Objectives

Objective 1: Identification and selection of candidate genes for behaviour related to reinforcer sensitivity and executive control.

Candidate genes will be selected using two complementary strategies:

Systematic analysis of genes differentially expressed in extreme phenotypes of rats analysed using tasks related to behavioural control, which are analogous to those applied in humans and will be cross-validated in inbred mouse strains. Differential expression will be analysed using DNA-chip and SAGE technology. Sex-specific analysis will be performed in both animal models.

Objective 2: Neuroimaging analysis of tasks measuring specific behavioural traits in humans

We will perform a multi-center study of a cohort of 2000 adolescents, aged 14 years and recruited according to epidemiological criteria. By selecting this age group, we can control for much of the environmental effect contributing to mental disorders, such as exposure to drugs. The adolescent cohort will be analysed with functional and structural neuroimaging using 3T-MR scanners and experimental tasks that measure individual differences in brain, cognitive and behavioural responses to reward and punishment, risk taking, impulsivity, novelty seeking and attentional control of emotional processes. Extensive psychometric characterisation for reinforcement-related and psychopathologically relevant phenotypes will be performed.

Objective 3: Genetic analysis of major tasks measuring behavioural traits in humans

Intermediate phenotypes resulting from neuroimaging analysis will be assessed for association with whole genome data. Particular emphasis will be placed on multivariate analyses of combined effects of genes expressed in pertinent brain regions as indicated by the fMRI bold response and findings of the animal studies. Results obtained will be validated in the Saguenay Youth study cohort of 1000 siblings from a genetic isolate population in Northern Quebéc, characterised using structural MRI and genotype-specific functional MRI.

Objective 4: Identification of the neural basis of disorders related to reinforcer sensitivity and executive control.

To identify the neural basis of such disorders and to determine the predictive value of intermediate neuroimaging phenotype-genotype associations for behavioural risk patterns, our cohort will be longitudinally assessed during recruitment and at year 4 of the project (16-18 years). In the first assessment an extensive behavioural and psychopathological characterisation will be carried out. The second assessment will focus on the development of symptoms, which pertain to mental disorders related to reinforcer sensitivity and executive control, with a special emphasis on drug use disorders. The resulting information on the neural basis of mental disorders will identify genes underlying morbidity and comorbidity and will result in more refined patient-treatment matching strategies with the potential to target specific pathological processes rather than broad, heterogeneous categories of mental disorders.

Objective 5: Gender-specific analysis

Since there is a strong gender effect in some but not all behaviours related to reinforcer sensitivity and executive control, for example alcohol drinking but not smoking in 16 year old adolescents (BZGA 2004), particular emphasis will be placed on gender-specific analyses, both of the neuroimaging as well as the psychometric characterisation.