German Title: Stressbewältigung: Die Bedeutung des Hypothalamus Hypophysen Nebennieren Systems und neurotropher Regelkreise im Depressions-Model der erlernten Hilflosigkeit

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Abstract

Animal models currently represent a viable route for gaining further insights into the mechanisms involved in the pathogenesis of particular diseases. Depression, in this respect, constitutes a major challenge since the characterization of disease-specific traits is complicated due to the multifactorial nature of the disorder. The understanding of diverse factors, e.g. neurotrophic circuits and the role of the HPA axis, which have to be considered in the pathophysiology of the disease represent a major target of behavioural animal models of depression. Working on a model such as Learned Helplessness, consequently requires careful consideration of modulating aspects to ensure representative results. This work aims at elucidating the role of recently postulated target genes of depression as well as the impact of potential distorting factors, such as housing conditions of the experimental animals. To guarantee a specific readout, which permits concrete statements regarding the role of particular target genes like BDNF, CREB, and GR, we compared both, the effects of different social and as environmental factors with regard to general and Helplessness-specific effects on behaviour. Furthermore, we confirmed the model by a pharmacological validation, simultaneously monitoring effects of the obligatory handling procedure. In studies of depression and emotionality it is important to establish standardized protocols, involving the animal’s environment, to be able to precisely assess potential sources of stress and exclude artefacts. The design and modification of animal models like the Learned Helplessness subsequently bears the advantage of not only detecting potential genetic aspects by investigating mice carrying mutations of particular target genes, e.g. the glucocorticoid receptor, in which significant differences with regard to helpless behaviour and further depressive-like parameters became evident, but also to exploit fundamental causes of depressive-like phenotypes such as stress effects. The detailed evaluation of the Learned Helplessness in mice as a model of depression suggests it as a valuable instrument to investigate mouse models for depression, like GR heterozygous animals, in which the behavioural phenotype was associated with depressive-like characteristics such as a decrease of BDNF protein and relevant physiological parameters which mimick stress, i.e. a depression-typical Dex/CRH Test and elevated corticosterone levels after restraint stress.