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. 2011 Mar 24:12:29.
doi: 10.1186/1471-2202-12-29.

Sleep disturbances in highly stress reactive mice: modeling endophenotypes of major depression

Thomas Fenzl  1 , Chadi Touma, Christoph Pn Romanowski, Jörg Ruschel, Florian Holsboer, Rainer Landgraf, Mayumi Kimura, Alexander Yassouridis
Affiliations

Sleep disturbances in highly stress reactive mice: modeling endophenotypes of major depression

Thomas Fenzl et al. BMC Neurosci. .

Abstract

Background: Neuronal mechanisms underlying affective disorders such as major depression (MD) are still poorly understood. By selectively breeding mice for high (HR), intermediate (IR), or low (LR) reactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis, we recently established a new genetic animal model of extremes in stress reactivity (SR). Studies characterizing this SR mouse model on the behavioral, endocrine, and neurobiological levels revealed several similarities with key endophenotypes observed in MD patients. HR mice were shown to have changes in rhythmicity and sleep measures such as rapid eye movement sleep (REMS) and non-REM sleep (NREMS) as well as in slow wave activity, indicative of reduced sleep efficacy and increased REMS. In the present study we were interested in how far a detailed spectral analysis of several electroencephalogram (EEG) parameters, including relevant frequency bands, could reveal further alterations of sleep architecture in this animal model. Eight adult males of each of the three breeding lines were equipped with epidural EEG and intramuscular electromyogram (EMG) electrodes. After recovery, EEG and EMG recordings were performed for two days.

Results: Differences in the amount of REMS and wakefulness and in the number of transitions between vigilance states were found in HR mice, when compared with IR and LR animals. Increased frequencies of transitions from NREMS to REMS and from REMS to wakefulness in HR animals were robust across the light-dark cycle. Detailed statistical analyses of spectral EEG parameters showed that especially during NREMS the power of the theta (6-9 Hz), alpha (10-15 Hz) and eta (16-22.75 Hz) bands was significantly different between the three breeding lines. Well defined distributions of significant power differences could be assigned to different times during the light and the dark phase. Especially during NREMS, group differences were robust and could be continuously monitored across the light-dark cycle.

Conclusions: The HR mice, i.e. those animals that have a genetic predisposition to hyper-activating their HPA axis in response to stressors, showed disturbed patterns in sleep architecture, similar to what is known from depressed patients. Significant alterations in several frequency bands of the EEG, which also seem to at least partly mimic clinical observations, suggest the SR mouse lines as a promising animal model for basic research of mechanisms underlying sleep impairments in MD.

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Figures

Figure 1
Figure 1
Mean duration of vigilance states in high reactivity (HR), intermediate reactivity (IR) and low reactivity (LR) mice. The relative amounts of WAKE, NREMS and REMS are plotted in the panels L1 (light period 1, ZT0-6), L2 (light period 2, ZT6-12), D1 (dark period 1, ZT12-18, dark background) and D2 (dark period 2, ZT18-23, dark background). All three mouse lines display a typical circadian distribution of the vigilance states with significant differences observed in the HR line compared to IR and LR mice. Statistical differences between the mouse lines are indicated by asterisks ((*), Bonferroni modified LSD tests, p < 0.05). Data are given as means ± SEM.
Figure 2
Figure 2
Mean transition frequencies between the three vigilance states in HR, IR and LR mice. The relative amounts of transition frequencies for all vigilance states are plotted separately for L1, L2, D1 and D2. In L2 and D1, the HR animals had significantly more transitions from REMS to WAKE, when compared with both other lines. In D2, the HR line showed a different pattern of transitions for all combinations shown, when compared with IR and LR mice, except for the transition of REMS to NREMS. Statistical differences between the mouse lines are indicated by asterisks (*). Data are given as means ± SEM.
Figure 3
Figure 3
Mean REMS episode length in HR, IR and LR mice. Group-comparisons for all three breeding lines during L1, L2, D1 and D2 revealed no significant differences for the mean REMS episode length. Data are given as means ± SEM.
Figure 4
Figure 4
Stability of progressions over time in HR, IR and LR mice. Left column: The curve progressions of group means of normalized power (expressed in percent of the total power) are plotted separately for each breeding line during L1, L2, D1 and D2. The mean theta power and mean alpha power of the LR animals clearly showed a stable progression significantly below the mean of both frequency bands in HR and IR mice across the whole experimental time period. Right column: The number of transitions from NREMS to REMS and from REMS to WAKE in HR mice are significantly and robust above the transitions of IR and LR animals. Data are given as means without SEM for reasons of clarity.
Figure 5
Figure 5
Mean relative power of the EEG frequency bands in HR, IR and LR mice. The relative power, summarized for the vigilance states WAKE, NREMS and REMS are plotted separately for L1, L2, D1 and D2. Significant differences in particular frequency bands are highlighted with a striped background (L1: alpha-band at 10-15 Hz; L2: eta-band at 16-22.75 Hz and D2: theta-band at 6-9 Hz). Marginal differences are marked with a dotted background (L1: theta-band at 6-9 Hz and eta-band at 16-22.75 Hz; D1: theta-band at 6-9 Hz). Data are given as means without SEM for reasons of clarity.
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