A Simple Genetic Basis for a Complex Psychological Trait in Laboratory Mice

Flint, Jonathan; Corley, Robin P.; DeFries, John C.; Fulker, David W.; Gray, Jeffrey A.; Miller, Stacey; Collins, Allan C.

doi:10.1126/science.7660127

Cited by 406 publications

(215 citation statements)

References 31 publications

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“…Consistent with previous findings with F2 mice from these strains, QTL on chromosomes 1 and 15 show the largest effects on behavioral manifestations of anxiety (Flint et al, 1995, Turri et al, 2001b. The major influence of the QTL on chromosome 1 is to Although T1 and T2 QTL for the light-dark box were less consistent than the open-field results, with the exception of the Ch15 QTL T1-T2 differences described above, results for the two widely separated test sessions were largely comparable.…”

Section: Profiles Of Qtl Actionsupporting

confidence: 89%

“…A nonanxiety interpretation of open-runway behavior is supported by the lack of Ch7 QTL effects on the many other measures of anxiety assessed in the two elevated mazes and in the light-dark and mirror-chamber boxes. Several previous studies of mouse anxiety, failed to detect a Ch7 QTL effect (Flint et al, 1995;. We suggest that this may be due to two factors.…”

Section: Qtl Analysis Of Anxiety In Mice 281contrasting

confidence: 53%

“…During the past decade we have been using molecular mapping strategies to investigate the genetic architecture responsible for individual behavioral differences in the DeFries strains of mice (Flint et al, 1995;Turri et al, 2001a, b). The DeFries strains are derived from a cross of two inbred strains (BALB/cJ and C57/BL6) that were selected for differences in open-field activity, a test that is believed to model susceptibility to anxiety in rodents.…”

Section: Introductionmentioning

confidence: 99%

“…We found that genetic loci on chromosomes 1, 4, 15, and 18 influenced at least one measure obtained in all five tests, validating the assumption that there is a psychological construct, sometimes termed emotionality, influencing anxiety-related behavior (Turri et al, 2001b). In addition, the large size of our study, including over 1600 mice and a replicate of a previous intercross between L1 and H1 strains (Flint et al, 1995), provided a powerful test of the robustness of quantitative trait loci (QTL) mapping strategies (Turri et al, 2001a, b).…”

Section: Introductionmentioning

confidence: 99%

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QTL Analysis of Multiple Behavioral Measures of Anxiety in Mice

et al. 2004

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In a test battery consisting of an open-field arena, a light-dark box, a mirror-chamber box, an elevated plus maze, and an elevated square maze, 1,671 mice were tested, generating over 100 putative measures of anxiety in rodents. Quantitative trait loci (QTL) analysis was carried out on all measures, plus composite measures and phenotypic factor scores. Significant LOD scores were found for QTL on 17 chromosomes, with large and consistent QTL behavioral effects on chromosomes 1, 4, 7, 8, 14, 15, l8, and X. QTL on chromosomes 4 and 8 largely influence locomotor activity in both home cages and novel environments, whereas QTL on chromosomes 1, 15, and 18 influence anxiety-related behaviors. Five genetically separable, cross-test dimensions of anxiety could be identified: (i) the suppression of locomotor activity in low to moderately anxiogenic regions of the tests; (ii) a shift toward proportionally less time and activity spent in high-anxiogenic test areas; (iii) the suppression of rearing behavior; (iv) increased latency to enter novel areas; (v) increased autonomic responses, as assessed by defecation and urination. Patterns of QTL influence on cross-test composite scores were distinctive. For example, the QTL on chromosome 1 strongly influenced safe-area locomotor activity (LOD = 35) and autonomic responses (LOD = 16), whereas the QTL on chromosome 15 influenced the proportion of activity in high-anxiogenic areas (LOD = 16), latency to enter novel areas (LOD = 36) and rearing behavior (LOD = 57). Phenotypic factor analysis identified factors heavily loaded on single tests, rather than cross-test factors. The use of factor analysis or within-test principal components for data reduction before genetic analysis was less satisfactory than using genetic dissection methods on the original measures and logically derived composites.

