More than motor impairment: A spatiotemporal analysis of cognitive impairment and associated neuropathological changes following cortical photothrombotic stroke

Abstract

There is emerging evidence suggesting that a cortical stroke can cause delayed and remote hippocampal dysregulation, leading to cognitive impairment. In this study, we aimed to investigate motor and cognitive outcomes after experimental stroke, and their association with secondary neurodegenerative processes. Specifically, we used a photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Motor function was assessed using the cylinder and grid walk tasks. Changes in cognition were assessed using a mouse touchscreen platform. Neuronal loss, gliosis and amyloid-β accumulation were investigated in the peri-infarct and ipsilateral hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed persistent impairment in cognitive function post-stroke, whilst there was a modest spontaneous motor recovery over the investigated period of 84 days. In the peri-infarct region, we detected a reduction in neuronal loss and decreased neuroinflammation over time post-stroke, which potentially explains the spontaneous motor recovery. Conversely, we observed persistent neuronal loss together with concomitant increased neuroinflammation and amyloid-β accumulation in the hippocampus, which likely accounts for the persistent cognitive dysfunction. Our findings indicate that cortical stroke induces secondary neurodegenerative processes in the hippocampus, a region remote from the primary infarct, potentially contributing to the progression of post-stroke cognitive impairment.

Corticosterone Administration Alters White Matter Tract Structure and Reduces Gliosis in the Sub-Acute Phase of Experimental Stroke

“…Wallerian degeneration is characterised by the progressive degeneration of axons, followed by the infiltration of resident macrophages and infiltrating monocytes, which ultimately results in the degradation of myelin and atrophy of the WMTs [4]. The association between stroke and secondary Wallerian degeneration of white matter has been explored in a number of preclinical [2,[5][6][7][8] and clinical studies [9,10]. Neuroimaging studies suggest that these changes are associated with neurological deficits and poorer functional outcomes post-stroke [11][12][13].…”

Spatial Analysis of Neural Cell Proteomic Profiles following Ischemic Stroke in Mice using High-Plex Digital Spatial Profiling

“…However, large upregulation of GFAP within the peri-infarct region by almost 24-fold and confirmed with mean gray value fold change increase at the core border both at bregma +2 and +1 suggests strong reactivity of astrocytes within the border and peri-infarct region three-days after ischemia. GFAP has been shown by multiple studies to be increased specifically within the peri-infarct region beginning as early as 4 hours after ischemia up until 28 days (Kindy et al 1992, Nowicka et al 2008, Sanchez-Bezanilla et al 2021. Reactivity of astrocytes and microglia can lead to secondary tissue damage, progressive cavitation, and scar formation along the peri-infarct border (Fitch et al 1999).…”

“…This is also suggested by the 8-fold upregulation of CD11b and CD39 and a 3-fold upregulation of the CD39 receptor, P2RX7, which are all surface markers on leukocytes. Leukocytes are noted to begin infiltrating into the ischemic region as early as 12 hours after ischemia and persist, with peak levels at 7 days post-ischemia (Nowicka et al 2008, Ito et al 2001, Sanchez-Bezanilla et al 2021. Microglia reactivity post-ischemia is notoriously recognized to have both beneficial and deleterious effects.…”

“…Resident microglia demonstrate reactivity with a change in morphology and infiltration into the core (Nowicka et al 2008, Kawabori and Yenari 2015, Sanchez-Bezanilla et al 2021.…”

“…Astrocytes proliferate and increase expression of inflammatory factors such as glial fibrillary acidic protein (GFAP) which can later lead to astroglia scar formation along the infarct border (Pekny and Nilsson 2005, Nowicka et al 2008, Sanchez-Bezanilla et al 2021). These interactions become even more complex with the understanding that peri-infarct regions in relationship to the core lesion demonstrate distinct mechanisms in a spatial manner.…”