High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains

Genetic reference populations, particularly the BXD recombinant inbred (BXD RI) strains derived from C57BL/6J and DBA/2J mice, are a valuable resource for the discovery of the bio‐molecular substrates and genetic drivers responsible for trait variation and covariation. This approach can be profitably applied in the analysis of susceptibility and mechanisms of drug and alcohol use disorders for which many predisposing behaviors may predict the occurrence and manifestation of increased preference for these substances. Many of these traits are modeled by common mouse behavioral assays, facilitating the detection of patterns and sources of genetic coregulation of predisposing phenotypes and substance consumption. Members of the Tennessee Mouse Genome Consortium (TMGC) have obtained phenotype data from over 250 measures related to multiple behavioral assays across several batteries: response to, and withdrawal from cocaine, 3,4‐methylenedioxymethamphetamine; “ecstasy” (MDMA), morphine and alcohol; novelty seeking; behavioral despair and related neurological phenomena; pain sensitivity; stress sensitivity; anxiety; hyperactivity and sleep/wake cycles. All traits have been measured in both sexes in approximately 70 strains of the recently expanded panel of BXD RI strains. Sex differences and heritability estimates were obtained for each trait, and a comparison of early (N = 32) and recent (N = 37) BXD RI lines was performed. Primary data are publicly available for heritability, sex difference and genetic analyses using the MouseTrack database, and are also available in GeneNetwork.org for quantitative trait locus (QTL) detection and genetic analysis of gene expression. Together with the results of related studies, these data form a public resource for integrative systems genetic analysis of neurobehavioral traits.

[1]  K. Buck,et al.  Genetic factors in addiction: QTL mapping and candidate gene studies implicate GABAergic genes in alcohol and barbiturate withdrawal in mice. , 2001, Addiction.

[2]  Robert W. Williams,et al.  Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function , 2005, Nature Genetics.

[3]  L. A. Swiger,et al.  THE VARIANCE OF INTRACLASS CORRELATION INVOLVING GROUPS WITH ONE OBSERVATION , 1964 .

[4]  William Valdar,et al.  Strategies for mapping and cloning quantitative trait genes in rodents , 2005, Nature Reviews Genetics.

[5]  Charles E. Heckler,et al.  Applied Multivariate Statistical Analysis , 2005, Technometrics.

[6]  R. Williams,et al.  Anxiety-related behaviors in the elevated zero-maze are affected by genetic factors and retinal degeneration. , 2001, Behavioral neuroscience.

[7]  K. J. Parker,et al.  Social stress-related behavior affects hippocampal cell proliferation in mice , 2006, Physiology & Behavior.

[8]  Thomas R. Sutter,et al.  How replicable are mRNA expression QTL? , 2006, Mammalian Genome.

[9]  J. Crabbe,et al.  Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades , 2006, Proceedings of the National Academy of Sciences.

[10]  J. Mogil,et al.  Genetic variation in morphine analgesic tolerance A survey of 11 inbred mouse strains , 2002, Pharmacology Biochemistry and Behavior.

[11]  Jerry Hirsch,et al.  Behavior-Genetic Analysis , 1967 .

[12]  Scott F. Saccone,et al.  Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. , 2008, Drug and alcohol dependence.

[13]  M. Soller,et al.  Advanced intercross lines, an experimental population for fine genetic mapping. , 1995, Genetics.

[14]  Elissa J. Chesler,et al.  The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics , 2008, Mammalian Genome.

[15]  M. Iyo,et al.  Genome-wide association for methamphetamine dependence: convergent results from 2 samples. , 2008, Archives of general psychiatry.

[16]  G. Uhl,et al.  "Higher order" addiction molecular genetics: convergent data from genome-wide association in humans and mice. , 2008, Biochemical pharmacology.

[17]  Jay Snoddy,et al.  BMC Bioinformatics BioMed Central Database , 2004 .

