Verhaltensphänotypisierung von Mäusen.

According to the recent global burden of disease study of the World Health Organisation, mental and neurological disorders account for a substantial proportion of the world’s disease burden. In complex diseases, both life style and genetic predisposition contribute to disease development. The mouse has become a valuable animal model to understand di - sease etiology and to develop therapies, because mice can be easily genetically modified, and many disease symptoms can be readily measured in mice

High-troughput mouse phenotyping.

Here, we describe the systematic mouse phenotyping approach of the German Mouse Clinic (GMC), that works as an open-access phenotyping platform, and of the European Mouse Disease Clinic, which is an EU-funded multi-centre project characterising mutants generated by the large-scale mouse mutagenesis project European Conditional Mouse Mutagenesis Program. We explain the aims and the general framework of these large-scale projects and the resulting consequences for the phenotyping strategies. Then, we focus on the description of the behavioural tests used in the GMC to detect motor and nonmotor symptoms in mouse mutants that are genetic models of human movement disorders or neurodegenerative diseases

Phenotyping of behavioral characteristics.

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High-throughput mouse phenotyping.

Comprehensive phenotyping will be required to reveal the pleiotropic functions of a gene and to uncover the wider role of genetic loci within diverse biological systems. The challenge will be to devise phenotyping approaches to characterise the thousands of mutants that are being generated as part of international efforts to acquire a mutant for every gene in the mouse genome. In order to acquire robust datasets of broad based phenotypes from mouse mutants it is necessary to design and implement pipelines that incorporate standardised phenotyping platforms that are validated across diverse mouse genetics centres or mouse clinics. We describe here the rationale and methodology behind one phenotyping pipeline, EMPReSSslim, that was designed as part of the work of the EUMORPHIA and EUMODIC consortia, and which exemplifies some of the challenges facing large-scale phenotyping. EMPReSSslim captures a broad range of data on diverse biological systems, from biochemical to physiological amongst others. Data capture and dissemination is pivotal to the operation of large-scale phenotyping pipelines, including the definition of parameters integral to each phenotyping test and the associated ontological descriptions. EMPReSSslim data is displayed within the EuroPhenome database, where a variety of tools are available to allow the user to search for interesting biological or clinical phenotypes

Analysis of neuropsychiatric disease-related functional neuroanatomical markers in mice.

A better alignment of preclinical and clinical neurobiological measures could help improve neuropsychiatric disease therapeutic development. This unit describes a compendium of hypothesis-driven neuroanatomical phenotyping strategies to be employed in genetic mouse models. Using neuropsychiatric disease-based alterations as a guide, these are histological and immunohistochemical methodologies also applied to human tissue. They include quantification assays of neurochemical-, newly born neuron- and glial-cell markers, synaptic proteins, regional volumetrics, dendritic complexity and spine number as well as an index of excitation/inhibition balance. The techniques can be implemented in isolation or to complement concordant behavioral and electrophysiological analyses. Each outcome will provide functional detail necessary to decipher underlying neural circuit abnormalities associated with a brain-related phenotype in mice. Experimental design, timing, anticipated results and potential pitfalls are discussed. © 2018 by John Wiley & Sons, Inc

Voluntary wheel running in mice increases the rate of neurogenesis without affecting anxiety-related behaviour in single tests.

BACKGROUND: The role played by adult neurogenesis in anxiety is not clear. A recent study revealed a surprising positive correlation between increased anxiety and elevated neurogenesis following chronic voluntary wheel running and multiple behavioural testing in mice, suggesting that adult hippocampal neurogenesis is involved in the genesis of anxiety. To exclude the possible confounding effect of multiple testing that may have occurred in the aforementioned study, we assessed (1) the effects of mouse voluntary wheel running (14 vs. 28 days) on anxiety in just one behavioural test; the open field, and (2), using different markers, proliferation, differentiation, survival and maturation of newly born neurons in the dentate gyrus immediately afterwards. Effects of wheel running on anxiety-related behaviour were confirmed in a separate batch of animals tested in another test of anxiety, the light/dark box test. RESULTS: Running altered measures of locomotion and exploration, but not anxiety-related behaviour in either test. 14 days running significantly increased proliferation, and differentiation and survival were increased after both running durations. 28 day running mice also exhibited an increased rate of maturation. Furthermore, there was a significant positive correlation between the amount of proliferation, but not maturation, and anxiety measures in the open field of the 28 day running mice. CONCLUSIONS: Overall, this evidence suggests that without repeated testing, newly born mature neurons may not be involved in the genesis of anxiety per se

Urocortin 2 modulates aspects of social behaviour in mice.

Urocortin 2 (UCN2), a member of the corticotropin-releasing hormone family, is involved in the regulation of stress-related behaviours in rodents. To determine its physiological function we generated mice lacking UCN2 by applying a classical knockout strategy. We examined hypothalamus-pituitary-adrenocortical axis activity, anxiety- and depression-related behaviours without finding significant differences between mutant and wild-type littermates. Investigating social abilities we observed, that male, but not female, UCN2 knockout animals showed an altered social behaviour. Here we report that male UCN2 null mice showed more passive social interactions and reduced aggressiveness in comparison to wild-type animals. In conclusion, UCN2 seems to modulate aggressive behaviour in male mice. Furthermore, our findings provide additional evidence for previously reported sex-specific effects of UCN2

Activation of ERK/MAPK in the lateral amygdala of the mouse is required for acquisition of a fear-potentiated startle response.

There is considerable interest in examining the genes that may contribute to anxiety. We examined the function of ERK/MAPK in the acquisition of conditioned fear, as measured by fear-potentiated startle (FPS) in mice as a model for anticipatory anxiety in humans. We characterized the following for the first time in the mouse: (1) the expression of the ERK/MAPK signaling pathway components at the protein level in the lateral amygdala (LA); (2) the time course of activation of phospho-activated MAPK in the LA after fear conditioning; (3) if pharmacological inhibition of pMAPK could modulate the acquisition of FPS; (4) the cell-type specificity of pMAPK in the LA after fear conditioning. Using western blot and immunohistochemistry techniques and injecting the MEK inhibitor U0126 in the LA, we showed the following: (1) both MEK1/MEK2 and ERK1/ERK2 were co-expressed in the LA of the adult mouse brain; (2) there is a peak of pMAPK at 60 min after fear conditioning; (3) the ERK/MAPK signaling pathway activation is essential for the acquisition of an FPS response; (4) at 60 min, the pMAPK are exclusively neuronal and not glial. These results emphasize the importance of this signaling pathway in the acquisition of conditioned fear in the mouse. Given the widely held view that conditioned fear models the essential aspects of anxiety disorders, the results confirm the ERK/MAPK signaling pathway as a molecular target for the treatment of anxiety disorders in the clinic