Striatal functions in PDYN genotype variants

Genetic imaging is a new field of research that investigates the effects of genetic variations on brain function with neuroimaging. As brain activation is an intermediate link between cells and behaviour, this method bridges the gap between genetic studies on the cellular and the behavioural level. Ideally, the genetic effects to be studied should be based on well-defined functional polymorphisms with described impact in distinct brain regions and circuits. We aim to investigate a well-defined functional polymorphism that has previously not been investigated with genetic imaging. It is localised in the promotor region of the prodynorphin (PDYN) gene as variable repetitions (1- 4) of the AP1 binding site. The PDYN- gene codes for the dynorphin opioid peptides. Dynorphin has a neuromodulatory effect on the CNS. It functions as a negative feedback inhibition within the circuits it controls. The availability of three or four AP1 binding sites in the promotor region is associated with significantly higher gene expression, higher levels of dynorphin peptides and higher degrees of inhibition than with that of one or two copies. In the human brain the PDYN gene is predominately expressed in regions such as the prefrontal cortex and the striatum which play a critical role in rewardrelated learning. The proposed project aims to investigate the influence of the PDYN polymorphism on key functions of the reward system and the associated brain activation. Several different methodologies will be applied: functional magnetic imaging (fMRI), voxel-based morphometry and personality questionnaires. Using these methods, functions related to reward-processing will be compared in healthy carriers of high- versus low-expression alleles. To our knowledge, this would be the first genetic imaging study on the PDYN polymorphism. The results may not only help to understand how individual differences in striatal functions and behaviours emerge, but also, since PDYN is implicated in addiction, epilepsy and schizophrenia, how these differences may contribute to vulnerability to disease and addiction.

The opioid system is involved in the regulation of moods. It also modulates the rewarding effects of natural reinforcers such as food, as well as of drugs of abuse. Dynorphins are a particular class of opioid peptides that derive from the precursor protein prodynorphin. In the present project, healthy individuals with different variants of the prodynorphin (PDYN) gene were compared regarding their behaviour and brain activation during different reward-related tasks. The PDYN gene exists in two variants, going along with either higher (variant H) or lower (variant L) dynorpin levels. During the expectation of gains and losses, activation in regions of the reward system (medial orbitofrontal cortex and amygdala) was larger for the HH genotype, i.e., the gene variant associated with highest dynorphin production. Furthermore, this group made ??more errors during reversal learning, when a previously rewarded stimulus was not rewarded any more. These errors were associated with reduced activation in reward-relevant brain areas. The results of our project suggest that a higher production of dynorphin is both associated with a larger sensitivity for upcoming rewards as well as with lower cognitive flexibility. This may help to explain the role of the PDYN gene in the development and maintenance of addictive behaviour.