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A suite of enhancer AAVs and transgenic mouse lines for genetic access to cortical cell types

Authors
Yoav Ben‐Simon,Marcus Hooper
Sujatha Narayan,Tanya Daigle,Deepanjali Dwivedi,Sharon Way,Aaron Oster,David Stafford,John Mich,Michael Taormina,Refugio Martinez,Ximena Opitz-Araya,John Roth,Shona Allen,Antonio Ayala,Trygve Bakken,Tyler Barcelli,Stuard Barta,Jacqueline Bendrick,Darren Bertagnolli,Jessica Bowlus,Gabriella Boyer,Krissy Brouner,Brittny Casian,Tamara Casper,Anish Chakka,Rushil Chakrabarty,Rebecca Chance,Sakshi Chavan,Max Departee,Nicholas Donadio,Nadia Dotson,Tom Egdorf,Mariano Gabitto,Amanda Gary,Molly Gasperini,Jeff Goldy,Bryan Gore,Lucas Graybuck,Noah Greisman,Françoise Haeseleer,Carliana Halterman,Olivia Helback,Dirk Hockemeyer,Cindy Huang,Sydney Huff,Avery Hunker,Nelson Johansen,Zoe Juneau,Brian Kalmbach,Shannon Khem,Rana Kutsal,Rachael Larsen,Changkyu Lee,Angus Lee,Madison Leibly,Garreck Lenz,Elizabeth Liang,Nicholas Lusk,Jocelin Malone,Tyler Mollenkopf,Elyse Morin,Dakota Newman,Lydia Ng,Kiet Ngo,Victoria Omstead,Akiko Oyama,Trangthanh Pham,Alice Pom,Lydia Potekhina,Shea Ransford,Dean Rette,Christine Rimorin,Dominique Rocha,Augustin Ruiz,Raymond Sánchez,Adriana Sedeño-Cortés,Josh Sevigny,Nadiya Shapovalova,L. Shulga,Ana Sigler,La’Akea Siverts,Saroja Somasundaram,K.J. Stewart,Michael Tieu,Cameron Trader,Cindy Velthoven,Miranda Walker,Natalie Weed,Morgan Wirthlin,T.L. Wood,Brooke Wynalda,Zizhen Yao,Tiantong Zhou,Jeanelle Ariza,Nick Dee,Melissa Reding,Kara Ronellenfitch,Shoaib Mufti,Susan Sunkin,Kimberly Smith,Luke Esposito,Jack Waters,Bargavi Thyagarajan,Shenqin Yao,Boaz Levi,John Ngai,Jonathan Ting,Hongkui Zeng,Ed Lein,Angela Ayala,Nadezhda Dotson,Dana Rocha
+111 authors
,Bosiljka Tasic
Published
Jun 10, 2024
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Abstract

The mammalian cortex is comprised of cells with different morphological, physiological, and molecular properties that can be classified according to shared properties into cell types. Defining the contribution of each cell type to the computational and cognitive processes that are guided by the cortex is essential for understanding its function in health and disease. We use transcriptomic and epigenomic cortical cell type taxonomies from mice and humans to define marker genes and enhancers, and to build genetic tools for cortical cell types. Here, we present a large toolkit for selective targeting of cortical populations, including mouse transgenic lines and recombinant adeno-associated virus (AAV) vectors containing genomic enhancers. We report evaluation of fifteen new transgenic driver lines and over 680 different enhancer AAVs covering all major subclasses of cortical cells, with many achieving a high degree of specificity, comparable with existing transgenic lines. We find that the transgenic lines based on marker genes can provide exceptional specificity and completeness of cell type labeling, but frequently require generation of a triple-transgenic cross for best usability/specificity. On the other hand, enhancer AAVs are easy to screen and use, and can be easily modified to express diverse cargo, such as recombinases. However, their use depends on many factors, such as viral titer and route of administration. The tools reported here as well as the scaled process of tool creation provide an unprecedented resource that should enable diverse experimental strategies towards understanding mammalian cortex and brain function.

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