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

Abstract

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.

Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques

“…The glutamate NMDA receptor blocker AP5 (50 M) was added to the aCSF during incubation to prolong the viability of neurons, and slices were washed with regular oxygenated aCSF for at least 20 min before the whole-cell recordings were performed. Although AP5 is reported to wash out of acute slice preparations (Dozmorov et al, 2004;Herman et al, 2011), application of AP5 for Ն12 h enhances evoked firing (Ishikawa et al, 2009;Lee and Chung, 2014), suggesting that there may be a compensatory increase in intrinsic excitability under these recording conditions. However, all groups were treated identically, so this is unlikely to explain a difference in firing between treatment groups.…”

“…Parameters for peptide identification were as follows: precursor mass tolerance of 10 ppm, fragment mass tolerance was set at 0.8 Da for the CID spectra and 0.1 Da for the HCD spectra, fully tryptic peptides with a maximum of two missed cleavages, static modifications of peptide N termini, and lysines with the iTRAQ reagent and cysteine alkylation with methylthio; methionine oxidation was included as a variable modification. The search results were filtered using Percolator 2.04 (Käll et al, 2007) to yield peptides with a false discovery rate of Ͻ1%. The raw data for unique peptides were log transformed and normalized (central mean tendency), and fold changes were calculated using InfernoRDN software (Polpitiya et al, 2008).…”

“…Western blotting procedures for GluA1 followed our routine methods (Padula et al, 2015). Briefly, PSD-enriched fractions from three controls and all eight drinking monkeys were diluted with NuPAGE 4ϫ LDS sample loading buffer (Invitrogen; pH 8.5) containing 50 mM dithiothreitol, and samples were denatured for 10 min at 70°C.…”

Scoring the collective effects of SNPs: association of minor alleles with complex traits in model organisms

“…We then calculated MAC for each strain of a panel and plotted the MAC distribution curve (Figure 1; Table S1 in Supporting Information for strain descriptions). Great variations in MAC (~0.2 to ~0.7) were observed for C. elegans RILs from either the Kruglyak or the Kammenga laboratory ( Figure 1A and B) [19,20], a yeast segregants panel analogous to a RIL panel in animals ( Figure 1C) [21,22], and the BXD mouse RIL panel ( Figure 1F) [24,25]. Relative to these RILs, D. melanogaster inbred panel derived from the wild showed lower MAC and smaller variation range ( Figure 1D) [23].…”

Csnk1e Is a Genetic Regulator of Sensitivity to Psychostimulants and Opioids

“…Variation in sensitivity to the locomotor stimulant effect of amphetamines and opioids is heritable (Belknap et al, 1998;Phillips et al, 2008;Gill and Boyle, 2008;Oliverio et al, 1975;Philip et al, 2010). Because epidemiological studies indicate that sensitivity to drug liking in humans can predict an individual's susceptibility to drug abuse (Haertzen et al, 1983;Schuckit, 2009), drug sensitivity and abuse are hypothesized to share a genetic basis.…”