Decoding molecular and cellular heterogeneity of mouse nucleus accumbens

Chen, Renchao; Blosser, Timothy R.; Djekidel, Mohamed Nadhir; Hao, Junjie; Bhattacherjee, Aritra; Chen, Wenqiang; Tuesta, Luis M.; Zhuang, Xiaowei; Zhang, Yi

doi:10.1038/s41593-021-00938-x

Cited by 103 publications

(124 citation statements)

References 73 publications

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“…5c, Fig. 2d, slices 8-11, 2-3), consistent with the spatial distribution of the atypical D1 MSNs defined by a previous MERFISH study 12 . Interestingly, we identified a core-shell-like structure in the retrosplenial cortex (RSP), presubiculum (PRE), and postsubiculum (POST), where layer 2 (region L2/3_E, marked by Tshz2 + Dkk3 + TEGLU_10) is surrounded by layers 1 and 3 (region L2/3_D, marked by Tshz2 + Cbln1 + TEGLU_35 or Tshz2 + Rxfp1 + TEGLU_30) (Fig.…”

Section: Molecularly Defined Tissue Regions In the Mouse Cnssupporting

confidence: 89%

Spatial Atlas of the Mouse Central Nervous System at Molecular Resolution

Shi

Zhou

et al. 2022

Preprint

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Spatially charting molecular cell types at single-cell resolution across the three-dimensional (3D) volume of the brain is critical for illustrating the molecular basis of the brain anatomy and functions. Single-cell RNA sequencing (scRNA-seq) has profiled molecular cell types in the mouse brain, but cannot capture their spatial organization. Here, we employed an in situ sequencing technique, STARmap PLUS, to map more than one million high-quality cells across the whole adult mouse brain and the spinal cord, profiling 1,022 genes at subcellular resolution with a voxel size of 194 X 194 X 345 nm in 3D. We developed computational pipelines to segment, cluster, and annotate molecularly defined cell types and tissue regions with single-cell resolution. To create a transcriptome-wide spatial atlas, we further integrated the STARmap PLUS measurements with a published scRNA-seq atlas, imputing 11,844 genes at the single-cell level. Finally, we engineered a highly expressed RNA barcoding system to delineate the tropism of a brain-wide transgene delivery tool, AAV-PHP.eB, revealing its single-cell resolved transduction efficiency across the molecular cell types and tissue regions of the whole mouse brain. Together, our datasets and annotations provide a comprehensive, high-resolution single-cell resource that integrates spatial molecular atlas, cell taxonomy, brain anatomy, and genetic manipulation accessibility of the mammalian central nervous system (CNS).

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Section: Molecularly Defined Tissue Regions In the Mouse Cnssupporting

confidence: 89%

Spatial Atlas of the Mouse Central Nervous System at Molecular Resolution

Shi

Zhou

et al. 2022

Preprint

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“… 72 , 73 In dLGE, the majority of cells were the TSHZ1 + striatonigral (D1) MSNs. In vLGE, there were two types of interneurons, with striatonigral (D1) MSNs expressing PDYN and striatopallidal (D2) MSNs expressing PENK 74 – 76 (Fig. 4b ).…”

Section: Resultsmentioning

confidence: 99%

Evolutionarily conservative and non-conservative regulatory networks during primate interneuron development revealed by single-cell RNA and ATAC sequencing

et al. 2022

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The differences in size and function between primate and rodent brains, and the association of disturbed excitatory/inhibitory balance with many neurodevelopmental disorders highlight the importance to study primate ganglionic eminences (GEs) development. Here we used single-cell RNA and ATAC sequencing to characterize the emergence of cell diversity in monkey and human GEs where most striatal and cortical interneurons are generated. We identified regional and temporal diversity among progenitor cells which give rise to a variety of interneurons. These cells are specified within the primate GEs by well conserved gene regulatory networks, similar to those identified in mice. However, we detected, in human, several novel regulatory pathways or factors involved in the specification and migration of interneurons. Importantly, comparison of progenitors between our human and published mouse GE datasets led to the discovery and confirmation of outer radial glial cells in GEs in human cortex. Our findings reveal both evolutionarily conservative and nonconservative regulatory networks in primate GEs, which may contribute to their larger brain sizes and more complex neural networks compared with mouse.

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“…Recent single-cell transcriptome profiling has uncovered the neuronal heterogeneity beyond the conventional D1/D2 MSN in striatum, which may underlie the structural/functional complexity of this brain region ( 25 ). To determine whether Setd1a heterozygosity causes uniform or neuron subtype–specific transcriptional changes on the striatal MSN subtypes, we classified the original D1 and D2 MSN populations into five D1 and six D2 subtypes based on their gene expression profiles ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Cell type–specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis

et al. 2022

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Schizophrenia (SCZ) is a chronic, serious mental disorder. Although more than 200 SCZ-associated genes have been identified, the underlying molecular and cellular mechanisms remain largely unknown. Here, we generated a Setd1a (SET domain containing 1A) haploinsufficiency mouse model to understand how this SCZ-associated epigenetic factor affects gene expression in brain regions highly relevant to SCZ. Single-cell RNA sequencing revealed that Setd1a heterozygosity causes highly variable transcriptional adaptations across different cell types in prefrontal cortex (PFC) and striatum. The Foxp2 + neurons exhibit the most prominent gene expression changes among the different neuron subtypes in PFC, which correlate with changes in histone H3 lysine 4 trimethylation. Many of the genes dysregulated in Setd1a +/− mice are involved in neuron morphogenesis and synaptic function. Consistently, Setd1a +/− mice exhibit certain behavioral features of patients with SCZ. Collectively, our study establishes Setd1a +/− mice as a model for understanding SCZ and uncovers a complex brain region– and cell type–specific dysregulation that potentially underlies SCZ pathogenesis.

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Decoding molecular and cellular heterogeneity of mouse nucleus accumbens

Cited by 103 publications

References 73 publications

Spatial Atlas of the Mouse Central Nervous System at Molecular Resolution

Spatial Atlas of the Mouse Central Nervous System at Molecular Resolution

Evolutionarily conservative and non-conservative regulatory networks during primate interneuron development revealed by single-cell RNA and ATAC sequencing

Cell type–specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis

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