Dr. Judith R Homberg
Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Centre
Dept Cognitive Neuroscience
Nijmegen, The Netherlands
Mainstream psychiatric research is focussed on understanding how genes and environmental components interact in shaping behaviour. The human serotonin transporter promoter polymorphism (5-HTTLPR) is a model par example for gene x environment interactions in psychiatry, as it is associated with trait anxiety and increases risk for depression in the context of early life stress. Yet, along with the view that common polymorphisms will only be maintained across evolution when having beneficial consequences for the human population, recent studies have revealed that the 5-HTTLPR is associated with a decreased risk for depression under favourable environmental conditions, as well as various cognitive improvements. Because these beneficial 5-HTTLPR effects can be used offset its adverse effects (e.g. depression), it is our aim to understand more precisely under what environmental conditions the 5-HTTLPR mediates ‘for better’ and ‘for worse’ behavioural manifestations. To this end we are using serotonin transporter (5-HTT) knockout rats, which have been generated by target-selected ENU-driven mutagenesis and extensively characterized. Like people carrying the 5-HTTLPR low activity short (s) allelic variant, the animals show increased anxiety and depression-related phenotypes, as well as cognitive improvements. Our studies reveal that 5-HTT knockout rats are sensitive to both rewarding and aversive stimuli, based on which they acquire strong conditioned responses. When exposed to a single stimulus, they engage into perseverative habitual behaviour (anxiety- and addiction-related behaviour). However, when exposed to two stimuli with varying valences, they show high flexibility and adjust behavioural towards the most motivationally relevant one. This phenomenon has heuristic value for psychotherapies in the treatment of gene x environment psychiatric disorders. We are currently studying underlying (epi)genetic and neuroplastic mechanisms.