Dr. Ben Anthony A. Lopez
University of the Philippines Manila

Pre-clinical animal models are poor predictors of human drug response, which contributes to the high failure rate in neurological drug development. In neuropsychopharmacology, over 90% of neurological drug candidates with promising animal data fail in human clinical trials1. Evolutionary divergence occurs at multiple levels in the brain including different gross architecture and circuitry, variable sizes of cell populations, different cell types, and altered molecular properties of homologous cell types2,3, thereby constraining utility of animal models. Identification of the similarity and divergence at cellular and molecular levels across animal models and the human brain will provide better guidance in translational research in the study of human disorders, such as neurodegenerative diseases, schizophrenia, and drug addiction.

This study focuses on the striatum, which is a major input nucleus in the basal ganglia, a key set of networked nuclei region involved in motor control, motor learning, cognition, and emotional processing. Predominant neurons in the striatum are the medium spiny neurons, which canonically comprise D1 and D2 neurons, named after their dopamine receptor expression and which correspond with the extrinsic circuits, the direct striatonigral and the indirect striatopallidal pathways. There are also molecularly and electrophysiologically diverse locally projecting interneurons which provide critical modulation of striatal circuits. Recent single-cell/nucleus RNA sequencing technology has uncovered greater neuronal heterogeneity than previously suggested in the mammalian striata4-6. However, the extent of conservation and divergence of the striatum at the cellular and molecular levels across human, monkey, and mice remain poorly characterized. 

The study aims to understand the translatability of monkeys and mice to human neurobiology and disease by comparing striatal neuronal populations.

Single-cell/nucleus transcriptomes of mouse, rhesus macaque, and human striatal neurons were compared to dissect the cellular and molecular conservation and divergence. In situ spatial transcriptomics was employed in the human putamen, describing the regional localization and clustering of the neuronal populations.

Multiple classical medium spiny neuron (MSN) subpopulations were highly conserved across the three species but differed in some genes that have crucial therapeutic importance. There was differential conservation of non-canonical MSNs and interneurons at the cellular, molecular, and transcriptional regulatory network levels, with some populations shared across all three species, whereas others being distinctly different. Molecular distinction between the matrix and patch compartments in the striatum were largely conserved between primates but substantively diverged from the mouse. Spatial transcriptomics revealed distinct spatial distribution of the MSNs and interneurons within the human putamen.A

Using high-resolution gene expression profiling, the study profiled the neuronal heterogeneity as well as described novel neuronal subpopulations in the human putamen. Furthermore, employing massively multiplexed, error-robust, single-cell in situ transcriptomics imaging (MERSCOPE), this study was able to describe distinct distributions of the neuronal subpopulations, with compartmentalization of MSN and certain interneuron subpopulations in assemblages.