Association of a locus on rat chromosome 4 with anxiety-related behaviors in two selectively bred rat lines (original) (raw)
Related papers
A Quantitative Trait Locus Influencing Anxiety in the Laboratory Rat
Genome Research, 2002
A critical test for a gene that influences susceptibility to fear in animals is that it should have a consistent pattern of effects across a broad range of conditioned and unconditioned models of anxiety. Despite many years of research, definitive evidence that genetic effects operate in this way is lacking. The limited behavioral test regimes so far used in genetic mapping experiments and the lack of suitable multivariate methodologies have made it impossible to determine whether the quantitative trait loci (QTL) detected to date specifically influence fear-related traits. Here we report the first multivariate analysis to explore the genetic architecture of rodent behavior in a battery of animal models of anxiety. We have mapped QTLs in an F2 intercross of two rat strains, the Roman high and low avoidance rats, that have been selectively bred for differential response to fear. Multivariate analyses show that one locus, on rat chromosome 5, influences behavior in different models of anxiety. The QTL influences two-way active avoidance, conditioned fear, elevated plus maze, and open field activity but not acoustic startle response or defecation in a novel environment. The direction of effects of the QTL alleles and a coincidence between the behavioral profiles of anxiolytic drug and genetic action are consistent with the QTL containing at least one gene with a pleiotropic action on fear responses. As the neural basis of fear is conserved across species, we suggest that the QTL may have relevance to trait anxiety in humans. 6 Corresponding author. E-MAIL jf@molbiol.ox.ac.uk; FAX (44) 1861 287501. Article and publication are at
Quantitative trait loci (QTLs) mapping has been performed during the past decades in an attempt to identify genes, gene products and mechanisms underlying numerous quantitative traits. It’s a strategy based on natural variations in genes and gene products, which facilitates translation from animal models to human clinical conditions. Our team has shown that the inbred rat strains Lewis (LEW) and Spontaneously Hypertensive Rats (SHR) differ with respect to several emotionality- related behaviors, one of which (inner locomotion in the open field) was strongly influenced by a QTL (Anxrr16) on rat chromosome 4. Since then, several other studies not only corroborated the initial description of Anxrr16, but also extrapolated its effects to a broader context (rats from both sexes and regardless of the estrous cycle phase) and suggested that this same region influences other emotionality-related behaviors as well as alcohol intake. Other QTLs affecting neurobiological traits were also found on rat chromosome 4 and several candidate genes have been pointed out as possibly influencing those phenotypes. Altogether, these studies suggest that rat chromosome 4 constitutes an interesting target for the study of the molecular bases of anxiety and other traits related to emotional reactivity.
A genetic and multifactorial analysis of anxiety-related behaviours in Lewis and SHR intercrosses
Behavioural Brain Research, 1998
Lewis (LEW) and spontaneously hypertensive rats (SHR) have been shown to differ in a series of fear-related behaviours measured in different anxiety/emotionality tests. In the present study, we have investigated some of the genetic mechanisms underlying these differences. To this end, male and female rats from the two inbred strains were crossed to produce two parental (LEW and SHR), two F1 (LEW or SHR mother), and two F2 (LEW or SHR grandmother) groups. All rats were tested in the elevated plus-maze and in the open field, besides being characterised for systolic blood pressure (BP). LEW rats approached the open arms of the plus-maze and the central area of the open field less than SHRs. The two strains also differed in their BP (SHR\ LEW). LEW/SHR differences were found to be due to direct effects of the genes, rather than to indirect maternal and grand-maternal effects. Central locomotion in the open field was shown to be the most heritable of all the traits considered herein. A factor analysis on the segregating F2 population produced three independent factors. The first one was associated to measures of anxiety from the elevated plus-maze, and the second to measures of locomotion in novel environments. Factor scores revealed that the parental strains differ in relation to the first but not to the second factor. This study demonstrates the usefulness of coupling genetic and multifactorial methods to investigate behavioural traits and it confirms LEW and SHR strains as an interesting genetic tool for the study of anxiety.
What can we learn on rodent fearfulness/anxiety from the genetically heterogeneous NIH-HS rat stock?