[18]  Lu Lu,et al.  The genetic control of neocortex volume and covariation with neocortical gene expression in mice , 2009, BMC Neuroscience.

[19]  Robert W. Williams,et al.  A new set of BXD recombinant inbred lines from advanced intercross populations in mice , 2004, BMC Genetics.

[20]  William Valdar,et al.  Genetic and Environmental Effects on Complex Traits in Mice , 2006, Genetics.

[21]  Robert Plomin,et al.  Use of recombinant inbred strains to detect quantitative trait loci associated with behavior , 1991, Behavior genetics.

[22]  T. Robinson,et al.  Sex differences and estrous cycle variations in amphetamine-elicited rotational behavior. , 1982, European journal of pharmacology.

[23]  M. Kreek,et al.  Stress responsivity, addiction, and a functional variant of the human mu-opioid receptor gene. , 2007, Molecular interventions.

[24]  M. Devor,et al.  Social variables affect phenotype in the neuroma model of neuropathic pain , 2002, Pain.

[25]  Robert C. Thompson,et al.  Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry , 2009, Proceedings of the National Academy of Sciences.

[26]  Shuang Li,et al.  Social Defeat Stress-Induced Behavioral Responses are Mediated by the Endogenous Kappa Opioid System , 2006, Neuropsychopharmacology.

[27]  M. Max,et al.  Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations , 2006, Molecular Psychiatry.

[28]  G. Mcclearn,et al.  Use of recombinant inbred strains to identify quantitative trait loci in psychopharmacology , 1991, Psychopharmacology.

[29]  J. Warter.  Genes, brain and behavior. , 1991, Research publications - Association for Research in Nervous and Mental Disease.

[30]  G. Mcclearn,et al.  Sex-exclusive quantitative trait loci influences in alcohol-related phenotypes. , 1999, American journal of medical genetics.

[31]  J. Becker,et al.  Sex differences in drug abuse , 2008, Frontiers in Neuroendocrinology.

[32]  V. Gribkoff.  The therapeutic potential of neuronal KV7 (KCNQ) channel modulators: an update , 2008 .

[33]  Kevin D Donohue,et al.  Assessment of a non-invasive high-throughput classifier for behaviours associated with sleep and wake in mice , 2008, Biomedical engineering online.

[34]  A. Termin,et al.  Small molecules targeting sodium and calcium channels for neuropathic pain. , 2009, Current opinion in drug discovery & development.

[35]  Hyuna Yang,et al.  On the subspecific origin of the laboratory mouse , 2007, Nature Genetics.

[36]  R. Mott,et al.  The Collaborative Cross, developing a resource for mammalian systems genetics: A status report of the Wellcome Trust cohort , 2008, Mammalian Genome.

[37]  P. Skolnick,et al.  Differences in fear motivated behaviors among inbred mouse strains , 2005, Psychopharmacology.

[38]  Jintao Wang,et al.  Genetic correlates of gene expression in recombinant inbred strains , 2007, Neuroinformatics.

[39]  Robert W. Williams,et al.  Genetic relationship between anxiety-related and fear-related behaviors in BXD recombinant inbred mice , 2009, Behavioural pharmacology.

[40]  M. Devor,et al.  Sex‐specific variability and a ‘cage effect’ independently mask a neuropathic pain quantitative trait locus detected in a whole genome scan , 2007, The European journal of neuroscience.

[41]  J. Flint,et al.  QTL Analysis of Multiple Behavioral Measures of Anxiety in Mice , 2004, Behavior Genetics.

[42]  Jay Snoddy,et al.  Large-scale mutagenesis of the mouse to understand the genetic bases of nervous system structure and function. , 2004, Brain research. Molecular brain research.

[43]  S. Holtzman,et al.  Development and maintenance of morphine tolerance and dependence in the rat by scheduled access to morphine drinking solutions. , 1978, The Journal of pharmacology and experimental therapeutics.

