Spatiotemporal analysis of impaired microglia process movement at sites of secondary neurodegeneration post-stroke

Abstract

It has recently been identified that after motor cortex stroke, the ability of microglia processes to respond to local damage cues is lost from the thalamus, a major site of secondary neurodegeneration (SND). In this study, we combine a photothrombotic stroke model in mice, acute slice and fluorescent imaging to analyse the loss of microglia process responsiveness. The peri-infarct territories and thalamic areas of SND were investigated at time-points 3, 7, 14, 28 and 56 days after stroke. We confirmed the highly specific nature of non-responsive microglia processes to sites of SND. Non-responsiveness was at no time observed at the peri-infarct but started in the thalamus seven days post-stroke and persisted for 56 days. Loss of directed process extension is not a reflection of general functional paralysis as phagocytic function continued to increase over time. Additionally, we identified that somal PY was present on non-responsive microglia in the first two weeks after stroke but not at later time points. Finally, both classical microglia activation and loss of process extension are highly correlated with neuronal damage. Our findings highlight the importance of microglia, specifically microglia dynamic functions, to the progression of SND post-stroke, and their potential relevance as modulators or therapeutic targets during stroke recovery.

Inflammatory Responses in the Secondary Thalamic Injury After Cortical Ischemic Stroke

“…Recently, a spatio-temporal analysis study reports differential process extension response of microglia in the secondary thalamic injury than in the primary injury (79). As a highly conserved response to localized damage, microglia rapidly extend their fine processes toward the site of injury.…”

“…These processes promptly respond to injury through binding of ATP released from the damaged cells to P 2 Y 12 receptors expressed on microglia. In Kluge and colleagues' study, laser damage is applied to the incubated brain sections as external stimulus, and the microglia/macrophages are labeled with GFP in Cx3CR1 GFP/WT mice (79). Microglia/macrophages in the degenerative thalamus lose the process extension feature upon laser damage but show an increase in the phagocytic function during the late phase after photothrombotic cortical stroke.…”

Rosiglitazone polarizes microglia and protects against pilocarpine‐induced status epilepticus

“…Microglia are known to play a critical role in maintaining brain homeostasis . The polarization of microglia has been suggested to play pivotal roles in several different neurological disorders . The activation of microglia after seizure in the epileptic brain has been investigated in several studies .…”

“…39 The polarization of microglia has been suggested to play pivotal roles in several different neurological disorders. [40][41][42][43][44] The activation of microglia after seizure in the epileptic brain has been investigated in several studies. 37,45,46 Furthermore, the role of activated microglia in epileptogenesis has been determined in both inflammatory and noninflammatory processes.…”

Growth Hormone Promotes Motor Function after Experimental Stroke and Enhances Recovery-Promoting Mechanisms within the Peri-Infarct Area

“…Immunofluorescence staining was performed as previously described [85,96]. Free-floating fixed sections were rinsed in PBS, and 3% bovine serum albumin was used to block non-specific binding.…”