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

Lei, Ying; Cheng, Mengnan; Li, Zihao; Zhuang, Zhenkun; Wu, Liang; Han, Lei; Liu, Shang; Huang, Zhi‐Hao; Wei, Jingkuan; Wang, Yuzhou; Wang, Zifei; Xu, Liqin; Pan, Tao; Xie, Junping; Liu, Chuanyu; Volpe, Giacomo; Ward, Carl; Lai, Yiwei; Xu, Jiangshan; Yuan, Yue; Wang, Mingyue; Yu, Hao; Sun, Hai‐Xi; Yu, Qichao; Chen, Dandan; Wang, Chunqing; Wong, Chi Wai; Liu, Wei; Xu, Liangzhi; Shang, Zhouchun; Li, Guibo; Ma, Kun; Cheng, Le; Ling, Fei; Tan, Tao; Chen, Kai; Chen, Ao; Tasic, Bosiljka; Dean, Michael; Ji, Weizhi; Yang, Huanming; Gu, Ying; Esteban, Miguel A.; Xu, Xun; Zeng, Hongkui; Liu, Longqi; Niu, Yuyu; Hou, Yong; Liu, Shiping

doi:10.1101/2020.05.14.087601

Cited by 3 publications

(3 citation statements)

References 122 publications

(176 reference statements)

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“…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 .…”

Section: Discussionsupporting

confidence: 89%

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

Chao

Chen

et al. 2022

Preprint

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Abnormalities in temporal and frontal lobes (TL and FL) have been linked to cognition and neuropsychiatric disorders. While structural and functional differences between the brain lobes have been documented in disease, the cellular heterogeneity in FL and TL and its impact to the vulnerability to genetic risk factors for neuropsychiatric disorders is not well studied. We hypothesize that intrinsic cellular-level differences between TL and FL explain the vulnerability of specific cell types to genetic risk factors and psychoactive drugs. To test this, we integrated single-nucleus transcriptome analysis in fresh human FL and TL with data related to genetic susceptibility and gene dysregulation in neuropsychiatric disease, and response to psychoactive drugs. We also investigate how these differences are associated with gene dysregulation in disease brain. Neuronal cell populations were the most vulnerable to psychiatric genetic risk factors, and more specifically parvalbumin interneurons (PVALB neurons). These PVALB-expressed genetic risk factors were mostly upregulated in the TL compared with FL, and dysregulated in the brain of patients with obsessive-compulsive disorder, bipolar disorder and schizophrenia. We found GRIN2A and HCN1, implicated in schizophrenia by genome-wide association studies, to be significantly upregulated in PVLAB from the TL and in brain cortex from schizophrenia patients. Our analysis provides comprehensive evidence for PVALB neurons as the most vulnerable cell type that is implicated in several psychiatric disorders. PVALB neurons showed the highest vulnerability to psychoactive drug response, which was 3.6-fold higher than the vulnerability to genetic risk factors. In summary, we show high vulnerability of PVALB neurons that is specific to the temporal lobe, implying that differences between TL and FL greatly influence the cell vulnerability to genetic risk factors as well as the response to psychoactive drugs. These findings offer insights into how regional brain differences affect the cell type vulnerabilities in neuropsychiatric disorders.

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Section: Discussionsupporting

confidence: 89%

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

Chao

Chen

et al. 2022

Preprint

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“…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).…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

Global Spatial Transcriptome of Macaque Brain at Single-Cell Resolution

Chen

Sun

Lei

et al. 2022

Preprint

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Global profile of gene expression at single-cell resolution remains to be determined for primates. Using a recently developed technology (“Stereo-seq”), we have obtained a comprehensive single-cell spatial transcriptome map at the whole-brain level for cynomolgus monkeys, with ∼600 genes per cell for 10 μm-thick coronal sections (up to 15 cm2 in size). Large-scale single-nucleus RNA-seq analysis for ∼1 million cells helped to identify cell types corresponding to Stereo-seq gene expression profiles, providing a 3-D cell type atlas of the monkey brain. Quantitative analysis of Stereo-seq data revealed molecular fingerprints that mark distinct neocortical layers and subregions, as well as domains within subcortical structures including hippocampus, thalamus, striatum, cerebellum, hypothalamus and claustrum. Striking whole-brain topography and coordinated patterns were found in the expression of genes encoding receptors and transporters for neurotransmitters and neuromodulators. These results pave the way for cellular and molecular understanding of organizing principles of the primate brain.

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scPair: Boosting single cell multimodal analysis by leveraging implicit feature selection and single cell atlases

Hu,

Quon

2024

Nat Commun

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Multimodal single-cell assays profile multiple sets of features in the same cells and are widely used for identifying and mapping cell states between chromatin and mRNA and linking regulatory elements to target genes. However, the high dimensionality of input features and shallow sequencing depth compared to unimodal assays pose challenges in data analysis. Here we present scPair, a multimodal single-cell data framework that overcomes these challenges by employing an implicit feature selection approach. scPair uses dual encoder-decoder structures trained on paired data to align cell states across modalities and predict features from one modality to another. We demonstrate that scPair outperforms existing methods in accuracy and execution time, and facilitates downstream tasks such as trajectory inference. We further show scPair can augment smaller multimodal datasets with larger unimodal atlases to increase statistical power to identify groups of transcription factors active during different stages of neural differentiation.

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

Cited by 3 publications

References 122 publications

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

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

Global Spatial Transcriptome of Macaque Brain at Single-Cell Resolution

scPair: Boosting single cell multimodal analysis by leveraging implicit feature selection and single cell atlases

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