Community effort to unravel the complex human neuronal landscape exemplified for the striatum

Precise determination of cellular identity and molecular phenotypes through advanced high-throughput technologies is crucial for understanding intricate tissue functions, especially in complex organs like the brain. Given the complexity of the brain, community efforts are needed but currently underexploited to unravel the function of the human brain. In this study, we present findings from a multi-center investigation performed as a community effort involving seven genome centers. We analyzed single-nucleus transcriptomes obtained from NeuN+ neurons from the putamen and caudate nucleus of both healthy individuals and Parkinson's Disease (PD) patients. Our results demonstrate the potential for establishing community-wide standards, fostering collaborative networks, and enhancing brain cell classification efforts. We propose a transcriptional architecture that encodes synaptic communication patterns in the striatum, comprising of cell-adhesion molecules (CAMs), transmitter/modulator receptors, ion channels, signaling proteins, neuropeptides, vesicular release components, and transcription factors. This classification serves as a foundation for mapping and integrating publicly available datasets, showcasing the value of deep sampling in defined brain regions for comprehensive brain-wide analyses. Importantly, this nomenclature can serve as a template for other brain regions. This community effort enabled the precise mapping of cellular alterations in Parkinson's Disease. Transcriptional changes predominantly occurred in specific cell states of medium spiny neurons within the putamen matrix, pointing towards increased excitability. Additionally, a disbalance in specific interneuron cell states was associated with heightened glutamatergic signaling, further contributing to increased overall excitability.