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Behavioral trait genetics in mice; Opportunities for translational...

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Title Behavioral trait genetics in mice; Opportunities for translational research of psychiatric endophenotypes
Period 09 / 2004 - 04 / 2009
Status Completed
Dissertation Yes
Research number OND1313695
Data Supplier Rudolf Magnus Instituut

Abstract

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.

Abstract (NL)

Een van de problemen bij het ontwikkelen van selectieve medicatie voor psychiatrische stoornissen is dat de achterliggende pathofysiologie grotendeels onbekend is. Het identificeren van genen die de gevoeligheid voor psychiatrische stoornissen beïnvloeden is van groot belang voor het ontrafelen van deze complexe systemen. Annetrude de Mooij-van Malsen richtte zich in haar promotieonderzoek op het gebruik van inter-species genetica om mechanismen te ontdekken die bij stemmingsstoornissen betrokken zijn. Ze heeft een panel van chromosoomsubstitutie-muizenstammen in een geautomatiseerde thuiskooiopstelling gescreend. Hierin mat ze meerdere dagen continu het gedrag van de dieren. Door deze methode van testen kon ze een link aantonen tussen genetische locaties die in de muis de angstniveaus beïnvloedt en de humane genetische regio die geassocieerd worden met manisch depressiviteit. Binnen beide regio s liggen kandidaat-genen die functioneel zijn in dezelfde moleculaire cascade. Verder toonde De Mooij-van Malsen expressieverschillen voor een van deze genen in het muizenbrein aan. Indien de veranderingen in gedrag geassocieerd met deze twee onafhankelijke genetische locaties inderdaad veroorzaakt worden door veranderingen in dezelfde cascade, kan het testen van deze en andere stammen in de thuiskooi grote mogelijkheden bieden om een genetisch gevalideerd model te gebruiken om selectievere medicatie te ontwikkelen voor deze psychiatrische aandoening.

Related organisations

Related people

Supervisor Prof.dr. J.P.H. Burbach
Supervisor Prof.dr. B. Olivier
Co-supervisor Dr. M.J.H. Kas
Doctoral/PhD student Dr. J.G. de Mooij-van Malsen

Classification

A70000 Public health and health care
D21400 Genetics
D22300 Animal ethology, animal psychology
D23230 Neurology, otorhinolaryngology, opthalmology

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