Amyloid-ß disrupts unitary calcium entry through endothelial NMDA receptors in mouse cerebral arteries.

Transient increases in intracellular Ca2+ activate endothelium-dependent vasodilatory pathways. This process is impaired in cerebral amyloid angiopathy, where amyloid-ß(1-40) accumulates around blood vessels. In neurons, amyloid-ß impairs the Ca2+-permeable N-methyl-D-aspartate receptor (NMDAR), a mediator of endothelium-dependent dilation in arteries. We hypothesized that amyloid-ß(1-40) reduces NMDAR-elicited Ca2+ signals in mouse cerebral artery endothelial cells, blunting dilation. Cerebral arteries isolated from 4-5 months-old, male and female cdh5:Gcamp8 mice were used for imaging of unitary Ca2+ influx through NMDAR (NMDAR sparklets) and intracellular Ca2+ transients. The NMDAR agonist NMDA (10 µmol/L) increased frequency of NMDAR sparklets and intracellular Ca2+ transients in endothelial cells; these effects were prevented by NMDAR antagonists D-AP5 and MK-801. Next, we tested if amyloid-ß(1-40) impairs NMDAR-elicited Ca2+ transients. Cerebral arteries incubated with amyloid-ß(1-40) (5 µmol/L) exhibited reduced NMDAR sparklets and intracellular Ca2+ transients. Lastly, we observed that NMDA-induced dilation of pial arteries is reduced by acute intraluminal amyloid-ß(1-40), as well as in a mouse model of Alzheimer's disease, the 5x-FAD, linked to downregulation of Grin1 mRNA compared to wild-type littermates. These data suggest that endothelial NMDAR mediate dilation via Ca2+-dependent pathways, a process disrupted by amyloid-ß(1-40) and impaired in 5x-FAD mice.

Neural Correlates of Morphology Acquisition through a Statistical Learning Paradigm.

The neural basis of statistical learning as it occurs over time was explored with stimuli drawn from a natural language (Russian nouns). The input reflected the "rules" for marking categories of gendered nouns, without making participants explicitly aware of the nature of what they were to learn. Participants were scanned while listening to a series of gender-marked nouns during four sequential scans, and were tested for their learning immediately after each scan. Although participants were not told the nature of the learning task, they exhibited learning after their initial exposure to the stimuli. Independent component analysis of the brain data revealed five task-related sub-networks. Unlike prior statistical learning studies of word segmentation, this morphological learning task robustly activated the inferior frontal gyrus during the learning period. This region was represented in multiple independent components, suggesting it functions as a network hub for this type of learning. Moreover, the results suggest that subnetworks activated by statistical learning are driven by the nature of the input, rather than reflecting a general statistical learning system.

An fMRI study of implicit language learning in developmental language impairment.

Individuals with developmental language impairment can show deficits into adulthood. This suggests that neural networks related to their language do not normalize with time. We examined the ability of 16 adults with and without impaired language to learn individual words in an unfamiliar language. Adults with impaired language were able to segment individual words from running speech, but needed more time to do so than their normal-language peers. ICA analysis of fMRI data indicated that adults with language impairment activate a neural network that is comparable to that of adults with normal language. However, a regional analysis indicated relative hyperactivation of a collection of regions associated with language processing. These results are discussed with reference to the Statistical Learning Framework and the sub-skills thought to relate to word segmentation.

Language lateralization shifts with learning by adults.

For the majority of the population, language is a left-hemisphere lateralized function. During childhood, a pattern of increasing left lateralization for language has been described in brain imaging studies, suggesting that this trait develops. This development could reflect change due to brain maturation or change due to skill acquisition, given that children acquire and refine language skills as they mature. We test the possibility that skill acquisition, independent of age-associated maturation can result in shifts in language lateralization in classic language cortex. We imaged adults exposed to an unfamiliar language during three successive fMRI scans. Participants were then asked to identify specific words embedded in Norwegian sentences. Exposure to these sentences, relative to complex tones, resulted in consistent activation in the left and right superior temporal gyrus. Activation in this region became increasingly left-lateralized with repeated exposure to the unfamiliar language. These results demonstrate that shifts in lateralization can be produced in the short term within a learning context, independent of maturation.