Rhythmicity in mice selected for extremes in stress reactivity: behavioural, endocrine and sleep changes resembling endophenotypes of major depression

Abstract

Background: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyper- or hypo-activity of the stress hormone system, plays a critical role in the pathophysiology of mood disorders such as major depression (MD). Further biological hallmarks of MD are disturbances in circadian rhythms and sleep architecture. Applying a translational approach, an animal model has recently been developed, focusing on the deviation in sensitivity to stressful encounters. This so-called 'stress reactivity' (SR) mouse model consists of three separate breeding lines selected for either high (HR), intermediate (IR), or low (LR) corticosterone increase in response to stressors.

Methodology/principle findings: In order to contribute to the validation of the SR mouse model, our study combined the analysis of behavioural and HPA axis rhythmicity with sleep-EEG recordings in the HR/IR/LR mouse lines. We found that hyper-responsiveness to stressors was associated with psychomotor alterations (increased locomotor activity and exploration towards the end of the resting period), resembling symptoms like restlessness, sleep continuity disturbances and early awakenings that are commonly observed in melancholic depression. Additionally, HR mice also showed neuroendocrine abnormalities similar to symptoms of MD patients such as reduced amplitude of the circadian glucocorticoid rhythm and elevated trough levels. The sleep-EEG analyses, furthermore, revealed changes in rapid eye movement (REM) and non-REM sleep as well as slow wave activity, indicative of reduced sleep efficacy and REM sleep disinhibition in HR mice.

Conclusion/significance: Thus, we could show that by selectively breeding mice for extremes in stress reactivity, clinically relevant endophenotypes of MD can be modelled. Given the importance of rhythmicity and sleep disturbances as biomarkers of MD, both animal and clinical studies on the interaction of behavioural, neuroendocrine and sleep parameters may reveal molecular pathways that ultimately lead to the discovery of new targets for antidepressant drugs tailored to match specific pathologies within MD.

Figure 1. Corticosterone increase in the stress reactivity test (SRT) of the experimental animals selected from the seventh generation of the high (HR), intermediate (IR) and low (LR) reactivity mouse lines.

Data are given as box plots showing medians (lines in the boxes), 25% and 75% percentiles (boxes) as well as 10% and 90% percentiles (whiskers). Statistical differences between the three lines (KWH-test, for details see text) are given at the top of the panel and results of the pairwise group comparisons (post-hoc MWU-tests) are indicated below (Bonferroni corrected p<0.001 ***).

Figure 2. Distribution of motor activity over the 24-h light-dark cycle in high (HR), intermediate (IR), and low (LR) reactivity males from generation VII.

Data are given as means±SEM for each line. Statistical differences between the three lines are indicated by asterisks (KWH-tests, for details see text, p<0.05 *). The dark phase of the light-dark cycle is indicated by the shaded area.

Figure 3. Distribution of explorative behaviour over the 24-h light-dark cycle in high (HR), intermediate (IR), and low (LR) reactivity males from generation VII.

Data are given as means±SEM for each line. Statistical differences between the three lines are indicated by asterisks (KWH-tests, for details see text, p<0.05 *, p<0.01 **). The dark phase of the light-dark cycle is indicated by the shaded area.

Figure 4. Diurnal variation of immunoreactive corticosterone metabolites (CM) in faecal samples of high (HR), intermediate (IR), and low (LR) reactivity males from generation VII over the 24-h light-dark cycle.

Data are given as means±SEM for each line. Statistical differences between the three lines are indicated by asterisks (KWH-tests, for details see text, p<0.05 *, p<0.01 **, p<0.001 ***). The dark phase of the light-dark cycle is indicated by the shaded area.

Figure 5. Distribution of vigilance states over the 24-h light-dark cycle in high (HR), intermediate (IR), and low (LR) reactivity males from generation VII.

The relative amount of wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep are plotted in panel A, B and C, respectively. Data are given as means±SEM for HR and LR mice and as SEM-area for the IR mouse line. Statistical differences between the three lines are indicated by asterisks (KWH-tests, for details see text, p<0.05 *). The dark phase of the light-dark cycle is indicated by the shaded area.

Figure 6. Distribution of the relative amount of slow wave activity (SWA) over the 24-h light-dark cycle in high (HR), intermediate (IR), and low (LR) reactivity males from generation VII.

Data are given as means±SEM for HR and LR mice and as SEM-area for the IR mouse line. Statistical differences between the three lines are indicated by asterisks (KWH-tests, for details see text, p<0.05 *). The dark phase of the light-dark cycle is indicated by the shaded area.