Towards a reproducible model for subcortical capsular strokes

Nudi, Evan Taylor
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Following stroke, survivors often experience long lasting upper limb motor impairments that can vary in severity. A prominent category of these upper limb deficits are caused by damage to the capsular region caused by ischemia in the anterior choroidal artery. However, animal research has focused on motor impairments caused by cortical damage. This overreliance on cortical models of stroke exists because currently there is no focal model of stroke damage to the posterior limb of the internal capsule (PLIC) that is as reliable and replicable as current cortical models. The current most used animal model of global stroke that damages the internal capsule is the middle cerebral artery occlusion (MCAO) model; however, this model is not a precise representation of stroke, causing large amounts of damage outside of the region on interest. Additionally, damage caused by the MCAO model can cause a variability in lesion sizes reducing its replicability. There are additional models available, but they are understudied for use in stroke damage to the PLIC: (1) a method of infusing an endogenous vasoconstrictor, endothelin-1 (ET-1), into the internal capsule and (2) a model of photothrombotic stroke that uses a photosensitive dye to cause ischemic-like damage and modified to induce focal lesions to subcortical regions. The difficulty with the ET-1 models comes down to targeting as well as there being no way to control how ET-1 diffuses into the tissue. Photothrombotic PLIC lesions are a novel method of lesion induction, and more research is needed to assess efficacy. Both methods have the potential to bridge the gap between preclinical and clinical research by creating models that more closely resemble what is seen in clinical research. The goal for this set of work is to determine whether the ET-1 and photothrombotic models of subcortical stroke can produce reliable and replicable lesions to the posterior limb of the internal capsule that cause acute and chronic forelimb motor deficits. Three experiments were conducted to accomplish this goal, the first using the ET-1 method and the second and third using the photothrombotic methods. In the first experiment, the ET-1 method of PLIC lesions was used to model forelimb deficits into the chronic phases of stroke. A slow infusion of ET-1 was infused into the internal capsule causing localized stroke-like damage. Endothelin-1 PLIC lesions were shown to produce marked initial deficits in reaching success and forelimb strength that recovered in most subjects by 1-month out from lesioning. Even though ET-1 lesions were able to produce marked deficits, the size and localization of the lesions was highly variable suggesting that this model was not ideal for preclinical studies of forelimb impairments without modifications to reduce that variability. In the next two experiments, photothrombotic lesions to the PLIC were induced to test whether the model could produce reliable and replicable damage that causes both acute and chronic motor impairments. Using this method, to ensure precision of lesion placement, a light emitting optrode with an attached electrode stimulated the internal capsule before lesioning, signaling that the optrode was in the forelimb motor bundle. This method was shown to produce persistent acute forelimb motor impairments that partially improved into the chronic phases of recovery. Furthermore, more lateral damage to the posterior limb of the internal capsule was shown to produce larger and more persistent motor impairments, suggesting the lateral realm of the PLIC could be an ideal target for these focal photothrombotic lesions. The damage caused to the internal capsule was highly localized, causing only minor damage to other subcortical regions. The results suggest that the photothrombotic model of subcortical lesions has the potential to be a replicable and reliable method of lesioning the posterior limb of the internal capsule. Overall, these studies indicate the potential of both ET-1 and photothrombotic stroke methods for the study of forelimb motor impairments. Both models were able to produce significant initial motor impairments; however, the photothrombotic method appeared to create more localized and replicable lesions.