Investigation into the pathogenesis of ischaemic brain damage, by live imaging of peri-lesion spreading depression (SD) in stroke models. (360G-Wellcome-079430_B_06_Z)

Studies with stroke models showed that recurrent spreading depression (SDs, waves of cellular depolarisation that propagate slowly across grey matter regions) occur in the vicinity of the ischaemic core and contribute to lesion progression. Peri-lesion SDs were also found in patients suffering from a stroke or traumatic brain injury. It is often speculated that SDs are initiated in the ischaemic penumbra (i.e. where residual blood supply is insufficient for synaptic function but still capable of sustaining vital biological processes) but this hypothesis conflicts with robust data. Two important questions must be answered: - Are peri-lesion SDs elicited in the penumbra, or only at sharp interfaces between severely ischaemic regions and spared regions? - How do SDs contribute to lesion progression? We have identified a new experimental strategy that should produce definite answers: Live imaging of the ischaemic region and of peri-lesion SDs, using two fluorescent dyes, one voltage-sensitive and the other pH-sensitive. This pilot study will aim to: (i) Adapt existing fluorescent-dye imaging technology for this specific application; (ii) Validate this novel approach in models where the pattern of focal ischaemia can be accurately controlled; (iii) Obtain preliminary data that will allow us to seek financial support for a full project.