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High-Throughput Behavioral Phenotyping in the Expanded Panel of BXD Recombinant Inbred Strains

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High-Throughput Behavioral Phenotyping in the Expanded Panel of BXD Recombinant Inbred Strains Genes, Brain and Behavior (2010) 9: 129–159 © 2009 The Authors Journal compilation © 2009 Blackwell Publishing Ltd/International Behavioural and Neural Genetics Society High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains V. M. Philip†,S.Duvvuru†,B.Gomero†, despair and related neurological phenomena; pain T. A. Ansah‡,C.D.Blaha§,M.N.Cook§, sensitivity; stress sensitivity; anxiety; hyperactivity and K. M. Hamre¶, W. R. Lariviere∗∗, sleep/wake cycles. All traits have been measured in D. B. Matthews††,‡‡,G.Mittleman§, both sexes in approximately 70 strains of the recently D. Goldowitz§§ andE.J.Chesler†,∗ 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) † Systems Genetics Group, Biosciences Division, Oak Ridge BXD RI lines was performed. Primary data are publicly ‡ National Laboratory, Oak Ridge TN, Department of available for heritability, sex difference and genetic Neurobiology and Neurotoxicology, Meharry Medical College, analyses using the MouseTrack database, and are also § Nashville, TN, Department of Psychology, The University of available in GeneNetwork.org for quantitative trait locus ¶ Memphis, Memphis, TN, Departments of Anatomy and (QTL) detection and genetic analysis of gene expression. Neurobiology, University of Tennessee Health Science Center, Together with the results of related studies, these data ** Memphis, TN, Departments of Anesthesiology and form a public resource for integrative systems genetic Neurobiology, University of Pittsburgh School of Medicine, analysis of neurobehavioral traits. Pittsburgh, PA, and ††Departments of Psychology and Neuroscience, Baylor University, Waco, TX, USA, ‡‡Present Keywords: gene expression, heritability, sex differences, address: Department of Psychology, Nanyang Technological systems genetics University, Singapore, and §§Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University Received 2 October 2008, revised 14 August 2009, of British Columbia, Vancouver, BC, Canada 9 September 2009, accepted for publication 9 September *Corresponding author: E. J. Chesler, The Jackson Laboratory, 2009 Bar Harbor ME, 04609, USA. E-mail: [email protected] BXD recombinant inbred (BXD RI) mice are an established Genetic reference populations, particularly the BXD behavior genetics resource, often used for the study of recombinant inbred (BXD RI) strains derived from alcoholism and other neuropharmacological traits (Crabbe C57BL/6J and DBA/2J mice, are a valuable resource et al. 1996; Gora-Maslak et al. 1991; Plomin et al. 1991). for the discovery of the bio-molecular substrates and These lines have been used for three decades to map the genetic drivers responsible for trait variation and covariation. This approach can be profitably applied in genetic basis of complex phenotypes, and allow detection of the analysis of susceptibility and mechanisms of drug causative genetic loci even for traits with modest heritability and alcohol use disorders for which many predisposing (Belknap 1998). The population also serves as a genetic behaviors may predict the occurrence and manifestation reference population, allowing correlation and comparison of increased preference for these substances. Many across traits, both within and among different laboratories of these traits are modeled by common mouse to evaluate common genetic determinants of correlated behavioral assays, facilitating the detection of patterns phenotypes (Crabbe et al. 1996). This approach has been and sources of genetic coregulation of predisposing facilitated through the development of GeneNetwork phenotypes and substance consumption. Members of (www.genenetwork.org), an Internet resource for the multi- the Tennessee Mouse Genome Consortium (TMGC) variate genetic analysis of complex traits in genetic reference have obtained phenotype data from over 250 measures populations (Chesler et al. 2003, 2004; Wang et al. 2003). related to multiple behavioral assays across several GeneNetwork aids in identification of candidate genes batteries: response to, and withdrawal from cocaine, 3,4- and bio-molecular mechanisms underlying addiction-related methylenedioxymethamphetamine; ‘‘ecstasy” (MDMA), phenotypes and includes a wealth of data on mRNA morphine and alcohol; novelty seeking; behavioral expression profiles from various tissues of the central nervous system (Chesler et al. 2005; Peirce et al. 2006; Rosen et al. 2003, 2007). Despite a wealth of data from many Re-use of this article is permitted in accordance with the previous studies in these lines, the potential for integrative Terms and Conditions set out