Association of novelty-related behaviors and intravenous cocaine self-administration in Diversity Outbred mice

Dickson, Price E.; Ndukum, Juliet; Wilcox, Troy; Clark, James D.; Roy, Brittany D.; Zhang, Lifeng; Li, Yun; Lin, Da-Ting; Chesler, Elissa J.

doi:10.1007/s00213-014-3737-5

Cited by 39 publications

(51 citation statements)

References 103 publications

(132 reference statements)

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“…The structured genetic diversity in the DO allows for the association of founder haplotypes with the trait of interest, which can then be connected with the DO founder strain’s genome. The DO has been used to identify quantitative trait loci (QTL) for a wide variety of traits, including behavior, prostate cancer, cocaine self-administration, pain sensitivity, and atherosclerosis (Logan et al 2013; Recla et al 2014; Smallwood et al 2014; Dickson et al 2015; Tyler et al 2017; Winter et al 2016). The structured genetic diversity, and previous mapping successes make the DO research population ideal for exploring the genetic architecture of complex health-related traits such as heart size.…”

Section: Introductionmentioning

confidence: 99%

Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size

et al. 2017

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Heart size is an important factor in cardiac health and disease. In particular, increased heart weight is predictive of adverse cardiovascular outcomes in multiple large community-based studies. We use two cohorts of Diversity Outbred (DO) mice to investigate the role of genetics, sex, age, and diet on heart size. DO mice (n = 289) of both sexes from generation 10 were fed a standard chow diet, and analyzed at 12-15 weeks of age. Another cohort of female DO mice (n = 258) from generation 11 were fed either a high-fat, cholesterol-containing (HFC) diet or a low-fat, high-protein diet, and analyzed at 24-25 weeks. We did not observe an effect of diet on body or heart weight in generation 11 mice, although we previously reported an effect on other cardiovascular risk factors, including cholesterol, triglycerides, and insulin. We do observe a significant genetic effect on heart weight in this population. We identified two quantitative trait loci for heart weight, one (Hwtf1) at a genome-wide significance level of p ≤ 0.05 on MMU15 and one (Hwtf2) at a genome-wide suggestive level of p ≤ 0.1 on MMU10, that together explain 13.3% of the phenotypic variance. Hwtf1 contained collagen type XXII alpha 1 chain (Col22a1), and the NZO/HlLtJ and WSB/EiJ haplotypes were associated with larger hearts. This is consistent with heart tissue Col22a1 expression in DO founders and SNP patterns within Hwtf1 for Col22a1. Col22a1 has been previously associated with cardiac fibrosis in mice, suggesting that Col22a1 may be involved in pathological cardiac hypertrophy.

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Section: Introductionmentioning

confidence: 99%

Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size

et al. 2017

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“…1,2 Variance in the initial choice to experiment with addictive substances and the progression to addiction that is observed in some users can be partially explained by the multifaceted sensation seeking personality trait. [4][5][6][7][8] Genetic correlations among sensation seeking and substance use indicate shared biological mechanisms, 9 but the genes and networks underlying these relationships remain elusive. [4][5][6][7][8] Genetic correlations among sensation seeking and substance use indicate shared biological mechanisms, 9 but the genes and networks underlying these relationships remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Systems genetics of sensation seeking

