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

Abstract

BackgroundNeuronal 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.ResultsDifferences 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.ConclusionsThe 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.

Neuroligin 3 R451C mutation alters electroencephalography spectral activity in an animal model of autism spectrum disorders

“…We found that both WT and Nlgn3 R451C mutant mice spent more time sleeping during the light phase compared to the dark, consistent with the typical time distribution of vigilance states in nocturnal rodents [40]. Nlgn3 R451C mutant mice were also not different from their WT controls in the total amount of time as well as the total number and durations of episodes for each sleep/wake state, suggesting that Nlgn3 R451C mutation alone may not be sufficient to cause reduced sleep time or frequent waking observed in patients with ASD [3, 4, 11].…”

“…Consistent with this finding, suppression of delta oscillations was also observed following the administration of diazepam, a GABA agonist [38, 50]. Theta oscillations, which are predominantly generated by the hippocampal network [40, 51, 52], were also reduced in Nlgn3 R451C mutant mice during NREM sleep. Previously, Nlgn3 R451C mutants mice were demonstrated to have increased excitatory glutamatergic synaptic transmission without alterations in inhibitory GABAergic transmission in the hippocampus, resulting in an augmented E/I ratio in this region [30].…”

Sleep electroencephalography as a biomarker in depression

“…120,125,126 Similarly, the distinct stress reactivity mouse model in reference to the HPA axis that shows high stress reactivity, spends time in more REM sleep than the other lines with intermediate or low stress reactivity. 127,128 The amount of non-REM sleep is indistinguishable between these three separate breeding lines selected for high (HR), intermediate (IR), or low (LR) corticosterone increases in response to stressors. However, the high stress reactivity line shows lower SWA during non-REM sleep, whereas the theta power in the LR line is lower than the others across all vigilance states.…”

Distinct Parameters in the EEG of the PLP α-SYN Mouse Model for Multiple System Atrophy Reinforce Face Validity

“…For that, we re-analyzed the corresponding EMG activity for each single REMS epoch identified by the semi-automatic sleep scoring and/or manual re-scoring. The re-analysis was necessary to detect REM-A epochs/episodes that were scored as WAKE during the semi-automatic process of sleep scoring due to EMG-activity which is defined as WAKE per se in our scoring routines (Fenzl et al, 2007, 2011; Polta et al, 2012; Kreuzer et al, 2015). We only assigned muscle activity to REM-A if the EEG could be unmistakably discriminated from an WAKE EEG (different scorers blind to each other and to the data sets).…”