Integrative computational analysis of the substantia nigra pars compacta and the locus coeruleus

The cells of the human brain show levels of functional specialization arguably unparalleled in biology. The recent advent of high-throughput, genome-wide assays to measure expression in individual cells offers an opportunity to characterize cellular variation in the human brain in a comprehensive, unbiased manner, providing a foundation for a brain-wide cell atlas. Crucial to the success of an atlas-scale project, however, is delivering a classification framework that is robust to variation across individuals, age and gender. Developing experimental and analytical tools that parse core, shared molecular signatures from inter-individual variation is therefore critically needed. The first step towards building these important tools is the acquisition and analysis of datasets from tissues known to possess biologically meaningful variation both within the tissue of one human being, and across the same tissue derived from different people. Here, we propose to molecularly profile two regions of the human brain known to display biologically meaningful cellular variation across individuals—the substantia nigra pars compacta (SNc) and the locus coeruleus (LC). These regions are highly susceptible to degeneration and are related to the two most common neurodegenerative diseases, Parkinson’s disease and Alzheimer’s disease. We will use high-throughput single-nucleus profiling of post-mortem human tissue to acquire 75,000 profiles each from SNc and LC, and analyze cellular diversity within and across individuals.

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