Spatially resolved gene regulatory and disease vulnerability map of the adult Macaque cortex

Abstract

Non-human primates (NHP) provide a unique opportunity to study human neurological diseases, yet detailed characterization of the cell types and transcriptional regulatory features in the NHP brain is lacking. We applied a combinatorial indexing assay, sci-ATAC-seq, as well as single-nuclei RNA-seq, to profile chromatin accessibility in 43,793 single cells and transcriptomics in 11,477 cells, respectively, from prefrontal cortex, primary motor cortex and the primary visual cortex of adult cynomolgus monkey Macaca fascularis. Integrative analysis of these two datasets, resolved regulatory elements and transcription factors that specify cell type distinctions, and discovered area-specific diversity in chromatin accessibility and gene expression within excitatory neurons. We also constructed the dynamic landscape of chromatin accessibility and gene expression of oligodendrocyte maturation to characterize adult remyelination. Furthermore, we identified cell type-specific enrichment of differentially spliced gene isoforms and disease-associated single nucleotide polymorphisms. Our datasets permit integrative exploration of complex regulatory dynamics in macaque brain tissue at single-cell resolution.

Decoding frontotemporal and cell type-specific vulnerabilities to neuropsychiatric disorders and psychoactive drugs

“…Activity of vesicular glutamate transporters (VGLUTs), responsible for the uptake of glutamate into the synaptic vesicle 78 , is increased in TL in schizophrenia and bipolar patients after treatment with SSRI 79 . Our identification of PVALB neurons as strongly enriched for genes dysregulated in brain from schizophrenia patients is also in keeping with recent studies in adult Macaque cortex sowing schizophrenia DEGs in excitatory neuron subtypes, where the PVALB-type was the most affected inhibitory subtype 80 .…”

Global Spatial Transcriptome of Macaque Brain at Single-Cell Resolution

“…Brain is a complex organ comprising a large number of diverse cell types (Hodge et al, 2019; Kebschull et al, 2020; Khrameeva et al, 2020; Krienen et al, 2020; Lei et al, 2020; Network et al, 2020; Tasic et al, 2018; Yuste et al, 2020; Zhu et al, 2018), interconnected to form specific neural circuits that are responsible for animal cognition and behavior (Luo, 2020). Species with higher cognitive and social abilities tend to have larger brains and more neurons relative to the body size (Herculano-Houzel, 2016; Sousa et al, 2017).…”

“…Recent advances in single-cell transcriptome analyses have uncovered gene expression profiles of diverse cell types in many brain regions of various species (Bakken et al, 2021; Berg et al, 2021; Khrameeva et al, 2020; Krienen et al, 2020; Lei et al, 2020; Lein et al, 2017; Network, 2021; Yao et al, 2021a; Zhu et al, 2018). Cell types that are unique to mouse and human prefrontal cortex, hippocampus and cerebellum have been found (Aldinger et al, 2021; Berg et al, 2021; Lui et al, 2021; Yao et al, 2021b).…”