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Functional Ultrasound (fUS) imaging of brain hemodynamics in a rat middle-cerebral artery occlusion (MCAo) model of selective neuronal loss (SNL) mimicking transient ischemic attack (TIA)
Clément BRUNNER1,*, Clothilde ISABEL1,*, Abraham MARTIN2, Clara DUSSAUX1, Anne SAVOYE1, Gabriel MONTALDO1, Jean-Claude BARON1,+ and Alan URBAN1,+
1 Centre de Psychiatrie et Neurosciences, INSERM U894, Hôpital Sainte-Anne, Optogenetics and Brain Imaging, Stroke Research Team, Paris, 75014, France.
2 Molecular Imaging Unit, CICbiomaGUNE, Paseo Miramon 182, San Sebastian, Spain.
Objectives: SNL is a known outcome of brief MCAo in rodents, affecting mainly the striatum or cortex with proximal and distal MCAo, respectively . SNL is important as it might also occur after TIAs, potentially impacting the cognitive and plastic ‘reserve’. However, both the behavioral and tissue perfusion changes underlying to SNL are scarcely understood so far. For this reason, we used fUS, a new imaging for chronic whole-brain mapping of cerebral blood volume with high spatiotemporal resolution (CBV).
Methods: Eight adult Sprague-Dawley rats were subjected to 45 minutes MCAo with reperfusion under 1.5% isoflurane and 100% oxygen. Four sham rats were used as controls. fUS data were acquired through previously thinned skull serially before, during and at 3 and 6 days after reperfusion. Ipsilateral/contralateral CBV ratios (CBVr) were computed for a template of atlas-based cytoarchitectonic ROIs modified from . The Neuroscore and subtle sensorimotor functions (modified Sticky Label test and Beam Walking test) were assessed before and serially after tMCAo. Brains were collected at day 21 for immunofluorescence (IF) using NeuN, Iba1 and GFAP.
Results: We observed a marked (>50%) reduction in CBVr in the MCA territory during occlusion in 7/8 rats (one rat with no CBVr decrease was excluded from further analysis). Maximal CBVr reduction affected the somatosensory cortex (79±13% relative to baseline; p<0.0001). At 15 minutes after reperfusion, CBVr returned to near-baseline and followed , then to normal thereafter (p<0.05,). No statistical significant behavioral effects emerged across the group at any time point. No changes in CBVr or behavior were present in sham rats. There was marked striatal SNL (associated with moderate microglial activation and marked astrocytosis) in 6/8 MCAo rats vs 0/4 sham (p<0.05), whereas mild cortical SNL was found in 4/8 MCAo rats vs 1/4 sham (NS). There was no correlation among CBV, behavioral scores and IF lesion volumes in cortical areas.
Conclusions: This study shows the feasibility of fUS to serially map CBV during and days following MCAo. Little cortical SNL occurred despite marked initial rCBV reductions, however, mostly striatal SNL no behavioral effects, as also reported for infarcts ; and iv) SNL is a frequent sequelae of brief MCAo in rodents that likely also occurs after TIAs, with potential clinical and therapeutic relevance. J.C. Baron et al, JCBFM, 34 (2014) 2-18.  A. Urban et al, Neuroimage, 101 (2014) 138-49.  J.L. Hughes et al, Neuroimage, 49 (2010) 19-31.  Ejaz S. et al, Stroke (in press)  S. Wegener et al, J Magn Reson Imaging, 21 (2005) 340-6.