Transcriptional and Anatomical Diversity of Medium Spiny Neurons in the Primate Striatum

He, Jianxing; Kleyman, Michael; Chen, Jianjiao; Alikaya, Aydin; Rothenhoefer, Kathryn M.; Öztürk, Bilge Esin; Wirthlin, Morgan; Fish, Kenneth N.; Byrne, Leah C.; Pfenning, Andreas R.; Stauffer, William R.

doi:10.2139/ssrn.3815985

Cited by 5 publications

(18 citation statements)

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“…In addition to S and M clusters, we identified, within the iSPN/D2 cluster, a distinct yet small subcluster, here provisionally named 'outlier D2' (O-D2), which appeared in all samples across both phenotypes in both murine and human species. The O-D2 cluster is transcriptomically closer to the striosomal identity than to that of the matrix and shares markers with the 'D1/D2 hybrid' recently identified in the non-human primate 20 . On the other hand, O-D2 is likely distinct from 'eccentric SPNs' 19 (Extended Data Fig.…”

Section: Resultsmentioning

confidence: 59%

“…3), which seems a class of striatal interneuron according to our preliminary data (Pineda et al, in preparation). These cell types, identified by ACTIONet [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] , co-clustered perfectly atop each other between controls and the HD samples (magenta and cyan dots, Fig. 1A-C), affirming the consistency of cell-type annotations across phenotypes.…”

Section: Resultsmentioning

confidence: 67%

“…We analyzed snRNA-seq data by using ACTIONet [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] (Extended Data Fig. 1), from striatal samples harvested from human striatum and from R6/2 and zQ175 HD model mice, and originally reported in an initial study without attention to the coordinated compartmental transcriptomics examined here (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We further encountered in our analyses a group of D2-expressing putative iSPNs with an extreme and idiosyncratic transcriptional identity, and we here provisionally refer to them as outlier D2 (O-D2) cells. Their marker genes partially overlap with those of 'D1/D2 hybrid' in primate 20 and 'eccentric SPNs' in mice 19 (Extended Data Fig. 3).…”

Section: Discussionmentioning

confidence: 98%

“…We used the ACTIONet and scran R packages to normalize, batch correct, and cluster single-nucleus gene counts. Batch-corrected data were used as input to the archetypal analysis for cell type identification (ACTION) algorithm [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] to identify a set of landmark cells or 'archetypes', each representing a potential underlying cell state. Using ACTION-decompositions with varying numbers of archetypes, we employed the ACTION-based network (ACTIONet) framework [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] to create a multi-resolution nearest neighbor graph.…”

Section: Methodsmentioning

confidence: 99%

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Huntington’s Disease Produces Multiplexed Transcriptional Vulnerabilities of Striatal D1-D2 and Striosome-Matrix Neurons

Matsushima

Pineda

Crittenden

et al. 2022

Preprint

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Striatal cell-type-specific vulnerability in Huntington’s disease (HD) preferentially affects dopamine D2R-expressing projection neurons (SPNs), compatible with manifest motor symptomatology in HD. Transcriptional studies of striatal striosome-matrix compartmentalization in HD are, however, limited, despite pathologic evidence for striosome vulnerability aligning with early mood symptomatology. We used single-nucleus RNA-sequencing on striatal samples from two murine models, and rare Grade 1 HD patient tissues, to examine striosome and matrix sub-clusters within parent D1 and D2 SPN clusters. In human HD, striosomal SPNs were the most depleted SPN population. Surprisingly, for both mouse models, transcriptomic distinctiveness was diminished more for striosome-matrix SPNs than for D1-D2 SPNs. Compartmental markers were dysregulated so as to cancel endogenous identities as striosomal or matrix SPNs, but markers for D1-D2 exhibited less identity obscuring. The canonical striosome-matrix as well as D1-D2 organizations of the striatum thus are both strongly, but differentially, compromised in HD and are targets for therapeutics.

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Section: Resultsmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Huntington’s Disease Produces Multiplexed Transcriptional Vulnerabilities of Striatal D1-D2 and Striosome-Matrix Neurons

Matsushima

Pineda

Crittenden

et al. 2022

Preprint

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Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease

et al. 2023

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Striatal projection neurons (SPNs), which progressively degenerate in human patients with Huntington’s disease (HD), are classified along two axes: the canonical direct-indirect pathway division and the striosome-matrix compartmentation. It is well established that the indirect-pathway SPNs are susceptible to neurodegeneration and transcriptomic disturbances, but less is known about how the striosome-matrix axis is compromised in HD in relation to the canonical axis. Here we show, using single-nucleus RNA-sequencing data from male Grade 1 HD patient post-mortem brain samples and male zQ175 and R6/2 mouse models, that the two axes are multiplexed and differentially compromised in HD. In human HD, striosomal indirect-pathway SPNs are the most depleted SPN population. In mouse HD models, the transcriptomic distinctiveness of striosome-matrix SPNs is diminished more than that of direct-indirect pathway SPNs. Furthermore, the loss of striosome-matrix distinction is more prominent within indirect-pathway SPNs. These results open the possibility that the canonical direct-indirect pathway and striosome-matrix compartments are differentially compromised in late and early stages of disease progression, respectively, differentially contributing to the symptoms, thus calling for distinct therapeutic strategies.

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Cocaine addiction-like behaviors are associated with long-term changes in gene regulation, energy metabolism, and GABAergic inhibition within the amygdala

Zhou

Guglielmo

et al. 2022

Preprint

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The amygdala contributes to negative emotional states associated with relapse to drug seeking, but the cell type-specific gene regulatory programs that are involved in addiction are unknown. Here we generate an atlas of single nucleus gene expression and chromatin accessibility in the amygdala of outbred rats with low and high cocaine addiction-like behaviors following a prolonged period of abstinence. Between rats with different addiction indexes, there are thousands of cell type-specific differentially expressed genes and these are enriched for molecular pathways including GABAergic synapse in astrocytes, excitatory, and somatostatin neurons. We find that rats with higher addiction severity have excessive GABAergic inhibition in the amygdala, and that hyperpolarizing GABAergic transmission and relapse-like behavior are reversed by pharmacological manipulation of the metabolite methylglyoxal, a GABAA receptor agonist. By analyzing chromatin accessibility, we identify thousands of cell type-specific chromatin sites and transcription factor (TF) motifs where accessibility is associated with addiction-like behaviors, most notably at motifs for pioneer TFs in the FOX, SOX, and helix-loop-helix families.

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Transcriptional and Anatomical Diversity of Medium Spiny Neurons in the Primate Striatum

Cited by 5 publications

References 0 publications

Huntington’s Disease Produces Multiplexed Transcriptional Vulnerabilities of Striatal D1-D2 and Striosome-Matrix Neurons

Huntington’s Disease Produces Multiplexed Transcriptional Vulnerabilities of Striatal D1-D2 and Striosome-Matrix Neurons

Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease

Cocaine addiction-like behaviors are associated with long-term changes in gene regulation, energy metabolism, and GABAergic inhibition within the amygdala

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