Harnessing the potential of human stem cells for modelling the physiology and diseases of cortical circuitry requires monitoring cellular dynamics in vivo. Here, we show that human iPSC-derived cortical neurons transplanted in the adult mouse cortex consistently organized in large (up to ~100 mm3) vascularized neuron-glia territories with complex cytoarchitecture. Longitudinal imaging of >4000 grafted developing human neurons revealed that neuronal arbors refined via branch-specific retraction; human synaptic networks substantially restructured over 4 months, with balanced rates of synapse formation and elimination; oscillatory population activity mirrored the patterns of fetal neural networks. Finally, we found increased synaptic stability and reduced oscillations in transplants from two individuals with Down syndrome, demonstrating the potential of in vivo imaging in human tissue grafts for patient-specific modelling of cortical development, physiology and pathogenesis.
We set out to study whether single-subject grey matter (GM) networks show disturbances that are specific for Alzheimer's disease (AD) (n=90) or behavioral variant Frontotemporal dementia (bvFTD) (n=59), and whether such disturbances would be related to cognitive deficits measured with Mini-mental state examination (MMSE) and a neuropsychological battery, using subjective cognitive decline subjects (SCD) as reference. AD and bvFTD patients had a lower degree, connectivity density, clustering, path length, betweenness centrality and small world values compared to SCD. AD patients had a lower connectivity density than bvFTD patients (F = 5.79, p = 0.02; Mean±SD bvFTD 16.10% ± 1.19; Mean±SD AD 15.64% ± 1.02). Lasso logistic regression showed that connectivity differences between bvFTD and AD were specific to 23 anatomical areas, in terms of local GM volume, degree and clustering. Lower clustering values and lower degree values were specifically associated with worse MMSE scores and lower performance on the neuropsychological tests. GM showed disease-specific alterations, when comparing bvFTD with AD patients, and these alterations were associated with cognitive deficits.
The sleep-wake cycle is determined by circadian and sleep homeostatic processes. However, the molecular impact of these processes and their interaction in different brain cell populations remain unknown. To fill this gap, we profiled the single-cell transcriptome of adult Drosophila brains across the sleep-wake cycle and four circadian times. We show cell type-specific transcriptomic changes with glia displaying the largest variation. Glia are also among the few cell types whose gene expression correlates with both sleep homeostat and circadian clock. The sleep-wake cycle and sleep drive level affect expression of clock gene regulators in glia, while diminishing the circadian clock specifically in glia impairs homeostatic sleep rebound after sleep deprivation. These findings reveal a comprehensive view of the effects of sleep homeostatic and circadian processes on distinct cell types in an entire animal brain and reveal glia as an interaction site of these two processes to determine sleep-wake dynamics.
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