Probing cortical and sub-cortical contributions to instruction-based learning: Regional specialisation and global network dynamics.

Diverse cortical networks and striatal brain regions are implicated in instruction-based learning (IBL); however, their distinct contributions remain unclear. We use a modified fMRI paradigm to test two hypotheses regarding the brain mechanisms that underlie IBL. One hypothesis proposes that anterior caudate and frontoparietal regions transiently co-activate when new rules are being bound in working memory. The other proposes that they mediate the application of the rules at different stages of the consolidation process. In accordance with the former hypothesis, we report strong activation peaks within and increased connectivity between anterior caudate and frontoparietal regions when rule-instruction slides are presented. However, similar effects occur throughout a broader set of cortical and sub-cortical regions, indicating a metabolically costly reconfiguration of the global brain state. The distinct functional roles of cingulo-opercular, frontoparietal and default-mode networks are apparent from their activation throughout, early and late in the practice phase respectively. Furthermore, there is tentative evidence of a peak in anterior caudate activity mid-way through the practice stage. These results demonstrate how performance of the same simple task involves a steadily shifting balance of brain systems as learning progresses. They also highlight the importance of distinguishing between regional specialisation and global dynamics when studying the network mechanisms that underlie cognition and learning.

Cerebrovascular pathology during the progression of experimental Alzheimer's disease.

Clinical and experimental evidence point to a possible role of cerebrovascular dysfunction in Alzheimer's disease (AD). The 5xFAD mouse model of AD expresses human amyloid precursor protein and presenilin genes with mutations found in AD patients. It remains unknown whether amyloid deposition driven by these mutations is associated with cerebrovascular changes. 5xFAD and wild type mice (2 to 12months old; M2 to M12) were used. Thinned skull in vivo 2-photon microscopy was used to determine Aß accumulation on leptomeningeal or superficial cortical vessels over time. Parenchymal microvascular damage was assessed using FITC-microangiography. Collagen-IV and CD31 were used to stain basal lamina and endothelial cells. Methoxy-XO4, Thioflavin-S or 6E10 were used to visualize Aß accumulation in living mice or in fixed brain tissues. Positioning of reactive IBA1 microglia and GFAP astrocytes at the vasculature was rendered using confocal microscopy. Platelet-derived growth factor receptor beta (PDGFRß) staining was used to visualize perivascular pericytes. In vivo 2-photon microscopy revealed Methoxy-XO4(+) amyloid perivascular deposits on leptomeningeal and penetrating cortical vessels in 5xFAD mice, typical of cerebral amyloid angiopathy (CAA). Amyloid deposits were visible in vivo at M3 and aggravated over time. Progressive microvascular damage was concomitant to parenchymal Aß plaque accumulation in 5xFAD mice. Microvascular inflammation in 5xFAD mice presented with sporadic FITC-albumin leakages at M4 becoming more prevalent at M9 and M12. 3D colocalization showed inflammatory IBA1(+) microglia proximal to microvascular FITC-albumin leaks. The number of perivascular PDGFRß(+) pericytes was significantly decreased at M4 in the fronto-parietal cortices, with a trend decrease observed in the other structures. At M9-M12, PDGFRß(+) pericytes displayed hypertrophic perivascular ramifications contiguous to reactive microglia. Cerebral amyloid angiopathy and microvascular inflammation occur in 5xFAD mice concomitantly to parenchymal plaque deposition. The prospect of cerebrovascular pharmacology in AD is discussed.