Abstract Dysfunctions of the hypothalamic-pituitary-adrenal (HPA) axis are closely associated with the pathophysiology of affective disorders such as major depression (MD). Accordingly, patients suffering from MD frequently show profound neuroendocrine alterations with hyper- or hypo-cortisolism as a result of a dysregulated stress hormone system. Focusing on this key endophenotype of MD, a new genetic mouse model has been established in our group by applying a selective breeding approach in order to unravel the molecular mechanisms underlying increased versus decreased stress reactivity, including concomitant alterations in brain function.
Various experiments have been performed to in-depth characterize these high (HR), intermediate (IR) and low (LR) reactivity mouse lines, particularly addressing clinically relevant aspects.
Interestingly, the hyper- (HR) and hypo- (LR) reactivity to stressors in our mouse model are accompanied by alterations in emotional behaviour, vegetative functions (including rhythmicity and sleep architecture) and cognitive processes, revealing phenotypic similarities to patients suffering from MD, in particular, when the two subtypes of melancholic and atypical depression are considered. Morphometric and neurobiological findings also support this view. Moreover, the stable differences in stress reactivity are associated with a hyper- or hypo-responsiveness at all levels of the HPA axis (peripheral, central and regulatory functions), indicating profound differences in the activation and feedback regulation of this important neuroendocrine system.
The results gathered so far demonstrate that the stress reactivity mouse model shows functional alterations in many relevant parameters, revealing endophenotypes highly similar to those observed in MD patients, thus proving a high level of face and construct validity of the model.
In conclusion, by selectively breeding mice for extremes in stress reactivity clinically relevant endophenotypes of MD can be modelled, presumably including the symptomatology and pathophysiology of specific subtypes of the disease. Given its unique strength as an experimental system for studying genetics, neurobiology and behaviour, the stress reactivity mouse model can be central to meeting the challenge for cross-species translational research in biological psychiatry. Thus, the HR/IR/LR mouse lines are a highly valuable tool to significantly improve our understanding of the biological underpinnings and pathways involved in the aetiology of affective disorders, including the discovery/refinement of novel targets for drugs tailored to match specific pathologies.
