title: Targeting cells with single vectors using multiple-feature Boolean logic.
abstract: Precisely defining the roles of specific cell types is an intriguing frontier in the study of intact biological systems and has stimulated the rapid development of genetically encoded tools for observation and control. However, targeting these tools with adequate specificity remains challenging: most cell types are best defined by the intersection of two or more features such as active promoter elements, location and connectivity. Here we have combined engineered introns with specific recombinases to achieve expression of genetically encoded tools that is conditional upon multiple cell-type features, using Boolean logical operations all governed by a single versatile vector. We used this approach to target intersectionally specified populations of inhibitory interneurons in mammalian hippocampus and neurons of the ventral tegmental area defined by both genetic and wiring properties. This flexible and modular approach may expand the application of genetically encoded interventional and observational tools for intact-systems biology.
authors.affiliation: 1] Department of Neuroscience, Stanford University, Stanford, California, USA. [2] Department of Bioengineering, Stanford University, Stanford, California, USA. [3].
authors.forename: Lief E
authors.initials: LE
authors.lastname: Fenno
authors.affiliation: 1] Department of Neuroscience, Stanford University, Stanford, California, USA. [2] Department of Bioengineering, Stanford University, Stanford, California, USA. [3].
authors.forename: Joanna
authors.initials: J
authors.lastname: Mattis
authors.affiliation: 1] Department of Bioengineering, Stanford University, Stanford, California, USA. [2].
authors.forename: Charu
authors.initials: C
authors.lastname: Ramakrishnan
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California, USA.
authors.forename: Minsuk
authors.initials: M
authors.lastname: Hyun
authors.affiliation: 1] Department of Bioengineering, Stanford University, Stanford, California, USA. [2] CNC Program, Stanford University, Stanford, California, USA.
authors.forename: Soo Yeun
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.affiliation: 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. [2] Program in Neuroscience, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Tucciarone
authors.affiliation: Department of Neuroscience, Stanford University, Stanford, California, USA.
authors.forename: Aslihan
authors.initials: A
authors.lastname: Selimbeyoglu
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, California, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Berndt
authors.affiliation: 1] Department of Neuroscience, Stanford University, Stanford, California, USA. [2] Department of Bioengineering, Stanford University, Stanford, California, USA. [3] CNC Program, Stanford University, Stanford, California, USA.
authors.forename: Logan
authors.initials: L
authors.lastname: Grosenick
authors.affiliation: 1] Department of Neuroscience, Stanford University, Stanford, California, USA. [2] CNC Program, Stanford University, Stanford, California, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Zalocusky
authors.affiliation: Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Bernstein
authors.affiliation: CNC Program, Stanford University, Stanford, California, USA.
authors.forename: Haley
authors.initials: H
authors.lastname: Swanson
authors.affiliation: CNC Program, Stanford University, Stanford, California, USA.
authors.forename: Chelsey
authors.initials: C
authors.lastname: Perry
authors.affiliation: 1] Department of Bioengineering, Stanford University, Stanford, California, USA. [2] Ernst Struengmann Institute for Neuroscience, Frankfurt, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Diester
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Cambridge, Massachusetts, USA.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Boyce
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Bass
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Neve
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
authors.forename: Z Josh
authors.initials: ZJ
authors.lastname: Huang
authors.affiliation: 1] Department of Bioengineering, Stanford University, Stanford, California, USA. [2] CNC Program, Stanford University, Stanford, California, USA. [3] Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA. [4] Howard Hughes Medical Institute, Stanford University, Stanford, California, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D000229:Dependovirus / Q000235:genetics; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D005822:Genetic Vectors; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D019426:Integrases / Q000378:metabolism; D007395:Interneurons / Q000502:physiology*; D007438:Introns; D008128:Logic; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D019076:Transgenes
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria; C045073:Cre recombinase; D019426:Integrases