| Aim. Testing of chromosome substitution strains and available mutant mouse lines in conventional and newly developed laboratory methods. This will allow dissection of exploratory behaviour into refined behavioural phenotypes and to select chromosomal substitution strains and mutant mouse lines that contribute to specific behavioural components of this behaviour. From the selected strains, the underlying physiological processes for these specific behavioural components can now be studied (such as for example, stress hormone responsiveness, gene expression and metabolite release profiles in brain regions known to be involved the regulation of these behavioural components). Summary. By applying genetic strategies in mice that are tested in a variety of behavioral set-ups, the project aims at the identification of novel genetic pathways and gene functions in the regulation of refined behavioral traits within complex behaviours. In this project the AIO will focus on behavioural traits within exploratory behaviour, such as hyperactivity and anxiety. Recently, an automated behavioral set-up has been developed that allows dissection of this complex behaviour into different behavioural traits (e.g., the expression of locomotor activity and anxiety behaviour). This will allow the refinement of gene function in these dissected behavioural components. In order to identify new genes for these traits, a forward genetics approach (from phenotype to genotype) has recent successfully been initiated with chromosome substitution (CS) strains that allow direct testing of which chromosome contributes to phenotypic differences of these two strains. A panel of chromosomal substitution (CS) strains is available that consists of sub-strains of the C57BL/6 mouse, which each are homozygous for one of the 21 chromosomes of the AJ mouse strain. In initial studies, we identified CS strains with specific anxiety or hyperactive phenotypes. This new behavior is due to the AJ genes present on the C57/Bl6 genetic background strain. In addition, mouse lines with mutations in genes (such as in the serotonin-1a and -1b receptor, CRF overexpression, and dopamine transporter genes knock-out and knock-downs) are available that are known to affect components of exploratory behaviour in conventional laboratory methods. Testing of these mutant mice in the novel home cage environment will contribute to the refinement of the behavioural phenotypes for these specific genes. The combination of novel genetic strategies with the described behavioural tests will contribute to identification of gene function in behaviour and opens opportunities to study physiological processes specific to refined behavioural traits within complex behaviours. The proteins encoded by these genes or pathways affected by these genes may serve as new therapeutic targets in the field of anxiety and impulsivity disorders. |