at http://www3.interscience. multi-variate analysis has been limited by the depth and wiley.com/authorresources/onlineopen.html breadth of previous behavioral phenotyping. doi: 10.1111/j.1601-183X.2009.00540.x 129 Philip et al. The BXD RI lines were initially derived by B. A. Taylor from the same litter. Litter information is stored in the MouseTrack (e.g. Taylor et al. 1977) through inbreeding the progeny of system and can be obtained for further modeling. Approximately 70 strains were available for phenotyping, allowing an intercross of C57BL/6J mice (B6) and DBA/2J mice (D2). improved power for QTL mapping and genetic correlation. BXD Additional lines were added in 1999 (Taylor et al. 1999), 1–42/TyJ strains were obtained from the Jackson Laboratory (Bar resulting in a set of approximately 35 strains. A recent Harbor, ME, USA). Recent BXD RI lines (Peirce et al. 2004) were expansion has increased the population to 79 lines in total provided by Dr Lu Lu and Dr Robert W. Williams (University of (Peirce et al. 2004). The new lines are derived from an Tennessee Health Science Center, Memphis, TN, USA). Housing and testing environment conditions were maintained advanced intercross implemented as described by Darvasi throughout testing. Except where noted, BXD RI lines were imported and Soller (1995) and have a higher number of recombi- into the Russell Vivarium at Oak Ridge National Laboratory (ORNL) nations per line, allowing an increase in the precision with for environmentally controlled, year round breeding and distribution which quantitative trait loci (QTL) can be detected (Shifman for all assays except for handling-induced convulsion (HIC) and footshock vocalization, for which mice were bred at University of et al. 2006). Although the BXD RI lines are becoming more Tennessee Health Science Center (UTHSC) and housed as described widely used, many common behavioral phenotypes have not in Matthews et al. (2008). Litters were weaned at about 3 weeks been studied to date, have been measured in only a few of age and shipped to various test sites in the TMGC’s climate lines or have only been studied in one sex. controlled, specific pathogen-free (SPF) mouse transport van at about 6–7 weeks of age, allowing at least 1 week of acclimation to their The present study is one of several ongoing efforts that new home colony. Animals were transported in static micro-isolators. will allow for an integrative multi-variate analysis through the Housing conditions, apparatus information and testing protocols collection of a large set of broad-based behavioral phenotyp- specific to each battery are summarized in Table 2. All mice were ing data in the newly expanded BXD RI strain population. housed in rooms lit with fluorescent ceiling lights and had Harlan Softcob bedding. No other species were present in the room and It emphasizes behavioral predictors of susceptibility to sub- mice received daily health checks. stance use disorders. The same genetic polymorphisms and To avoid seasonal and other cohort-type effects on the correlation environmental interactions that influence predisposing phe- of trait values, each of the batteries was run in parallel with the notypes may also influence preference and addiction-related exception of footshock vocalization and HIC which were collected traits including drug self-administration and withdrawal. In independently in a related project. For all other test batteries in this study, all strains were tested in all batteries over the same period this study, we have focused on potential predisposing phe- of several years by the collaborating laboratories. Confounding envi- notypes including stress or pain sensitivity, anxiety, despair, ronmental variation with strain variation was minimized by sampling hyperactivity and abnormal circadian rhythms, pharmacoki- individuals from the various strains across this multi-year project. netic and pharmacodynamic responses to drugs of abuse, Because phenotype analyses can be influenced by fluctuations in laboratory environment that interact with genotype (Chesler et al. including withdrawal, sensitization, activity effects, anxiolytic 2002a,b; Crabbe et al. 1999), we recorded laboratory variables such and neurological effects including neurogenesis. By making as experimenter, age and test date, which can be matched to records these data public, we further hope to provide a resource of pertaining to the animal colonies and test rooms. These remained neurobehavioral phenotype data in the expanded BXDs that largely consistent through the course of this study. complement existing molecular phenotype data for systems genetic analysis of brain and behavior. Neurobehavioral testing procedures Each mouse was assigned to one and only one battery of testing, and Materials and methods transported by ground
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