A Reproducible and Translatable Model of Focal Ischemia in the Visual Cortex of Infant and Adult Marmoset Monkeys

Abstract

Models of ischemic brain injury in the nonhuman primate (NHP) are advantageous for investigating mechanisms of central nervous system (CNS) injuries and testing of new therapeutic strategies. However, issues of reproducibility and survivability persist in NHP models of CNS injuries. Furthermore, there are currently no pediatric NHP models of ischemic brain injury. Therefore, we have developed a NHP model of cortical focal ischemia that is highly reproducible throughout life to enable better understanding of downstream consequences of injury. Posterior cerebral arterial occlusion was induced through intracortical injections of endothelin-1 in adult (n = 5) and neonatal (n = 3) marmosets, followed by magnetic resonance imaging (MRI), histology and immunohistochemistry. MRI revealed tissue hyperintensity at the lesion site at 1-7 days followed by isointensity at 14-21 days. Peripheral macrophage and serum albumin infiltration was detected at 1 day, persisting at 21 days. The proportional loss of total V1 as a result of infarction was consistent in adults and neonates. Minor hemorrhagic transformation was detected at 21 days at the lesion core, while neovascularization was detected in neonates, but not in adults. We have developed a highly reproducible and survivable model of focal ischemia in the adult and neonatal marmoset primary visual cortex, demonstrating similar downstream anatomical and cellular pathology to those observed in post-ischemic humans.

A pilot study on transient ischemic stroke induced with endothelin-1 in the rhesus monkeys

“…ET-1 has recently been used to induce focal ischemia leading to impaired executive memory function and to impaired pure-motor and sensorimotor behaviors that are dependent on the specific area of ischemic insult in rodents7891011. There have been a few non-human primate studies utilizing ET-1 induced cerebral ischemia models developed in marmoset monkeys1213. In marmosets, ET-1 was found to cause dose-dependent reductions in middle cerebral artery vessel caliber, which was followed by a gradual reperfusion.…”

“…The ET-1-treated marmosets also displayed contralateral motor deficits in grip strength and the ability to retrieve food rewards as well as displayed a contralateral sensory/motor neglect towards tactile stimulation12. Moreover, ET-1 intracortically injected into the primary visual cortex of adult and neonatal marmosets induced posterior cerebral arterial occlusions and developed a highly reproducible and survivable model of focal ischemia13. These results suggested that a marmoset model of ET-1 induced ischemia has the potential to assess long-term effects of stroke and to gauge the efficacy of novel therapeutic strategies targeted to treat clinical stroke1213.…”

“…Moreover, ET-1 intracortically injected into the primary visual cortex of adult and neonatal marmosets induced posterior cerebral arterial occlusions and developed a highly reproducible and survivable model of focal ischemia13. These results suggested that a marmoset model of ET-1 induced ischemia has the potential to assess long-term effects of stroke and to gauge the efficacy of novel therapeutic strategies targeted to treat clinical stroke1213. The marmoset, as a new world monkey, is limited as a model animal for human disease mechanisms in comparison to the rhesus monkey, an old world monkey.…”

MRI-guided stereotaxic brain surgery in the infant and adult common marmoset

“…Neuronal tract tracing and lesions of different cortices and thalamic nuclei in infant and adult marmosets are successfully and routinely performed in our laboratory (Fig. 5a-f) 9,11 . The use of the MRI-guided approach provides submillimeter precision, even if the head of the animal is not perfectly oriented in the stereotaxic frame.…”

“…This protocol has previously been applied for cortical and subcortical tracing, and lesions in both adult and infant marmosets [9][10][11] . However, the protocol is easily transferable to other paradigms.…”