Transient middle cerebral artery occlusion induces microglial priming in the lumbar spinal cord: a novel model of neuroinflammation

Katie Moisse,Ian Welch,Michael J Strong,Kathryn Volkening,Tracy Hill

doi:10.1186/1742-2094-5-29

Katie Moisse, Ian Welch + Show 3 more

Open Access

https://doi.org/10.1186/1742-2094-5-29

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Abstract

BackgroundMiddle cerebral artery occlusion (MCAo) in mice results in a brain infarct, the volume of which depends on the length of occlusion. Following permanent occlusion, neuropathological changes – including a robust glial inflammatory response – also occur downstream of the infarct in the spinal cord.MethodsWe have performed short, transient MCAo in mice to induce penumbral damage spanning the motor cortex. A 30 minute MCAo using a poly-L-lysine-coated intraluminal suture introduced through a common carotid artery incision was performed in 17 female C57BL/6 mice. Five sham-operated mice received common carotid artery ligation without insertion of the suture. Neurobehavioural assessments were performed during occlusion, immediately following reperfusion, and at 24 and 72 hours post-reperfusion. Routine histological and immunohistochemical studies were performed at 24 and 72 hours.ResultsIn 11 of the surviving 16 mice subjected to MCAo, we observed a focal, subcortical necrotic lesion and a reproducible, diffuse cortical lesion with accompanying upper motor neuron involvement. This was associated with contralateral ventral spinal cord microglial priming without significant reactive astrocytosis or lower motor neuron degeneration.ConclusionThe advantages to this method are that it yields a reproducible cortical lesion, the extent of which is predictable using behavioural testing during the period of ischemia, with upper motor neuron involvement and downstream priming, but not full activation, of microglia in the lumbar spinal cord. In addition, survival is excellent following the 30 minutes of occlusion, rendering this a novel and useful model for examining the effects of microglial priming in the spinal motor neuron pool.

Highlights

Middle cerebral artery occlusion (MCAo) in mice results in a brain infarct, the volume of which depends on the length of occlusion
We have observed that a 30 minute occlusion time was associated with 100% survival at the 24 hour post-reperfusion time interval. We propose that this model, performed in mice, will allow for the study of microglial priming in the lumbar spinal cord in a reproducible manner that will be instrumental in determining the exact roles of early microglial priming and activation, an event that can apparently produce two very opposing outcomes following neuronal injury
All images taken at magnification 40× prior to reproduction unless noted

Summary

Introduction

Middle cerebral artery occlusion (MCAo) in mice results in a brain infarct, the volume of which depends on the length of occlusion. Neuropathological changes – including a robust glial inflammatory response – occur downstream of the infarct in the spinal cord. Neuroinflammation is a pathological feature of several neurodegenerative conditions including amyotrophic lateral sclerosis (ALS), which involves the selective degeneration of motor neurons in the brain and spinal cord. Anti-inflammatory therapies have shown efficacy in mouse models of ALS [3,4,5,6], and activated microglia can have cytotoxic effects on motor neurons in culture [7,8,9,10]. Microglial activation is a response to damage signals from neurons and astrocytes. This activation is seen morphologically as a transition from a resting, ramified state to an active, amoeboid state through a "primed" intermediate state [11]

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