A suite of transgenic driver and reporter mouse lines with enhanced brain cell type targeting and functionality

Modern genetic approaches are powerful in providing access to diverse types of neurons within the mammalian brain and greatly facilitating the study of their function. We here report a large set of driver and reporter transgenic mouse lines, including 23 new driver lines targeting a variety of cortical and subcortical cell populations and 26 new reporter lines expressing an array of molecular tools. In particular, we describe the TIGRE2.0 transgenic platform and introduce Cre-dependent reporter lines that enable optical physiology, optogenetics, and sparse labeling of genetically-defined cell populations. TIGRE2.0 reporters broke the barrier in transgene expression level of single-copy targeted-insertion transgenesis in a wide range of neuronal types, along with additional advantage of a simplified breeding strategy compared to our first-generation TIGRE lines. These novel transgenic lines greatly expand the repertoire of high-precision genetic tools available to effectively identify, monitor, and manipulate distinct cell types in the mouse brain.

[1]  Nathan C. Klapoetke,et al.  Transgenic Mice for Intersectional Targeting of Neural Sensors and Effectors with High Specificity and Performance , 2015, Neuron.

[2]  Jason Tucciarone,et al.  Strategies and Tools for Combinatorial Targeting of GABAergic Neurons in Mouse Cerebral Cortex , 2016, Neuron.

[3]  L. Luo,et al.  A global double‐fluorescent Cre reporter mouse , 2007, Genesis.

[4]  Ian Nauhaus,et al.  Topography and Areal Organization of Mouse Visual Cortex , 2014, The Journal of Neuroscience.

[5]  James S Trimmer,et al.  A Novel Targeting Signal for Proximal Clustering of the Kv2.1 K+ Channel in Hippocampal Neurons , 2000, Neuron.

[6]  Stefan R. Pulver,et al.  Ultra-sensitive fluorescent proteins for imaging neuronal activity , 2013, Nature.

[7]  S. Nelson,et al.  A Resource of Cre Driver Lines for Genetic Targeting of GABAergic Neurons in Cerebral Cortex , 2011, Neuron.

[8]  R. Reid,et al.  Broadly Tuned Response Properties of Diverse Inhibitory Neuron Subtypes in Mouse Visual Cortex , 2010, Neuron.

[9]  Allan R. Jones,et al.  A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing , 2012, Nature Neuroscience.

[10]  Michael Z. Lin,et al.  Fast two-photon imaging of subcellular voltage dynamics in neuronal tissue with genetically encoded indicators , 2017, eLife.

[11]  Andrew C. N. Chen,et al.  Intact skull chronic windows for mesoscopic wide-field imaging in awake mice , 2016, Journal of Neuroscience Methods.

[12]  Hongkui Zeng,et al.  A Cre-Dependent GCaMP3 Reporter Mouse for Neuronal Imaging In Vivo , 2012, The Journal of Neuroscience.

[13]  Elina A K Jacobs,et al.  Aberrant Cortical Activity in Multiple GCaMP6-Expressing Transgenic Mouse Lines , 2017, eNeuro.

[14]  Yang Li,et al.  An extended retinotopic map of mouse cortex , 2017, eLife.

[15]  E. P. Gardner,et al.  Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex , 2008, Nature Reviews Neuroscience.

[16]  Oscar Marín,et al.  Interneuron dysfunction in psychiatric disorders , 2012, Nature Reviews Neuroscience.

[17]  Russell S. Ray,et al.  Mapping cell fate and function using recombinase-based intersectional strategies. , 2010, Methods in enzymology.

[18]  Allan R. Jones,et al.  A robust and high-throughput Cre reporting and characterization system for the whole mouse brain , 2009, Nature Neuroscience.

[19]  P. Somogyi,et al.  Defined types of cortical interneurone structure space and spike timing in the hippocampus , 2005, The Journal of physiology.

[20]  R. Masland.  Neuronal cell types , 2004, Current Biology.

[21]  D. Kleinfeld,et al.  ReaChR: A red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation , 2013, Nature Neuroscience.

[22]  Kevin T. Beier,et al.  Neuroanatomy goes viral! , 2015, Front. Neuroanat..

[23]  K. Svoboda,et al.  Genetic Dissection of Neural Circuits , 2008, Neuron.

[24]  E. Bamberg,et al.  Ultra light-sensitive and fast neuronal activation with the Ca2+-permeable channelrhodopsin CatCh , 2011, Nature Neuroscience.

[25]  G. Feng,et al.  Acute brain slice methods for adult and aging animals: application of targeted patch clamp analysis and optogenetics. , 2014, Methods in molecular biology.

[26]  Ian R. Wickersham,et al.  The BRAIN Initiative Cell Census Consortium: Lessons Learned toward Generating a Comprehensive Brain Cell Atlas , 2017, Neuron.

[27]  Simon Pieraut,et al.  Inducible control of gene expression with destabilized Cre , 2013, Nature Methods.

[28]  Hongkui Zeng,et al.  Neocortical Chandelier Cells Developmentally Shape Axonal Arbors through Reorganization but Establish Subcellular Synapse Specificity without Refinement , 2017, eNeuro.

[29]  Stefan R. Pulver,et al.  Independent Optical Excitation of Distinct Neural Populations , 2014, Nature Methods.

[30]  Li I. Zhang,et al.  Visual Representations by Cortical Somatostatin Inhibitory Neurons—Selective But with Weak and Delayed Responses , 2010, The Journal of Neuroscience.

