Inflammatory Responses in the Secondary Thalamic Injury After Cortical Ischemic Stroke

Abstract

Stroke is one of the major causes of chronic disability worldwide and increasing efforts have focused on studying brain repair and recovery after stroke. Following stroke, the primary injury site can disrupt functional connections in nearby and remotely connected brain regions, resulting in the development of secondary injuries that may impede long-term functional recovery. In particular, secondary degenerative injury occurs in the connected ipsilesional thalamus following a cortical stroke. Although secondary thalamic injury was first described decades ago, the underlying mechanisms still remain unclear. We performed a systematic literature review using the NCBI PubMed database for studies that focused on the secondary thalamic degeneration after cortical ischemic stroke. In this review, we discussed emerging studies that characterized the pathological changes in the secondary degenerative thalamus after stroke; these included excitotoxicity, apoptosis, amyloid beta protein accumulation, blood-brain-barrier breakdown, and inflammatory responses. In particular, we highlighted key findings of the dynamic inflammatory responses in the secondary thalamic injury and discussed the involvement of several cell types in this process. We also discussed studies that investigated the effects of blocking secondary thalamic injury on inflammatory responses and stroke outcome. Targeting secondary injuries after stroke may alleviate network-wide deficits, and ultimately promote stroke recovery.

Keywords: degeneration; inflammatory responses; ischemia; secondary injury; stroke; thalamic injury.

Figure 1

Secondary injury in the connected thalamic nucleus after primary cortical stroke. (A) The schematic diagram illustrates neural circuit connections between cortex and thalamus. Left, intact cortico-thalamic and thalamo-cortical circuit connections under normal condition. Right, primary injury in the cortex disrupts cortico-thalamic and thalamo-cortical circuit connections, resulting in secondary injury in the connected thalamus. (B) Nissl-stained images show a darkly stained region (arrow) in ipsilesional thalamus at 1-month post-stroke. C, contralesional side; I, ipsilesional side. Scale bar = 1 mm. Adapted from Cao et al. (9), under the CC BY license. (C) Left: Enlarged image highlights the degenerative neuronal damage in the ipsilesional thalamus (outlined by a solid line); scale bar = 500 μm. Right: The well-defined boundary between degenerating and healthy neurons in thalamus at 1-month post-stroke. Black arrows indicate normal neurons and red arrows indicate typical injured neurons, scale bar = 50 μm. Adapted from Cao et al. (9), under the CC BY license.

Figure 2

The systematic review progress under Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance.

Figure 3

Inflammatory responses in the secondary thalamic injury after primary cortical stroke. (A) Immunostaining shows neuronal loss and reactive astrocytes clustered in the ipsilesional thalamic area (indicated by arrows) at 1 month post-stroke. Note that sham animals exhibit healthy neurons in the thalamus and reactive astrocytes were not detected. Anti-NeuN stains neurons, anti-GFAP stains astrocytes, and DAPI stains nuclei. Scale bar = 500 μm. CA, cornu ammonis; LV, lateral ventricle. A red square marks the posteromedial complex (PoM) and a white square marks the ventral posteromedial nucleus (VPM) area on thalamus. (B) Enlarged images from PoM and VPM from ipsilesional thalamus. Scale bar = 100 μm. Adapted from Cao et al. (9), under the CC BY license.

Figure 4

Pathological changes in the secondary thalamic injury after primary cortical stroke. Glutamate-related excitotoxicity, increased caspase activation and apoptosis, Tau and Aβ protein accumulation, blood-brain-barrier (BBB) breakdown and activated inflammatory responses occur in the ipsilesional thalamus after cortical ischemia. Resident glia (microglia, astrocytes, and oligodendrocytes) are activated during the development of secondary thalamic injury, with dynamic morphological and molecular changes. Peripheral T cells infiltrate into the ipsilesional thalamus. Created with BioRender (https://biorender.com).