Abstract
The photothrombotic stroke model generates localized and reproducible ischemic infarcts that are useful for studying recovery mechanisms, but its failure to produce a substantial ischemic penumbra weakens its resemblance to human stroke. We examined whether a modification of this approach, confining photodamage to arteries on the cortical surface (artery-targeted photothrombosis), could better reproduce aspects of the penumbra. Following artery-targeted or traditional photothrombosis to the motor cortex of mice, post-ischemic cerebral blood flow was measured using multi-exposure speckle imaging at 6, 48, and 120 h post-occlusion. Artery-targeted photothrombosis produced a more graded penumbra at 48 and 120 h. The density of isolectin B4+ vessels in peri-infarct cortex was similarly increased after both types of infarcts compared to sham at 2 weeks. These results indicate that both models instigated post-ischemic vascular structural changes. Finally, we determined whether the strength of the traditional photothrombotic approach for modeling upper-extremity motor impairments extends to the artery-targeted approach. In adult mice that were proficient in a skilled reaching task, small motor-cortical infarcts impaired skilled-reaching performance for up to 10 days. These results support that artery-targeted photothrombosis widens the penumbra while maintaining the ability to create localized infarcts useful for modeling post-stroke impairments.
Highlights
The ischemic penumbra was first defined by Astrup and colleagues1,2 based on thresholds of reduced cerebral blood flow (CBF) that were associated with electrical silence in cortical tissue surrounding a core region of ischemia
We found a main effect of distance at each imaging time point (6 h: F[3,30] = 44.80, p < 0.001; 48 h: F[3,36] = 68.55, p < 0.001; and 120 h: F[3,33] = 17.21, p < 0.0001), confirming that CBF deficits were more severe closer to the core area of ischemia
The traditional photothrombotic stroke model is strong for modeling impairments and studying mechanisms of recovery following ischemia
Summary
The ischemic penumbra was first defined by Astrup and colleagues based on thresholds of reduced cerebral blood flow (CBF) that were associated with electrical silence (loss of somatosensory evoked responses) in cortical tissue surrounding a core region of ischemia. We recently established a variation of the photothrombotic approach, artery-targeted photothrombosis, in which a digital micromirror device (DMD) is used to confine illumination to a set of pre-identified arterial branches on the cortical surface, thereby minimizing damage to surrounding brain tissue. We recently established a variation of the photothrombotic approach, artery-targeted photothrombosis, in which a digital micromirror device (DMD) is used to confine illumination to a set of pre-identified arterial branches on the cortical surface, thereby minimizing damage to surrounding brain tissue27 We used this method to simultaneously monitor oxygen tension and CBF after vascular occlusion. The main goal of the present study was to test whether this modified photothrombotic stroke model could better reproduce a graded vascular penumbra compared to the traditional model Another goal was to determine whether there are changes in vascular density in peri-infarct cortex that may reflect neovascularization. We used histological measures of lectin-labeled vessels to assess vascular density change and its potential spatiotemporal variation after artery-targeted and traditional photothrombosis
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