[31]  Zhuo-Hua Pan,et al.  rAAV-Mediated Subcellular Targeting of Optogenetic Tools in Retinal Ganglion Cells In Vivo , 2013, PloS one.

[32]  Hongkui Zeng,et al.  Genetic approaches to neural circuits in the mouse. , 2013, Annual review of neuroscience.

[33]  Hongkui Zeng,et al.  Neuronal cell-type classification: challenges, opportunities and the path forward , 2017, Nature Reviews Neuroscience.

[34]  Christopher A Baker,et al.  Cellular resolution circuit mapping with temporal-focused excitation of soma-targeted channelrhodopsin , 2016, eLife.

[35]  Kristina D. Micheva,et al.  Visualizing the Distribution of Synapses from Individual Neurons in the Mouse Brain , 2010, PloS one.

[36]  Hongkui Zeng,et al.  An R-CaMP1.07 reporter mouse for cell-type-specific expression of a sensitive red fluorescent calcium indicator , 2017, PloS one.

[37]  Nathan C. Klapoetke,et al.  A High-Light Sensitivity Optical Neural Silencer: Development and Application to Optogenetic Control of Non-Human Primate Cortex , 2010, Front. Syst. Neurosci..

[38]  V. Gradinaru,et al.  Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems , 2017, Nature Neuroscience.

[39]  Tsai-Wen Chen,et al.  Comprehensive imaging of cortical networks , 2015, Current Opinion in Neurobiology.

[40]  Quanxin Wang,et al.  Modularity in the Organization of Mouse Primary Visual Cortex , 2015, Neuron.

[41]  C. Gerfen,et al.  GENSAT BAC Cre-Recombinase Driver Lines to Study the Functional Organization of Cerebral Cortical and Basal Ganglia Circuits , 2013, Neuron.

[42]  Staci A. Sorensen,et al.  Adult Mouse Cortical Cell Taxonomy Revealed by Single Cell Transcriptomics , 2016 .

[43]  W. Denk,et al.  The Big and the Small: Challenges of Imaging the Brain’s Circuits , 2011, Science.

[44]  Michael J. Yetman,et al.  Strain Background Influences Neurotoxicity and Behavioral Abnormalities in Mice Expressing the Tetracycline Transactivator , 2012, The Journal of Neuroscience.

[45]  Charles R. Gerfen,et al.  Targeting Cre Recombinase to Specific Neuron Populations with Bacterial Artificial Chromosome Constructs , 2007, The Journal of Neuroscience.

[46]  Hongkui Zeng,et al.  An Inducible and Reversible Mouse Genetic Rescue System , 2008, PLoS genetics.

[47]  Vincent A. Pieribone,et al.  Single Action Potentials and Subthreshold Electrical Events Imaged in Neurons with a Fluorescent Protein Voltage Probe , 2012, Neuron.

[48]  Staci A. Sorensen,et al.  Anatomical characterization of Cre driver mice for neural circuit mapping and manipulation , 2014, Front. Neural Circuits.

[49]  Jens Hjerling-Leffler,et al.  Disentangling neural cell diversity using single-cell transcriptomics , 2016, Nature Neuroscience.

[50]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[51]  Julie A. Harris,et al.  Organization of the connections between claustrum and cortex in the mouse , 2016, The Journal of comparative neurology.

[52]  Mark H. Ellisman,et al.  Supplementary Text: Mechanistic Investigation of Apex2 , 2014 .

[53]  Michael Z. Lin,et al.  Subcellular Imaging of Voltage and Calcium Signals Reveals Neural Processing In Vivo , 2016, Cell.

[54]  Weijian Yang,et al.  In vivo imaging of neural activity , 2017, Nature Methods.

[55]  H. Markram,et al.  Interneurons of the neocortical inhibitory system , 2004, Nature Reviews Neuroscience.

[56]  S. Nelson,et al.  The problem of neuronal cell types: a physiological genomics approach , 2006, Trends in Neurosciences.

[57]  R. Reid,et al.  Frontiers in Cellular Neuroscience Cellular Neuroscience Methods Article , 2022 .

[58]  Alison L. Barth,et al.  Somatostatin-expressing neurons in cortical networks , 2016, Nature Reviews Neuroscience.

[59]  Liang Liang,et al.  The Q System: A Repressible Binary System for Transgene Expression, Lineage Tracing, and Mosaic Analysis , 2010, Cell.

[60]  Mark Mayford,et al.  Localization of a Stable Neural Correlate of Associative Memory , 2007, Science.

[61]  Mark J. Schnitzer,et al.  Automated Analysis of Cellular Signals from Large-Scale Calcium Imaging Data , 2009, Neuron.

[62]  Lauren L. Orefice,et al.  The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn , 2017, Cell.

[63]  Marina Gertsenstein,et al.  Developmental and adult phenotyping directly from mutant embryonic stem cells , 2007, Proceedings of the National Academy of Sciences.

[64]  Philippe Soriano.  Generalized lacZ expression with the ROSA26 Cre reporter strain , 1999, Nature Genetics.

[65]  D. Tank,et al.  Imaging Large-Scale Neural Activity with Cellular Resolution in Awake, Mobile Mice , 2007, Neuron.

[66]  M. Stryker,et al.  A Cortical Circuit for Gain Control by Behavioral State , 2014, Cell.