Die Rolle von Neuropeptid S in Tiermodellen pathologischer Angst
Biologische Psychiatrie
Zusammenfassung der Projektergebnisse
The goal of this project was to investigate the role of neuropeptide S and its receptor NPSR in animal paradigms of pathological fear. Mainly, we took use of NPSR-deficient mice that were already described to be mildly more anxious and fearful than wildtype mice. We tested these mice in several behavioral paradigms of ‘pathological fear’. That means that in these paradigms not only ‘normal’ anxiety or fear was measured but these paradigms included also treatments or parameters, respectively (sodium lactate, corticosterone, CCK4, incubation time, high intensity of the aversive experience) that had the aim to ‘pathologically’ increase fear and anxiety. Of specific interest within our project was the generalization of conditioned fear, i.e. whether the mice were able to differentiate the original fear-associated stimulus from similar but different stimuli. It is well established that generalization of fear memory is a key symptom of several anxiety disorders. In different of our experiments, we could confirm that NPSR-deficient mice are mildly more anxious and fearful. Furthermore, we found that they are more prone to developed generalized contextual fear memory, i.e. they also express fear behavior when it is not necessary. First data indicates that NPSR- deficient mice are also more prone to treatments induced panic-like anxiety. Interestingly, we also discovered a very robust sex-dependent role of the NPSR in safety learning. Male NPSR-deficient mice expressed enhanced safety learning. However, if the mice were pre-exposed to stress before safety learning, this beneficial effect of NPSR-deficiency was not observed. Despite originally not planned, our experiments also included a human experiment on the role of polymorphism in the NPSR gene. In collaboration with Tanja Jovanovic in Detroit, we collected data indicating that TT carrier of a particular NPSR gene variant are less able to differentiate a fear cue from a safety cue than AT and AA carrier. Last, our data reveal also social deficits in NPSR-deficient mice. Furthermore, these mice seem to extinguish learned social fear faster. The present project faced several issues. Our experiments on fear generalization become very complex and long-lasting, since there was no obvious effect of NPSR deficiency first and the experimenters then changed protocols in the hope to finally see some phenotypes. This strategy lowered productivity of some of the experiments.
