of photothrombotic lesions and fluorescent microparticle injection as models for focal ischemic stroke, we designed experiments to define the subpopulations of cortical neuron most susceptible to cell death and dysfunction following ischemic stroke.

Using genetic driver mice to label canonical GABAergic (PV, VIP, SST) and glutamatergic neuronal cell types, we provide the first quantitative evidence that neural subtypes have differential susceptibility to ischemia in peri-infarct regions, and complete in vivo 2-photon imaging of the onset of ischemic cell death in medial prefrontal cortex and motor cortex using virally-encoded apoptosis markers. Using a combination of Gcamp voltage sensors and EEG. we also present an approach for recurrent monitoring of post-stroke neuronal activity changes leading to organizing network hyperexcitability in ischemic penumbrae. These results lay a foundation for investigation of cell type specific therapies to mitigate the maladaptive effect local cortical disinhibition following stroke.