Rodent models for psychiatric disorders: problems and promises

Psychiatric disorders are a prevalent global health problem, over 900 million individuals affected by a continuum of mental and substance use disorders. Due to this high prevalence, and the substantial direct and indirect societal costs, it is essential to understand the underlying mechanisms of these disorders to facilitate development of new and more effective treatments. Since the advent of recombinant DNA technologies in the early 1980s, genetically modified rodent models have significantly contributed to the genetic and molecular basis of psychiatric disorders. Despite significant advancements, many challenges remain after unsuccessful drug development based on rodent models. Recent human genetics show the polygenetic nature of mental disorders, identifying hundreds of allelic variants that confer increased risk. However, given the complexity of the brain, with many unique cell types, gene expression profiles, and developmental trajectories, proper animal models are needed more than ever to dissect genes and circuits in a cell type-specific manner to advance our understanding and treatment of psychiatric disorders. In this mini-review, we highlight current challenges and promises of using rodent models in advancing science and drug development, focusing on advanced techniques, and their applications to rodent models of psychiatric disorders.

[1]  K. Koketsu,et al.  Effects of Calcium Ions on Prolonged Action Potentials and Hyperpolarizing Responses , 1963, Nature.

[2]  E. B. Ridgway,et al.  Phasic entry of calcium in response to depolarization of giant axons of Loligo forbesi. , 1971, Journal of Physiology.

[3]  J. Connor.  Digital imaging of free calcium changes and of spatial gradients in growing processes in single, mammalian central nervous system cells. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[4]  D. Tank,et al.  Spatially resolved calcium dynamics of mammalian Purkinje cells in cerebellar slice. , 1988, Science.

[5]  R. Tsien,et al.  Imaging of cytosolic Ca2+ transients arising from Ca2+ stores and Ca2+ channels in sympathetic neurons , 1988, Neuron.

[6]  R. Kerr,et al.  Optical Imaging of Calcium Transients in Neurons and Pharyngeal Muscle of C. elegans , 2000, Neuron.

[7]  Hilde van der Togt,et al.  Publisher's Note , 2003, J. Netw. Comput. Appl..

[8]  K. Deisseroth,et al.  Millisecond-timescale, genetically targeted optical control of neural activity , 2005, Nature Neuroscience.

[9]  E. Boyden,et al.  Multiple-Color Optical Activation, Silencing, and Desynchronization of Neural Activity, with Single-Spike Temporal Resolution , 2007, PloS one.

[10]  Feng Zhang,et al.  Multimodal fast optical interrogation of neural circuitry , 2007, Nature.

[11]  B. Roth,et al.  Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand , 2007, Proceedings of the National Academy of Sciences.

[12]  M. Kringelbach,et al.  Translational principles of deep brain stimulation , 2007, Nature Reviews Neuroscience.

[13]  Laurie D. Burns,et al.  High-speed, miniaturized fluorescence microscopy in freely moving mice , 2008, Nature Methods.

[14]  W. C. Hall,et al.  Imaging synaptic inhibition throughout the brain via genetically targeted Clomeleon , 2008, Brain cell biology.

[15]  Raag D. Airan,et al.  Temporally precise in vivo control of intracellular signalling , 2009, Nature.

[16]  Michael A. Henninger,et al.  High-Performance Genetically Targetable Optical Neural Silencing via Light-Driven Proton Pumps , 2010 .

[17]  L. Looger,et al.  Chemical and Genetic Engineering of Selective Ion Channel–Ligand Interactions , 2011, Science.

[18]  K. Mikoshiba,et al.  Quantitative comparison of novel GCaMP-type genetically encoded Ca2+ indicators in mammalian neurons , 2012, Front. Cell. Neurosci..

[19]  J. Wess,et al.  Design and Functional Characterization of a Novel, Arrestin-Biased Designer G Protein-Coupled Receptor , 2012, Molecular Pharmacology.

[20]  Garret D Stuber,et al.  Construction of implantable optical fibers for long-term optogenetic manipulation of neural circuits , 2011, Nature Protocols.

[21]  T. Daigle,et al.  A Gαs DREADD Mouse for Selective Modulation of cAMP Production in Striatopallidal Neurons , 2013, Neuropsychopharmacology.

[22]  G. Ratto,et al.  Twenty years of fluorescence imaging of intracellular chloride , 2014, Front. Cell. Neurosci..

[23]  D. J. Harrison,et al.  Bright and fast multi-colored voltage reporters via electrochromic FRET , 2014, Nature Communications.

[24]  Steven S. Vogel,et al.  Deep brain optical measurements of cell type–specific neural activity in behaving mice , 2014, Nature Protocols.

[25]  J. Doudna,et al.  The new frontier of genome engineering with CRISPR-Cas9 , 2014, Science.

[26]  Tobias Bonhoeffer,et al.  Two-photon calcium imaging in mice navigating a virtual reality environment. , 2014, Journal of visualized experiments : JoVE.

[27]  Raag D. Airan,et al.  Natural Neural Projection Dynamics Underlying Social Behavior , 2014, Cell.

