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


RESULTS
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.


CONCLUSIONS
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.
Touma
Chadi
C
Max Planck Institute of Psychiatry, Munich, Germany. touma@mpipsykl.mpg.de
Fenzl
Thomas
T
Ruschel
Jörg
J
Palme
Rupert
R
Holsboer
Florian
F
Kimura
Mayumi
M
Landgraf
Rainer
R
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002940:Circadian Rhythm; D003345:Corticosterone / Q000378:metabolism; D003624:Darkness; D003865:Major Depressive Disorder / Q000503:physiopathology*; D004703:Endocrine System / Q000502:physiology*; D005106:Exploratory Behavior; D005243:Feces / Q000737:chemistry; D005938:Glucocorticoids / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008297:Male; D051379:Mice; D009043:Motor Activity; D010507:Periodicity; D010641:Phenotype; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D012890:Sleep / Q000502:physiology*; D013315:Stress, Psychological / Q000503:physiopathology*; D014851:Wakefulness
D005938:Glucocorticoids; D003345:Corticosterone