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Section: Profiles Of Qtl Actionsupporting

confidence: 89%

Section: Qtl Analysis Of Anxiety In Mice 281contrasting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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QTL Analysis of Multiple Behavioral Measures of Anxiety in Mice

et al. 2004

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“…Rodent and human emotional reactivity are psychological traits with a well-characterized genetic basis (Flint et al 1995;Eley and Plomin 1997). In each species, this trait is linked with susceptibility to anxiety (Belzung and Berton 1997;Eley and Plomin 1997).…”

Section: Clinical Relevance: a Mechanism Underlying Vulnerability To mentioning

confidence: 99%

Anxiogenic-Like Effects Limit Rewarding Effects of Cocaine in BALB/cByJ Mice

David

Gold

Koob

et al. 2001

Neuropsychopharmacology

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Previous studies have reported intravenous cocaine selfadministration behavior in several strains of mice with the exception of BALB/cByJ, a strain considered a mouse model of high emotional reactivity. The present experiments further investigated acquisition of self-administration in BALB/cByJ mice using a low dose and a habituation session. Following evidence of an initial drug-seeking behavior, we observed a progressive decline of intravenous self-administration. Pretreatment with diazepam (0.5 mg/ kg, IP), reinstated cocaine-maintained responding. To test the hypothesis that injections directly into a rewardrelevant brain region might support consistent cocaineseeking behavior, BALB/cByJ mice implanted in the nucleus accumbens (NAc) or the caudate-putamen nucleus (CPu) were trained to discriminate between the arm enabling a microinjection of cocaine (30 pmol/50 nl or 150 pmol/50 nl) The reinforcing effect of cocaine has long been demonstrated in several species including humans, (Pickens and Thompson 1968;Woods and Schuster 1968;Deneau et al. 1969;Goldberg 1973;Fischman and Schuster 1982). However, in studies using monkeys as well as rats, not all individual subjects exhibit acquisition of self-administration, and data from subjects that fail to acquire selfadministration are usually excluded (Davis and Smith 1987). Consistent with these observations, many humans experiencing psychostimulant drugs do not develop compulsive drug-seeking behavior (Siegel 1984;O'Brien et al. 1986). Recently, an increasing number of studies have investigated the biological basis of the vulnerability to drug abuse in outbred rats. From this work, it is possible to define a vulnerability profile based on a number of behavioral, neurochemical, and endocrinological features (Hooks et al. 1991;Piazza and Le Moal 1996). Importantly, traits associated with a vulnerable phenotype in rats, such as novelty-induced activity, can be compared to psychological dimensions measured in humans, such as novelty-seeking behavior (see Bardo et al. 1996). It is of special interest to note here that novelty- Cocaine Self-Administration in BALB/cByJ Mice 301 seeking and drug-seeking behaviors co-vary in humans as well as laboratory animals (Bardo et al. 1996). These behaviors are also expressed differentially in inbred strains of mice making these mice a potentially important model for further examining the relationship between behavioral traits, their underlying biological basis, and drug-seeking behavior (Crabbe et al. 1994).Of particular interest in this context is the difficulty of demonstrating intravenous cocaine self-administration in BALB/cByJ mice (Deroche et al. 1997;Roberts et al. 1997;Yu et al. 1997), using doses known to maintain self-administration in C57BL/6 or several other strains (Carney et al. 1991;Grahame et al. 1995;Deroche et al. 1997;Rocha et al. 1998). This observation cannot be accounted for by pharmacokinetic differences (Ruth et al. 1988), capacity to learn operant tasks (Cazala 1976;Deroche et al. 1997;Heyser et al. 199...

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Influence of RGS2 on Anxiety-Related Temperament, Personality, and Brain Function

Smoller

Paulus²,

Fagerness³

et al. 2008

Arch Gen Psychiatry

138

107

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These results provide the first evidence that a gene that influences anxiety in mice is associated with intermediate phenotypes for human anxiety disorders across multiple levels of assessment, including childhood temperament, adult personality, and brain function. This translational research suggests that some genetic influences on anxiety are evolutionarily conserved and that pharmacologic modulation of RGS2 function may provide a novel therapeutic approach for anxiety disorders.

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A Simple Genetic Basis for a Complex Psychological Trait in Laboratory Mice

Cited by 406 publications

References 31 publications

QTL Analysis of Multiple Behavioral Measures of Anxiety in Mice

QTL Analysis of Multiple Behavioral Measures of Anxiety in Mice

Anxiogenic-Like Effects Limit Rewarding Effects of Cocaine in BALB/cByJ Mice

Influence of RGS2 on Anxiety-Related Temperament, Personality, and Brain Function

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