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Thesis

English

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10670/1.5154kk

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Evolution of corticospinal tract integrity in stroked marmoset monkeys : Towards a bioimplant and stem cell therapeutic strategy

Abstract

Ischemic stroke frequently damages brain regions involved in the control of voluntary movement and remains a leading cause of adult-acquired disability. Although hundreds of therapeutic strategies have shown potential benefits in animal models of stroke, motor rehabilitation and physiotherapy remain the only validated treatments in Humans after the acute phase. This observation highlights the need to develop and characterize reproducible pre-clinical models, which will allow the assessment of experimental therapies. The first objective of this work was therefore to characterize the anatomical and functional consequences of a brain lesion induced by stereotaxic injection of malonate, a mitochondrial toxin, in rodents and primates. Multimodal Magnetic Resonance Imaging allowed longitudinal non-invasive assessment of tissue alterations. We then performed histological analyses to further describe tissue damage. Motor deficits and their recovery were evaluated using a battery of sensorimotor tests. We first show that stereotaxic injection of malonate into the internal capsule of rats creates targeted destruction of corticospinal tract fibers. This lesion is associated with long term motor impairments similar to those observed after lacunar stroke in humans. Secondly, I characterized the consequences of stereotaxic injection of malonate into the primary motor cortex of marmoset monkeys. This model was developed in order to reproduce the effects of middle cerebral artery stroke in Humans. Indeed, the blood supply of motor territories strongly depends on this vessel, which is often occluded in ischemic stroke. We show that this approach causes a focal lesion of predictable size and location. Secondary lesions together with astrocyte and microglial infiltration were observed in white matter tracts distant to the lesion site, and likely occur after degeneration of cortico-sub-cortical motor loop axons. Importantly, the lesion was associated with long-lasting loss of dexterity and grip strength of the contralateral forelimb. Stereotaxic injection of malonate therefore reproduces the consequences of ischemic stroke and should allow the investigation of innovative therapies. Stem cell therapy may hold promise for tissue regeneration in the central nervous system (CNS). Co-transplantation of stem cells with biomaterials is currently investigated to enhance the survival and maturation of transplanted cells within the lesion site. Biomaterials can help to create a microenvironment permissive to cell integration within host tissue. An approach combining intracerebral engraftment of semi-rigid micro patterned biomaterials with human neural stem cells (to form a "neuro-implant") improved the recovery of grip strength in stroked rats. [...]

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