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

Author:

Ben-Simon YoavORCID,Hooper MarcusORCID,Narayan SujathaORCID,Daigle TanyaORCID,Dwivedi DeepanjaliORCID,Way Sharon W.ORCID,Oster AaronORCID,Stafford David A.,Mich John K.ORCID,Taormina Michael J.ORCID,Martinez Refugio A.ORCID,Opitz-Araya XimenaORCID,Roth Jada R.ORCID,Allen ShonaORCID,Ayala AngelaORCID,Bakken Trygve E.ORCID,Barcelli TylerORCID,Barta StuardORCID,Bendrick JacquelineORCID,Bertagnolli DarrenORCID,Bowlus JessicaORCID,Boyer GabriellaORCID,Brouner KrissyORCID,Casian BrittnyORCID,Casper TamaraORCID,Chakka Anish B.ORCID,Chakrabarty RushilORCID,Chance Rebecca K.ORCID,Chavan SakshiORCID,Departee MaxwellORCID,Donadio NicholasORCID,Dotson NadezhdaORCID,Egdorf TomORCID,Gabitto MarianoORCID,Gary AmandaORCID,Gasperini MollyORCID,Goldy JeffORCID,Gore Bryan B.ORCID,Graybuck LucasORCID,Greisman NoahORCID,Haeseleer FrancoiseORCID,Halterman CarlianaORCID,Helback OliviaORCID,Hockemeyer DirkORCID,Huang CindyORCID,Huff SydneyORCID,Hunker AveryORCID,Johansen NelsonORCID,Juneau ZoeORCID,Kalmbach BrianORCID,Khem ShannonORCID,Kutsal RanaORCID,Larsen RachaelORCID,Lee ChangkyuORCID,Lee Angus Y.,Leibly MadisonORCID,Lenz Garreck H.ORCID,Liang ElizabethORCID,Lusk NicholasORCID,Malone JocelinORCID,Mollenkopf TylerORCID,Morin ElyseORCID,Newman DakotaORCID,Ng LydiaORCID,Ngo KietORCID,Omstead VictoriaORCID,Oyama AlanaORCID,Pham TrangthanhORCID,Pom Christina A.ORCID,Potekhina LydiaORCID,Ransford SheaORCID,Rette DeanORCID,Rimorin ChristineORCID,Rocha DanaORCID,Ruiz AugustinORCID,Sanchez Raymond E.A.ORCID,Sedeno-Cortes AdrianaORCID,Sevigny Joshua P.ORCID,Shapovalova NadiyaORCID,Shulga LyudmilaORCID,Sigler Ana R.ORCID,Siverts La’ AkeaORCID,Somasundaram SarojaORCID,Stewart KaiyaORCID,Tieu MichaelORCID,Trader CameronORCID,van Velthoven Cindy T.J.ORCID,Walker MirandaORCID,Weed NatalieORCID,Wirthlin MorganORCID,Wood TorenORCID,Wynalda BrookeORCID,Yao ZizhenORCID,Zhou ThomasORCID,Ariza JeanelleORCID,Dee NickORCID,Reding MelissaORCID,Ronellenfitch KaraORCID,Mufti ShoaibORCID,Sunkin Susan M.ORCID,Smith Kimberly A.ORCID,Esposito LukeORCID,Waters JackORCID,Thyagarajan BargaviORCID,Yao ShenqinORCID,Lein Ed S.ORCID,Zeng HongkuiORCID,Levi Boaz P.ORCID,Ngai JohnORCID,Ting JonathanORCID,Tasic BosiljkaORCID

Abstract

AbstractThe 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.

Publisher

Cold Spring Harbor Laboratory

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