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Chadi TOUMA" Mice Selected for Extremes in Stress Reactivity : Modelling Clinically Relevant Endophenotypes of Major Depression "

Abstract :


Affective disorders such as major depression are among the most prevalent and costly diseases of the central nervous system, but the underlying mechanisms are still poorly understood.
In recent years, it has become evident that alterations of the stress hormone system, in particular dysfunctions (hyper- or hypo-activity) of the hypothalamic-pituitary-adrenal (HPA) axis, play a prominent role in the etiology of major depression. Therefore, we aimed to generate and characterize a new animal model comprising these neuroendocrine core symptoms in order to unravel the mechanisms underlying increased or decreased stress reactivity.
Starting from a population of outbred mice, two breeding lines were established according to the outcome of a ‘stress reactivity test’ (SRT), consisting of a 15-min restraint period and tail blood samplings immediately before and after exposure to the stressor. Mice showing a high or a low secretion of corticosterone in the SRT were selected for the ‘high reactivity’ (HR) and the ‘low reactivity’ (LR) breeding line, respectively. Additionally, a third breeding line with an ‘intermediate reactivity’ (IR) in the SRT was established.
Already in the first generation, significant differences in the reactivity of the HPA axis between HR, IR, and LR mice were observed. Moreover, these differences remained stable across all subsequent generations and could be increased by selective inbreeding, indicating a genetic basis of the respective phenotype. Repeated testing of individuals in the SRT furthermore proved that the observed differences in stress responsiveness are already present early in life and can be regarded as a robust genetic predisposition. Behavioral emotionality testing as well as several morphometric, neuroendocrine, and gene expression findings also point to similarities with depressive patients, in particular when the two subtypes of melancholic and atypical depression are considered.
Taken together, our results indicate that distinct mechanisms influencing the function and regulation of the HPA axis seem to mediate the respective behavioral and neurobiological endophenotypes. Thus, the generated HR/IR/LR mouse lines can be a valuable model to elucidate the molecular underpinnings of altered stress reactivity, thereby improving our understanding of affective disorders.

Selected publications

Modeling psychotic and cognitive symptoms of affective disorders: Disrupted latent inhibition and reversal learning deficits in highly stress reactive mice.Knapman A, Heinzmann JM, Holsboer F, Landgraf R, Touma C. Neurobiol Learn Mem. 2010 May 6. [Epub ahead of print]
Increased stress reactivity is associated with cognitive deficits and decreased hippocampal brain-derived neurotrophic factor in a mouse model of affective disorders.Knapman A, Heinzmann JM, Hellweg R, Holsboer F, Landgraf R, Touma C.J Psychiatr Res. 2010 Jul;44(9):566-75. Epub 2009 Dec 24.

Scientific focus :

Chadi Touma studied Biology and Biochemistry in Muenster and Hanover, Germany. His doctoral studies focussed on the development, validation and application of a non-invasive technique to monitor stress hormones in mice. He graduated with ’summa cum laude’ at the University of Muenster and in 2004 joined the Max Planck Institute of Psychiatry (MPIP) in Munich. Recently, he was appointed Head of the Research Group of Psychoneuroendocrinology at the MPIP.
Current research projects encompass investigations to elucidate the molecular-genetic, neuroendocrine and behavioural mechanisms underlying affective disorders (focus: anxiety and depression, animal models: different selectively bred mouse lines and transgenic mice).

Marie Pierre Moisan