QTL Analysis of Multiple Behavioral Measures of Anxiety in Mice

Abstract

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.

Brain-Derived Neurotrophic Factor Serum Levels and Genotype: Association with Depression during Interferon-α Treatment

“…Finally, different genetic regions have been associated with specific mood and anxiety traits in both mice (Henderson et al, 2004), and humans (Foley et al, 2003;Jang et al, 2004), which can affect genetic association study results (Lotrich, 2011). Consistent with this, we have found that polymorphisms affecting TNF-a and IL-28b are associated with specific mood-related symptom clusters in individuals receiving IFN-a (Lotrich et al, 2010;Lotrich et al, 2011).…”

“…In fact, different specific depression symptoms may be influenced by different genes (Jang et al, 2004), a phenomenon long noted in mice where different chromosomal regions are implicated in anxiety-depending on what behavioral test is used (Henderson et al, 2004). The possibility that the Met allele is only associated with risk for a subset of symptoms may be one plausible reason that some studies do not replicate an association between depression risk and the BDNF Val/Met polymorphism Figueira et al, 2010;Middeldorp et al, 2010;Ribeiro et al, 2007;Suchanek et al, 2011;Wray et al, 2008).…”

The serotonin 1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety

“…We also show that the maternal 5-HT 1A R genotype, in combination with the offspring 5-HT 1A R genotype, results in reduced safe-area activity in the EPM. It has been shown previously that some of the QTLs in mice for threatening-and safe-area locomotor activity overlap (12). Nevertheless, the maternal 5-HT 1A R genotype alone was not sufficient to elicit a change in this measure.…”

“…Open field (OF) is another test of anxiety-like behavior, and, as in the EPM, reduced time spent and distance traveled in the center area of the field is indicative of an anxiety-like phenotype (7). However the OF is considered less stressful than the EPM (11), and quantitative trait locus (QTL) studies identified both shared and OF-specific loci (12). Anxiety in the OF was completely offspring-genotype dependent, and neither the post-nor the prenatal maternal environment, and not even their combination, increased anxiety ( Fig.…”

Anxiety and Hippocampus Volume in the Rat

“…The degree of avoidance of the open arms of the maze is considered a measure of the genetic predisposition, that is, trait anxiety, and is predictive of behavior in other tests of anxiety (Henderson et al, 2004;Trullas and Skolnick, 1993).…”