Description

Discrete and Continuous Striatal Cell Identity Vectors Revealed by Single Cell RNA-seq

Ozgun Gokce^1,5, Geoff Stanley², Barbara Treutlein^3,6, Norma F. Neff³, Gray J. Camp⁶, Thomas C. Südhof^3,5, Stephen R. Quake^2,3

¹Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich; ²Departments of Bioengineering and of Applied Physics, and ³Howard Hughes Medical Institute; ⁵Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford; ⁶Max Planck Institute for Evolutionary Anthropology, Department of Evolutionary Genetics, Leipzig

The striatum is the focal point of a large number of brain disorders. The major neuronal cell type in the striatum are spiny projection neurons (SPNs), which are classically classified into two subtypes: The ‘Direct-pathway’ neurons, which are supposed to drive action forward (“Go”) and the ‘Indirect-pathway’ neurons that are inhibiting action (“No Go”). However, recent anatomical and functional evidence suggest that this model, while heuristically useful, may need to be modified by incorporating the true phenotypic diversity of striatal SPNs.

For this goal, we have analyzed striatal cells via single cell RNA-seq and observed that up to 30% of SPNs are expressing overlapping D1R and D2R markers. Yet, this population of neurons remain largely ignored, largely due to the lack of a clear genetic definition. Our analyses of SPNs using single cell RNA-seq revealed six discrete subtypes with specific marker genes, which can provide genetic access to these neurons. Moreover, our computational analyses also describe continuous cellular identities within discrete cell subtypes. One of the continua vector within all SPN subtypes shared several genes (particularly Cnr1, Crym, and Wfs1), suggesting a common origin for these vectors. The in situ RNA detection of these vector markers revealed that the expression pattern increases and decreases through dorsal/ventral striatum axis. As a next step, we are addressing how continuous cellular identities are altered through inputs and disorders, in order to identify vectors that relate to the function of a complex tissue.