Dickson

Roy

McNaughton

et al. 2018

Genes Brain and Behavior

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Sensation seeking is a multifaceted, heritable trait which predicts the development of substance use and abuse in humans; similar phenomena have been observed in rodents. Genetic correlations among sensation seeking and substance use indicate shared biological mechanisms, but the genes and networks underlying these relationships remain elusive. Here, we used a systems genetics approach in the BXD recombinant inbred mouse panel to identify shared genetic mechanisms underlying substance use and preference for sensory stimuli, an intermediate phenotype of sensation seeking. Using the operant sensation seeking (OSS) paradigm, we quantified preference for sensory stimuli in 120 male and 127 female mice from 62 BXD strains and the C57BL/6J and DBA/2J founder strains. We used relative preference for the active and inactive levers to dissociate preference for sensory stimuli from locomotion and exploration phenotypes. We identified genomic regions on chromosome 4 (155.236-155.742 Mb) and chromosome 13 (72.969-89.423 Mb) associated with distinct behavioral components of OSS. Using publicly available behavioral data and mRNA expression data from brain regions involved in reward processing, we identified (a) genes within these behavioral QTL exhibiting genome-wide significant cis-eQTL and (b) genetic correlations among OSS phenotypes, ethanol phenotypes and mRNA expression. From these analyses, we nominated positional candidates for behavioral QTL associated with distinct OSS phenotypes including Gnb1 and Mef2c. Genetic covariation of Gnb1 expression, preference for sensory stimuli and multiple ethanol phenotypes suggest that heritable variation in Gnb1 expression in reward circuitry partially underlies the widely reported relationship between sensation seeking and substance use.

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“…Independent studies examining the association of novelty- and addiction-related traits using cocaine IVSA assays with high relevance to the addiction construct confirm the relationship between these phenotypes [reviewed in 33]. Importantly, we have recently identified a strong positive relationship between multiple novelty-related traits and cocaine IVSA in a large sample of DO mice [36]. Combined with results from the present study, this suggests that the relationships between ST, cocaine IVSA, and novelty-related traits can be mapped in the DO and CC populations.…”

Section: Discussionmentioning

confidence: 62%

“…Beckmann and colleagues [6] recently examined the phenotypic relationship between ST and novelty-related traits in outbred rats and detected a positive relationship between ST and novelty preference. Novelty preference, which is phenotypically [33, 34] and genetically [35] dissociable from novelty reactivity in rodents, has also been shown to covary positively with ST and cocaine IVSA [6], and we have previously observed a positive association between multiple novelty-related traits and cocaine IVSA in male and female DO mice [36]. Moreover, the strain distribution of ST propensity observed in the present study is similar to that of holeboard exploration (an index of novelty seeking) [35].…”

Section: Discussionmentioning

confidence: 99%

Sex and strain influence attribution of incentive salience to reward cues in mice

Dickson

McNaughton

Hou

et al. 2015

Behavioural Brain Research

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The propensity to attribute incentive salience to reward cues, measured by Pavlovian sign-tracking, is strongly associated with addiction-related traits including cocaine self-administration, impulsivity, novelty reactivity, and novelty preference. Despite its critical role in addiction, the genetic underpinnings of incentive salience attribution and its relationship to drug addiction are unknown. Mouse genetics can be a powerful means to discover genetic mechanisms underlying this relationship. However, feasibility of genetic dissection of sign-tracking in mice is unknown as only a single study limited to male C57BL/6J mice has rigorously examined this behavior, and limited sign-tracking was observed. Highly diverse mouse populations such as the Collaborative Cross (CC) and Diversity Outbred population (DO) possess a greater range of behavioral and genetic variation than conventional laboratory strains. In the present study, we evaluated sign-tracking and the related phenotype goal-tracking in mice of both sexes from five inbred CC and DO founder strains. Male CAST/EiJ mice exhibited robust sign-tracking; male NOD, male C57BL/6J, and female A/J mice also exhibited significant sign-tracking. Male and female mice from all strains exhibited significant goal-tracking, and significant strain and sex differences were observed. Sign-tracking in males was genetically correlated with exploration of a novel environment, and heritability of sign-tracking and goal-tracking ranged from .32 to .41. These data highlight the importance of considering genetic diversity when evaluating the occurrence of specific behavioral traits in the laboratory mouse and demonstrate that the CC and DO mouse populations can be used to discover mechanisms underlying genetic relationships among sign-tracking and addiction-related behaviors.

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Association of novelty-related behaviors and intravenous cocaine self-administration in Diversity Outbred mice

Cited by 39 publications

References 103 publications

Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size

Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size

Systems genetics of sensation seeking

Sex and strain influence attribution of incentive salience to reward cues in mice

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