A white matter stroke model in the mouse: Axonal damage, progenitor responses and MRI correlates

Abstract

Subcortical white matter stroke is a common stroke subtype but has had limited pre-clinical modeling. Recapitulating this disease process in mice has been impeded by the relative inaccessibility of the sub-cortical white matter arterial supply to induce white matter ischemia in isolation. In this report, we detail a subcortical white matter stroke model developed in the mouse and its characterization with a comprehensive set of MRI, immunohistochemical, neuronal tract tracing and electron microscopic studies. Focal injection of the vasoconstrictor endothelin-1 into the subcortical white matter produces an infarct core that develops a maximal MRI signal by day 2, which is comparable in relative size and location to human subcortical stroke. Immunohistochemical studies indicate that oligodendrocyte apoptosis is maximal at day 1 and apoptotic cells extend away from the stroke core into the peri-infarct white matter. The amount of myelin loss exceeds axonal fiber loss in this peri-infarct region. Activation of microglia/macrophages takes place at 1 day after injection near injured axons. Neuronal tract tracing demonstrates that subcortical white matter stroke disconnects a large region of bilateral sensorimotor cortex. There is a robust glial response after stroke by BrdU pulse-labeling, and oligodendrocyte precursor cells are initiated to proliferate and differentiate within the first week of injury. These results demonstrate the utility of the endothelin-1 mediated subcortical stroke in the mouse to study post-stroke repair mechanisms, as the infarct core extends through the partially damaged peri-infarct white matter and induces an early glial progenitor response.

Emergent properties of neural repair: elemental biology to therapeutic concepts

“…Stroke also stimulates oligodendrocyte progenitor cells (OPCs) to divide and partially differentiate adjacent to the lesion,9, 10 a form of poststroke gliogenesis. This has also been reported in human stroke 78.…”

“…These individual neural repair events interact in the aggregate and evolve over time to produce properties that are different, larger, and more important than the properties of the single reactive astrocyte or migrating neuroblast. In a definitional sense, the formation of new neurons,6, 7, 8 new oligodendrocytes,9, 10 or new connections11, 12, 13 has been interchangeably described as “repair” or “regeneration.” Both terms connote a process of renewal and growth of tissues after injury, and are literally true in a limited fashion in the central nervous system (CNS) after injury 12. This review will discuss emergent properties of neural repair from the epidemiology of stroke to the synapse, highlighting areas of clinical translation opportunity.…”

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

“…The direct injection of vasoconstrictor agents into the subcortical white matter has been used to induce focal white-matter stroke both in rats and in mice. [35][36][37] For example, when endothelin-1 is injected into the internal capsule in rats, tissue necrosis and demyelination occur in 14 days, which eventually causes sensorimotor deficits. 35 Also in mice, microinjection of endothelin-1 into the subcortical white matter produces an infarct core as in human subcortical stroke, which accompanies with oligodendrocyte apoptosis, myelin loss, axonal fiber loss, and activation of microglia/ macrophages.…”

A Rat Model of Photothrombotic Capsular Infarct with a Marked Motor Deficit: A Behavioral, Histologic, and microPET Study

“…9 Recently, injection of endothelin-1 has been considered as the most reliable way to simulate a capsular infarct while preserving the cortical motor cortex. [6][7][8] However, the destruction of IC fibers in this model was incomplete, leading to a lack of marked deficits in various tests of unskilled sensorimotor behavior. Establishing an animal model that is associated with persistent behavioral deficits is important for validating the model and for monitoring recovery (e.g., improvement of motor function or increased plasticity) when therapeutic or rehabilitative interventions are introduced.…”

“…Although many studies of therapeutic strategies have been performed using cortical infarct models, only a few studies have investigated subcortical capsular infarcts (SCIs), owing to a lack of pertinent rodent models for capsular infarct. [6][7][8] Specifically, to investigate motor deficits and their recovery after a stroke, a portion of the motor pathway from the motor cortex to the medullary pyramid should be selectively destroyed or modified to create animal models that have motor impairment. However, most of these models involve damage within the gray matter of the cortex, and only a few studies have attempted to damage the white matter to develop a stroke model.…”