Transcriptional and anatomical diversity of medium spiny neurons in the primate striatum

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

doi:10.1016/j.cub.2021.10.015

Cited by 49 publications

(65 citation statements)

References 95 publications

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“…In addition to S and M clusters, we identified, within the 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 31 . On the other hand, O-D2 is likely distinct from ‘eccentric SPNs’ 19 .…”

Section: Resultsmentioning

confidence: 57%

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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Section: Resultsmentioning

confidence: 57%

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

et al. 2023

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“…S1A) ( 31 ). Similarly, a recent study in primate has identified an equivalent D1 archetype in the primate striatum ( 39 ). In situ RNA hybridization revealed that Tac2 -expressing neurons are located in the dorsomedial part of the NAc shell and core (fig.…”

Section: Resultsmentioning

confidence: 77%

“…Our findings significantly contribute to the understanding of the role of NAc in drug addiction and have important clinical implications. First, the Tac2 -expressing D1 MSN subtype represents an evolutionally conservative D1 MSN subtype in both rodent and primate ( 31 , 39 ), and the discovery that Tac2 - expressing NAc D1 MSNs negatively regulate cocaine reward and addiction behaviors is a conceptual advance over the conventional dichotomy model, which suggests that D1 MSNs positively regulate addiction behaviors ( 10 , 40 ). Given that NAc D1 MSNs are highly heterogeneous and can be further classified into multiple molecularly and spatially distinct subtypes ( 29 – 31 ), our results call for functional characterizations of these neuron subtypes to gain more detailed knowledge with regard to the function of the NAc D1 MSNs.…”

Section: Discussionmentioning

confidence: 99%

A molecularly defined D1 medium spiny neuron subtype negatively regulates cocaine addiction

et al. 2022

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The striatum plays a critical role in regulating addiction-related behaviors. The conventional dichotomy model suggests that striatal D1/D2 medium spiny neurons (MSNs) positively/negatively regulate addiction-related behaviors. However, this model does not account for the neuronal heterogeneity and functional diversity of the striatum, and whether MSN subtypes beyond the pan-D1/D2 populations play distinct roles in drug addiction remains unknown. We characterized the role of a tachykinin 2 –expressing D1 MSN subtype ( Tac2 + ), present in both rodent and primate striatum, using cocaine addiction mouse models. We found that acute cocaine administration reduces Tac2 neuronal activity, and cocaine conditioning alters neuronal response related to cocaine reward contextual associations. In addition, activation/inhibition of Tac2 + neurons attenuates/promotes cocaine-induced conditioned place preference and cocaine intravenous self-administration. Furthermore, stimulation of the NAc-to-lateral hypothalamic projection of Tac2 + neurons suppresses cocaine reward behavior. Our study reveals an unconventional negative regulatory function of D1 MSNs in drug addiction that operates in a subtype- and projection-specific manner.

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“…These massive neurochemical inputs from corticostriatal, thalamostriatal, and nigrostriatal projections are largely processed by striatal MSNs, together with the interneurons in a topographically organized manner ( Bariselli et al, 2019 ; Filipovic et al, 2019 ; Chen et al, 2020 ). MSNs use γ-aminobutyric acid (GABA) as a neurotransmitter and constitute 90–95% of the striatal neuronal population ( He et al, 2021 ). Despite high homogeneity, MSNs can be divided into two distinct subpopulations based on their output projection pathways and neurochemical content ( Gerfen et al, 1990 ; Gong et al, 2003 ; He et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…MSNs use γ-aminobutyric acid (GABA) as a neurotransmitter and constitute 90–95% of the striatal neuronal population ( He et al, 2021 ). Despite high homogeneity, MSNs can be divided into two distinct subpopulations based on their output projection pathways and neurochemical content ( Gerfen et al, 1990 ; Gong et al, 2003 ; He et al, 2021 ). Meanwhile, the MSNs are the only striatal neurons with dendritic spines that are highly specialized structures of neuronal connectivity for the regulation of synaptic strength ( Bolam et al, 2000 ; Parisiadou et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Pitx3 deficiency promotes age-dependent alterations in striatal medium spiny neurons

Chen

Yang

Shao

et al. 2022

Front. Aging Neurosci.

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BackgroundThe classical motor symptoms of Parkinson’s disease (PD) are tightly linked to the gradual loss of dopamine within the striatum. Concomitantly, medium spiny neurons (MSNs) also experience morphological changes, such as reduced dendritic complexity and spine density, which may be potentially associated with motor dysfunction as well. Thus, MSNs may serve as the emerging targets for PD therapy besides the midbrain dopaminergic neurons.ResultsTo comprehensively examine pathological alterations of MSNs longitudinally, we established a THCre/Pitx3fl/fl (Pitx3cKO) mouse model that developed canonical PD features, including a significant loss of SNc DAergic neurons and motor deficits. During aging, the targeted neurotransmitter, MSNs morphology and DNA methylation profile were significantly altered upon Pitx3 deficiency. Specifically, dopamine, GABA and glutamate decreased in the model at the early stage. While nuclear, soma and dendritic atrophy, as well as nuclear invaginations increased in the aged MSNs of Pitx3cko mice. Furthermore, more nuclear DNA damages were characterized in MSNs during aging, and Pitx3 deficiency aggravated this phenomenon, together with alterations of DNA methylation profiling associated with lipoprotein and nucleus pathway at the late stage.ConclusionThe early perturbations of the neurotransmitters within MSNs may potentially contribute to the alterations of metabolism, morphology and epigenetics within the striatum at the late stage, which may provide new perspectives on the diagnosis and pathogenesis of PD.

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Transcriptional and anatomical diversity of medium spiny neurons in the primate striatum

Cited by 49 publications

References 95 publications

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

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

A molecularly defined D1 medium spiny neuron subtype negatively regulates cocaine addiction

Pitx3 deficiency promotes age-dependent alterations in striatal medium spiny neurons

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