[44]  Elissa J. Chesler,et al.  Supplementing High-Density SNP Microarrays for Additional Coverage of Disease-Related Genes: Addiction as a Paradigm , 2009, PloS one.

[45]  Elissa J. Chesler,et al.  Influences of laboratory environment on behavior , 2002, Nature Neuroscience.

[46]  G. Dussor,et al.  Cholinergic modulation of nociceptive responses in vivo and neuropeptide release in vitro at the level of the primary sensory neuron , 2004, Pain.

[47]  Benjamin A. Taylor,et al.  Genotyping new BXD recombinant inbred mouse strains and comparison of BXD and consensus maps , 1999, Mammalian Genome.

[48]  John D. Storey.  A direct approach to false discovery rates , 2002 .

[49]  L. Balmer,et al.  Establishment of “The Gene Mine”: a resource for rapid identification of complex trait genes , 2008, Mammalian Genome.

[50]  Bing Zhang,et al.  WebGestalt: an integrated system for exploring gene sets in various biological contexts , 2005, Nucleic Acids Res..

[51]  Martin S. Taylor,et al.  A High-Resolution Single Nucleotide Polymorphism Genetic Map of the Mouse Genome , 2006, PLoS biology.

[52]  K. Manly,et al.  Map Manager QTX, cross-platform software for genetic mapping , 2001, Mammalian Genome.

[53]  J. Mogil,et al.  Naloxone-precipitated withdrawal jumping in 11 inbred mouse strains: evidence for common genetic mechanisms in acute and chronic morphine physical dependence , 2002, Neuroscience.

[54]  R. Doerge,et al.  Permutation tests for multiple loci affecting a quantitative character. , 1996, Genetics.

[55]  V. Gribkoff.  The therapeutic potential of neuronal K V 7 (KCNQ) channel modulators: an update. , 2008, Expert opinion on therapeutic targets.

[56]  J. Crabbe,et al.  Genetics of mouse behavior: interactions with laboratory environment. , 1999, Science.

[57]  Jeremy J. Jay,et al.  Ontological Discovery Environment: a system for integrating gene-phenotype associations. , 2009, Genomics.

[58]  R. Gracely,et al.  Sex-dependent components of the analgesia produced by athletic competition. , 2001, The journal of pain : official journal of the American Pain Society.

[59]  R. Hen,et al.  Elevated alcohol consumption in null mutant mice lacking 5–HT1B serotonin receptors , 1996, Nature Genetics.

[60]  Julie A. Caplow,et al.  Genetic modulation of striatal volume by loci on Chrs 6 and 17 in BXD recombinant inbred mice , 2009, Genes, brain, and behavior.

[61]  Jing Liang,et al.  Involvement of CGRP and CGRPl receptor in nociception in the basolateral nucleus of amygdala of rats , 2008, Neuroscience Letters.

[62]  J. Mogil,et al.  Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity , 2002, Pain.

[63]  Elissa J Chesler,et al.  Identification and ranking of genetic and laboratory environment factors influencing a behavioral trait, thermal nociception, via computational analysis of a large data archive , 2002, Neuroscience & Biobehavioral Reviews.

[64]  Jonathan Flint,et al.  Analysis of quantitative trait loci that influence animal behavior. , 2003, Journal of neurobiology.

[65]  D. Goldowitz,et al.  Screening for ENU-induced mutations in mice that result in aberrant ethanol-related phenotypes. , 2007, Behavioral neuroscience.

[66]  E. Lander,et al.  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results , 1995, Nature Genetics.

[67]  Robert Hitzemann,et al.  Identification of an Acute Ethanol Response Quantitative Trait Locus on Mouse Chromosome 2 , 1999, The Journal of Neuroscience.

[68]  C. Heyser,et al.  Opiate withdrawal signs precipitated by naloxone following a single exposure to morphine: potentiation with a second morphine exposure , 1997, Psychopharmacology.