[28]  A. Saliba,et al.  Single-cell RNA-seq: advances and future challenges , 2014, Nucleic acids research.

[29]  E. Boyden,et al.  Optogenetic activation of intracellular adenosine A2A receptor signaling in hippocampus is sufficient to trigger CREB phosphorylation and impair memory , 2014, Molecular Psychiatry.

[30]  Xi-Ping Huang,et al.  A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior , 2015, Neuron.

[31]  J. Spudich,et al.  Natural light-gated anion channels: A family of microbial rhodopsins for advanced optogenetics , 2015, Science.

[32]  Aleksandra A. Kolodziejczyk,et al.  The technology and biology of single-cell RNA sequencing. , 2015, Molecular cell.

[33]  Masaaki Sato,et al.  Generation and Imaging of Transgenic Mice that Express G-CaMP7 under a Tetracycline Response Element , 2015, PloS one.

[34]  H. Piao,et al.  Combinatorial Mutagenesis of the Voltage-Sensing Domain Enables the Optical Resolution of Action Potentials Firing at 60 Hz by a Genetically Encoded Fluorescent Sensor of Membrane Potential , 2015, The Journal of Neuroscience.

[35]  Evan Z. Macosko,et al.  Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets , 2015, Cell.

[36]  A. Regev,et al.  Cpf1 Is a Single RNA-Guided Endonuclease of a Class 2 CRISPR-Cas System , 2015, Cell.

[37]  J. Rehm,et al.  The economic costs of mental disorders , 2016, EMBO reports.

[38]  R. Atun,et al.  Estimating the true global burden of mental illness. , 2016, The lancet. Psychiatry.

[39]  Junying Yuan,et al.  Single-Cell RNA Sequencing: Unraveling the Brain One Cell at a Time. , 2017, Trends in molecular medicine.

[40]  C. Chuong,et al.  The GCaMP-R Family of Genetically Encoded Ratiometric Calcium Indicators. , 2017, ACS chemical biology.

[41]  L. Luo,et al.  Genetic strategies to access activated neurons , 2017, Current Opinion in Neurobiology.

[42]  Fabian J Theis,et al.  The Human Cell Atlas , 2017, bioRxiv.

[43]  Qiang Sun,et al.  Homology-mediated end joining-based targeted integration using CRISPR/Cas9 , 2017, Cell Research.

[44]  Georg B. Keller,et al.  A Sensorimotor Circuit in Mouse Cortex for Visual Flow Predictions , 2017, Neuron.

[45]  Michael J. T. Stubbington,et al.  The Human Cell Atlas: from vision to reality , 2017, Nature.

[46]  Michael Z. Lin,et al.  A Suite of Transgenic Driver and Reporter Mouse Lines with Enhanced Brain-Cell-Type Targeting and Functionality , 2018, Cell.

[47]  Kenji F. Tanaka,et al.  Near-infrared deep brain stimulation via upconversion nanoparticle–mediated optogenetics , 2018, Science.

[48]  S. Orkin,et al.  Mapping the Mouse Cell Atlas by Microwell-Seq , 2018, Cell.

[49]  Behavioral changes and growth deficits in a CRISPR engineered mouse model of the schizophrenia-associated 3q29 deletion , 2018 .

[50]  Gregory L. Futia,et al.  Three dimensional two-photon brain imaging in freely moving mice using a miniature fiber coupled microscope with active axial-scanning , 2018, Scientific Reports.

[51]  K. Tye,et al.  A cortical-brainstem circuit predicts and governs compulsive alcohol drinking , 2019, Science.

[52]  CRISPR-Cas9-based mutagenesis frequently provokes on-target mRNA misregulation , 2019, Nature Communications.

[53]  M. Michaelides,et al.  Ultrapotent chemogenetics for research and potential clinical applications , 2019, Science.

[54]  David R. Liu,et al.  Search-and-replace genome editing without double-strand breaks or donor DNA , 2019, Nature.

[55]  Sa-Ik Hong,et al.  Indirect Medium Spiny Neurons in the Dorsomedial Striatum Regulate Ethanol-Containing Conditioned Reward Seeking , 2019, The Journal of Neuroscience.

[56]  Yi Li,et al.  Long-term Fiber Photometry for Neuroscience Studies , 2019, Neuroscience Bulletin.

[57]  J. J. Macklin,et al.  High-performance calcium sensors for imaging activity in neuronal populations and microcompartments , 2019, Nature Methods.

[58]  Lior Pachter,et al.  Barcode identification for single cell genomics , 2017, BMC Bioinformatics.

[59]  Yi Zhang,et al.  Cell type-specific transcriptional programs in mouse prefrontal cortex during adolescence and addiction , 2019, Nature Communications.

[60]  Danielle Posthuma,et al.  Genetic mapping of cell type specificity for complex traits , 2019, Nature Communications.

[61]  Sangkyun Lee,et al.  Non-invasive optical control of endogenous Ca2+ channels in awake mice , 2020, Nature Communications.