Longitudinal monitoring of mesoscopic cortical activity in a mouse model of microinfarcts reveals dissociations with behavioral and motor function

Abstract

Small vessel disease is characterized by sporadic obstruction of small vessels leading to neuronal cell death. These microinfarcts often escape detection by conventional magnetic resonance imaging and are identified only upon postmortem examination. Our work explores a brain-wide microinfarct model in awake head-fixed mice, where occlusions of small penetrating arterioles are reproduced by endovascular injection of fluorescent microspheres. Mesoscopic functional connectivity was mapped longitudinally in awake GCaMP6 mice using genetically encoded calcium indicators for transcranial wide-field calcium imaging. Microsphere occlusions were quantified and changes in cerebral blood flow were measured with laser speckle imaging. The neurodeficit score in microinfarct mice was significantly higher than in sham, indicating impairment in motor function. The novel object recognition test showed a reduction in the discrimination index in microinfarct mice compared to sham. Graph-theoretic analysis of functional connectivity did not reveal significant differences in functional connectivity between sham and microinfarct mice. While behavioral tasks revealed impairments following microinfarct induction, the absence of measurable functional alterations in cortical activity has a less straightforward interpretation. The behavioral alterations produced by this model are consistent with alterations observed in human patients suffering from microinfarcts and support the validity of microsphere injection as a microinfarct model.

Restoration of motor-evoked cortical activity is a distinguishing feature of the most effective rehabilitation therapy after stroke

“…Indeed, a less segregated activation involving almost the entire lesioned hemisphere is observed. The dissociation between behavioral and mesoscale cortical functionality was previously described by Balbi and colleagues in a recent work (Balbi et al, 2018), where post-stroke behavioral impairment was not associated to alterations in functional connectivity. In our study, a possible explanation for behavioral/cortical activity dissociation might lay in the intervention of the contralesional hemisphere.…”

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“…Using transgenic GCaMP3 mice, they were able to directly observe the ischemic depolarizing wave within 5 min of stroke induction. In another series of experiments, the same group employed a similar approach to study the changes in cortical connectivity using a mouse model of small vessel disease [392]. While behavioral test results confirmed the appearance of significant motor impairments after microinfarct induction, the authors were not able to show any functional changes in neuronal activity, probably due to the insufficient resolution of this method.…”

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“…However, a final proof for a functional connection, shutting-off correlated areas, was missing in this study. Balbi et al [ 19 ] used the same approach in awake GCaMP6 mice studying mososcopic functional connectivity longitudinally in a microinfarct model.…”