A Spatiomolecular Map of the Striatum

Abstract

The striatum is organized into two major outputs formed by striatal projection neuron (SPN) subtypes with distinct molecular identities. In addition, the histochemical division into patch and matrix compartments represents an additional spatial organization, proposed to mirror a functional specialization in a motor-motivation dimension. To map the molecular diversity of SPNs in the context of the patch and matrix division, we genetically labeled mu-opioid receptor (Oprm1) expressing striatal neurons and performed single-nucleus RNA sequencing (snRNA-seq). This allowed us to establish new molecular definitions of the patch-matrix compartments, resulting in a molecular code for mapping patch SPNs at the cellular level. In addition, Oprm1 expression labeled exopatch SPNs, which we found to be molecularly distinct from both patch as well as neighboring matrix SPNs, thereby forming a separate molecular entity. At the cell-type level, we found an unexpected SPN diversity, leading to the identification of a new Col11a1+ striatonigral SPN type. At the tissue level, we found that mapping the spatial expression of a number of markers revealed new definitions of spatial domains in the striatum, which were conserved in the non-human primate brain. Interestingly, the spatial markers were cell-type independent and instead represented a spatial code that was found across all SPNs within a spatially restricted domain. This spatiomolecular map establishes a formal system for targeting and studying the striatal subregions and SPNs subtypes, beyond the classical striatonigral and striatopallidal division.

Transcriptional Diversity of Medium Spiny Neurons in the Primate Striatum

“…Finally, it is worth discussing OPRM1, the gene for the µ-opioid receptor. Many studies use OPRM1 as a marker for striosomes (Märtin et al, 2019). Our data revealed that OPRM1 was upregulated in the striosome, as predicted, but the upregulation was not as dramatic as we expected.…”

Lesion of striatal patches disrupts habitual behaviors and increases behavioral variability

“…The Sepw1 NP67 line has been previously used to study patch connectivity [28,54] and activity [45]. Other recent studies have utilized alternative Cre lines to target patches, including Mash1-CreER [44], 599-CreER [63], or Oprm1-Cre [64], though each of these lines also has some off-target labeling of exo-patch or matrix neurons. Thus, while the current work suggests lesions preferentially targeting patches impair aspects of habitual behavior, we cannot rule out the contribution of exo-patch neurons in this process.…”

Transcriptomic analyses reveal prenatal stress promotes late-onset neural stem cell proliferation in adult male offspring

“…4E, Sup.Fig. 5C) [53,54]. Cell cycle position estimation analysis (estimating a continuous cell-cycle pseudotime by principal component analysis of cell-cycle genes) showed that most cells in cluster 3 (NPC), cluster 4 (NB), and some cells in cluster 8 (ElC) were actively dividing cells, while cells of other clusters were predicted to be in the G1-phase (Sup.Fig.…”