[69]  E. Chesler,et al.  Sex differences in thermal nociception and morphine antinociception in rodents depend on genotype , 2000, Neuroscience & Biobehavioral Reviews.

[70]  Robert W. Williams,et al.  WebQTL - Web-based complex trait analysis , 2003, Neuroinformatics.

[71]  Nengjun Yi,et al.  The Collaborative Cross, a community resource for the genetic analysis of complex traits , 2004, Nature Genetics.

[72]  B. Taylor,et al.  Genetic studies of the Fv-1 locus of mice: linkage with Gpd-1 in recombinant inbred lines , 1977, Journal of virology.

[73]  W. Ewens.  Genetics and analysis of quantitative traits , 1999 .

[74]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[75]  Robert W. Williams,et al.  Genome Reshuffling for Advanced Intercross Permutation (GRAIP): Simulation and Permutation for Advanced Intercross Population Analysis , 2008, PloS one.

[76]  T. Seale,et al.  Genetic determinants of susceptibility to the rewarding and other behavioral actions of cocaine. , 1991, Journal of addictive diseases.

[77]  J. Crabbe,et al.  Quantitative Trait Loci Involved in Genetic Predisposition to Acute Alcohol Withdrawal in Mice , 1997, The Journal of Neuroscience.

[78]  B. Paigen,et al.  Bioinformatics toolbox for narrowing rodent quantitative trait loci. , 2005, Trends in genetics : TIG.

[79]  J. Herman,et al.  Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner. , 2006, American journal of physiology. Endocrinology and metabolism.

[80]  Lu Lu,et al.  WebQTL: rapid exploratory analysis of gene expression and genetic networks for brain and behavior , 2004, Nature Neuroscience.

[81]  Christopher P Austin,et al.  The Knockout Mouse Project , 2004, Nature Genetics.

[82]  T. Yaksh,et al.  Quantitative assessment of tactile allodynia in the rat paw , 1994, Journal of Neuroscience Methods.

[83]  Laforge Ks,et al.  Stress responsivity, addiction, and a functional variant of the human mu-opioid receptor gene. , 2007 .

[84]  J. Belknap,et al.  Identification of a Sex-Specific Quantitative Trait Locus Mediating Nonopioid Stress-Induced Analgesia in Female Mice , 1997, The Journal of Neuroscience.

[85]  K. Strimmer,et al.  Statistical Applications in Genetics and Molecular Biology A Shrinkage Approach to Large-Scale Covariance Matrix Estimation and Implications for Functional Genomics , 2011 .

[86]  E. Chesler,et al.  Genetic Mapping of Vocalization to a Series of Increasing Acute Footshocks Using B6.A Consomic and B6.D2 Congenic Mouse Strains , 2008, Behavior genetics.

[87]  Robert W. Williams,et al.  An informatics approach to systems neurogenetics. , 2007, Methods in molecular biology.

[88]  Trevor W. Robbins,et al.  High Impulsivity Predicts the Switch to Compulsive Cocaine-Taking , 2008, Science.

[89]  R. Dubner,et al.  A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia , 1987, Pain.

[90]  E. Chesler,et al.  Neurobehavioral mutants identified in an ENU-mutagenesis project , 2007, Mammalian Genome.

[91]  J. Belknap,et al.  Effect of Within-Strain Sample Size on QTL Detection and Mapping Using Recombinant Inbred Mouse Strains , 1998, Behavior genetics.

[92]  J. Crabbe,et al.  Localization of genes affecting alcohol drinking in mice. , 1994, Alcoholism, clinical and experimental research.

[93]  J. Becker,et al.  Sex differences in the amphetamine stimulated release of catecholamines from rat striatal tissue in vitro , 1981, Brain Research.

[94]  Wim E Crusio.  A note on the effect of within‐strain sample sizes on QTL mapping in recombinant inbred strain studies , 2004, Genes, brain, and behavior.