Open Journal of Psychiatry, 2013
The "National Institutes of Health" genetically heterogeneous (NIH-HS) rat stock was created in the 1980s through an eight-way cross of as much as possible separate inbred rat strains (i.e. the MR/N, and BUF/N strains) which were readily available at that time. Hansen and Spuhler [1] developed a more naturalistic, genetically heterogeneous rat stock with the aim of optimizing the distribution of genotypic frequencies and recombination and under the hypothesis that the NIH-HS stock could yield a broad-range distribution of responses (broader than commonly used laboratory rat strains) to experimental conditions, and thus serve as a base population for selection studies. Along the last decade, in a series of studies we have phenotypically characterized the NIH-HS rat stock (a colony exists at our laboratory since 2004) for their anxiety/fearfulness profiles (using a battery of both unconditioned and conditioned tests/tasks), as well as regarding their stress-induced hormonal responses, coping style under inescapable stress and spatial learning ability. We have also compared the phenotypic profiles of NIH-HS rats with those of the low anxious RHA-I and the high anxious RLA-I rat strains. The NIH-HS rat stock is, as a population, a rather anxious type of rat, with predominantly reactive/passive coping style in unlearned and learned anxiety/fear tests, and elevated stress hormone responses (as well as enhanced "depressive" symptoms in the forced swimming test). Genetic studies currently under way have thus far revealed that the genetically heterogeneous NIH-HS rat stock constitutes a unique tool for fine mapping of QTL (for multiple behavioural and biological complex traits) to megabase resolution levels, thus enabling candidate gene identification. We give some examples of this in the present paper, while also highlighting that microarray gene expression studies reveal that HPA-axis-and prolactin-related genes (among others) in the amygdala appear to be related with (or associated to) the coping style and anxiety/fearfulness responses of NIH-HS rats.
Behavior Genetics, 2008
Male mice from a panel of chromosome substitution strains (CSS, also called consomic strains or lines)-in which a single full-length chromosome from the A/J inbred strain has been transferred onto the genetic background of the C57BL/6J inbred strain-and the parental strains were examined in the modified hole board test. This behavioral test allows to assess for a variety of different motivational systems in parallel (i.e. anxiety, risk assessment, exploration, memory, locomotion, and arousal). Such an approach is essential for behavioral characterization since the motivational system of interest is strongly influenced by other behavioral systems. Both univariate and bivariate analyses, as well as a factor analysis, were performed. The C57BL/6J and A/J mouse parental inbred strains differed in all motivational systems. The chromosome substitution strain survey indicated that nearly all mouse chromosomes (with the exception of chromosome 2) each contain at least one quantitative trait locus (QTL) that is involved in modified hole board behavior. The results agreed well with previous reports of QTLs for anxiety-related behavior using the A/J and C57BL/6J as parental strains. The present study confirmed that mouse chromosomes 5, 8, 10, 15, 18 and 19 likely contain at least one anxiety QTL. There was also evidence for a novel anxiety QTL on the Y chromosome. With respect to anxiety-related avoidance behavior towards an unprotected area, we have special interest for mouse chromosome 19. CSS-19 (C57BL/6J-Chr19 A /NaJ) differed in avoidance behavior from the C57BL/6J, but not in locomotion. Thus pleiotropic contribution of locomotion could be excluded.
Behavioral evaluation of eight rat lines selected for high and low anxiety-related responses
2013
h i g h l i g h t s • Genetic models are powerful tools to help understand anxiety disorders. • In order to determine the extent to which multiple anxiety traits generalize we compared eight genetic lines of rats selected for single high or low emotional responses. • We find many behavioral traits generalize across different animal lines selected for a single trait.
High-resolution mapping of quantitative trait loci for emotionality in selected strains of mice
Mammalian Genome, 1999
While a genetic contribution to many behavioral traits is not in doubt, attempts to find the genes themselves have not met with much success. One advance towards this goal has been the demonstration that it is possible to map genes that determine variation in quantitatively measured behavioral traits with crosses between inbred strains (both rodents and insects have been used). Further progress requires high-resolution mapping of quantitative trait loci (QTL). Current detection methods place QTLs within an interval of about half a chromosome, far too large for positional cloning to be a viable option, and a number of approaches have been advocated to increase resolution (Darvasi 1998).
Identification of female-specific QTLs affecting an emotionality-related behavior in rats
Molecular Psychiatry, 1999
The influence of genetic factors on psychological traits and disorders has been repeatedly demonstrated; however, the molecular mechanisms underlying such an influence remain largely unknown. Anxiety-related disorders constitute the most common class of mental disorder in humans, with women being diagnosed far more frequently than men. A better understanding of the genetic and gender-related mechanisms mediating anxiety traits should enable the development of more rational methods for preventing and treating anxiety disorders. In this study we have aimed to identify, for the first time, quantitative trait loci (QTL) influencing anxiety/emotionality-related traits in rats. To this end, two strains-Lewis (LEW) and Spontaneously Hypertensive Rats (SHR)-that differ for several behavioral measures of anxiety/emotionality were intercrossed. A QTL analysis of the F2 population revealed suggestive loci for various traits, including behaviors in the elevated plus-maze and blood pressure. In addition, one major QTL explaining 50.4% of the total variance (LOD = 7.22) was identified on chromosome 4 for the locomotion in the central and aversive area of the open field. Two other relevant QTLs have been recently mapped near this chromosomic region in the rat, which also harbors Tac1r, the gene encoding for the substance P receptor. Our major QTL affected females but not males and its effect depended on the type of cross (LEW or SHR grandmothers). The present results reveal a complex genetic basis underlying emotional behaviors and they confirm the existence of interactions between genetic factors and sex for this kind of trait. Further investigation of the loci identified herein may give clues to the pathophysiology of psychiatric disorders such as anxiety-related ones.