Genetic association between helpless trait and depression-related phenotypes: evidence from crossbreeding studies with H/Rouen and NH/Rouen mice

Abstract

Genetic factors are believed to be involved in the aetiology of unipolar depressive disorders. We have previously described a model built up by selective breeding of mice with different responses in the tail suspension test, a screening test for potential antidepressants. In this model, helpless H/Rouen mice are essentially immobile in this test, as well as in the Porsolt forced-swim test, whereas non-helpless NH/Rouen mice show the opposite behaviour, i.e. very low immobility. However, it is unclear whether or not the other phenotypic differences (forced swim test, locomotor activity, sucrose test, sleep patterns, effect of fluoxetine) observed between H/Rouen and the NH/Rouen mice may be attributed to a genetic drift phenomenon during the selection step, rather than being related to the trait of selection. In this study we used reciprocal crossbreeding between H/Rouen and NH/Rouen mice and obtained a segregating F2 population in order to determine whether phenotypic differences between the two lines co-segregate with the trait of selection. In the segregating F2 population, we found significant and strong genetic correlations between helplessness in the tail suspension test and some phenotypical features associated with depressive disorders such as 'alterations of sleep patterns', behavioural response to fluoxetine, immobility duration in the forced swim test, and anhedonia. Our results converge with clinical observations in depressed humans. These results strengthen the validity of the H/Rouen mouse as a model of depression, notably for preclinical studies with antidepressants. In addition, this model should open the way to identifying genes related to depression-like behaviours.

Altered brain network modules induce helplessness in major depressive disorder

“…Likewise, quantitative histochemistry studies showed opposite metabolic changes of cytochrome oxidase between the habenula and the ventral tegmental area (VTA) in helpless rat (Shumake et al, 2003, 2010). Finally, other genetic studies in animal models confirmed a correlation between helplessness and depression (Smalheiser et al, 2011; Yacoubi et al, 2012) as evidenced by differential gene expression in the hippocampus (Kohen et al, 2005; Lachman et al, 1992) and the frontal cortex (Hoyle et al, 2011). Taken together, these findings suggest that the prefrontal cortex, hippocampus, and some subcortical regions may be responsible for the organization alteration of brain functional network that underlies both helplessness and depression.…”

Anhedonic-like traits and lack of affective deficits in 18-month-old C57BL/6 mice: Implications for modeling elderly depression

“…These changes are often associated with a reduction in novelty exploration and grooming behavior in the splash test (Strekalova et al, 2004;Skrinskaia and Nikulina, 1994;Pothion et al, 2004). Antidepressant treatment counteracts the above-mentioned depressive-like traits in rodents (Porsolt and Papp, 1998;Willner, 2005;Strekalova et al, 2011;Yacoubi et al, 2011;Surget et al, 2008).…”

“…Anhedonic behavior defined by decreased sucrose intake and preference on one hand, and signs of behavioral despair in the forced swim and modified tail suspension tests on the other, have been extensively validated as parameters of reward sensitivity and affective traits in mice and rats (Porsolt and Papp, 1998;Willner, 2005;Strekalova et al, 2011;Yacoubi et al, 2011). In sum, using these paradigms and additional tests, the present study examined whether, in comparison with 3-month-old mice of the C57BL6N strain, 18-month-old mice (1) exhibit changes indicative of the depressive state in the sucrose test, novelty exploration, splash test, forced swim and modified tail suspension paradigms, (2) show the prevalence of one type of deficit, hedonic-or affective-like, over the other, whether (3) older animals have disturbances in daily liquid intake, anxiety-like behavior and locomotion that are non-specific to depressive-like traits and (4) parameters of depressive-like behavior in aged animals are sensitive to antidepressant treatment.…”

Research into an Association between Anhedonia and Decreased REM Latency in Moderately to Severely Depressed Patients

“…Interestingly, one study achieved on mice drew our attention to a correlation between a particular mouse phenotype (helpless) and alterations of sleep patterns but also anhedonia [ 35 ]. This suggests a future interest in the potential examination of genotype aspects of vulnerability to anhedonic symptoms and more generally to depression.…”