Assistant Scientist, Vollum Institute
Arpiar “Arpy” Saunders earned his B.A. in Biology and Linguistics from Swarthmore College in 2006. He researched wild-flower genomes at the University of Montana before moving to Harvard Medical School for doctoral and postdoctoral training. At Harvard, Saunders earned his Ph.D. in Neuroscience in the lab of Bernardo Sabatini, studying the synaptic organization of the mouse brain. As a Helen Hay Whitney Fellow in Steve McCarroll’s lab, he used single-cell genomics to describe molecular diversity of brain cells. Saunders joined the Vollum Institute as an assistant scientist in 2020.
Summary of current research
Brain function is enabled by selective and proportional synapses among neurons of specific molecular types. Human genetic data implicate synaptic function genes in psychiatric disorders, yet the principles and molecules that underlie development, maintenance and disease-induced changes in connectivity across diverse cellular populations — and the sensitivity of these synaptic relationships to genetic variation and illness — are largely unknown. Systematically addressing how thousands of genes may affect synaptic wiring of thousands of cell populations remains a daunting yet foundational challenge for neuroscience.
To address these fundamental questions in the cellular and synaptic organization of neural circuits, we develop and apply single-cell, single-virion genomic technologies. For example, we have recently developed a technique in which synaptic connectivity relationships are reconstructed from single-cell RNA-seq analyses in ways that are quantitative and connected to detailed molecular profiles of many thousands of individual cells. Synaptic inferences are made by tracking dendrite-to-axon infectivity paths of viral clones originating from single infections of single cells; clones are identified through expressed RNA “barcodes” engineered into each viral genome. We analyze these “big data” sets to build inductive hypotheses for how genomic regulation shapes synaptic function and cell-type-specific wiring. We then test our hypotheses using genetic manipulations coupled with imaging and electrophysiology.
In addition, the Saunders lab is particularly interested in interactions between neurotropic viruses and their host brain cells. Neurotropic viruses are widely used in Neuroscience research; yet while we rely on viral behaviors within and amongst host cells to teach us about the structures of neural circuits, the nature and impact of these interactions, especially in complex tissue, is largely unknown. To systematically quantify these interactions and determine how they are shaped by host cell type and genetic variation (of both host and virus), we use single-cell, single-virion genomic approaches to track molecules from nuclear and viral genomes across many individual cells in parallel.
Selected preprints and publications
♦ Preprint article
♦ Saunders A, Huang KW, Vondrak C, Hughes C, Smolyar K, Sen H, Philson AC, Nemesh J, Wysoker A, Kashin S, Sabatini BL, McCarroll SA. (2021) Ascertaining cells’ synaptic connections and RNA expression simultaneously with massively barcoded rabies virus libraries. bioRxiv Sep 6 https://doi.org/10.1101/2021.09.06.459177
Krienen FM, Goldman M, Zhang Q, del Rosario RCH, Florio M, Machold R, Saunders A, […] McCarroll SA. (2020) Innovations present in the primate interneuron repertoire. Nature 586(7828):262-269.
Saunders A*, Macosko E*, Wysoker A, Goldman M, Krienen FM, de Rivera H, Bien E, Baum M, Bortolin L, Wang S, Goeva A, Nemesh J, Kamitaki N, Brumbaugh S, Kulp D, McCarroll SA. (2018) Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174(4):1015-1030. *contributed equally to this work
Saunders A, Oldenburg IA, Berezovskii VK, Johnson CA, Kingery ND, Elliott HL, Xie T, Gerfen CR, Sabatini BL. (2015) A direct GABAergic output from the basal ganglia to frontal cortex. Nature 521(7550):85-89.
Saunders A*, Granger AJ*, Sabatini BL. (2015) Corelease of acetylcholine and GABA from cholinergic forebrain neurons. eLife 4:e06412. *contributed equally to this work
Saunders A, Johnson CA, Sabatini BL. (2012) Novel recombinant adeno-associated viruses for Cre activated and inactivated transgene expression in neurons. Front. Neural Circuits 6:47.
Kozorovitskiy Y*, Saunders A*, Johnson CA, Lowell BB, Sabatini BL. (2012) Recurrent network activity drives striatal synaptogenesis. Nature 485(7400):646-650. *contributed equally to this work
Fishman L, Saunders A. (2008) Centromere-associated female meiotic drive entails male fitness costs in monkeyflowers. Science 322(5907):1559-1562.