Positive affective functioning in anhedonic individuals' daily life:Anything but Flat and Blunted

Background Anhedonia, the decreased interest and pleasure, is often described as 'flat' or 'blunted' positive affect (PA). Yet, little is known about PA functioning in anhedonic individuals' daily lives. The current study investigates PA reactivity to pleasurable experiences in anhedonia together with its relevant temporal dynamics (i.e., variability, instability, and inertia), and expands current knowledge by exploring the role of arousal therein. Methods: Using the Experience Sampling Method (ESM), we collected 90 assessments of real-life PA experiences across 30 days in 18-24 year old individuals with anhedonia (N = 69) and without anhedonia (N = 69). Results: Multilevel analyses showed that anhedonia was associated with less intense pleasure experience, and lower levels of PA. Contrary to predictions from laboratory research and depression theory, individuals with anhedonia showed more variability and less stability in PA, and no signs of blunted PA reactivity. In fact, when exploring high and low arousal PA, individuals with anhedonia showed a slightly stronger reactivity to pleasurable experiences in high-arousal PA but not low-arousal PA. Limitations: We did not control for previous pleasure experiences and, instead of the last positive event, accumulation of positive events may have determined the change in high-arousal PA. Conclusions: Individuals with anhedonia are likely less 'flat' or 'blunted' than generally thought. Although replication is warranted, impairments in high-arousal positive emotions may be of particular interest in the clinical treatment of anhedonia

Systematic generation of in vivo G protein-coupled receptor mutants in the rat

G-protein-coupled receptors (GPCRs) constitute a large family of cell surface receptors that are involved in a wide range of physiological and pathological processes, and are targets for many therapeutic interventions. However, genetic models in the rat, one of the most widely used model organisms in physiological and pharmacological research, are largely lacking. Here, we applied N-ethyl-N-nitrosourea (ENU)-driven target-selected mutagenesis to generate an in vivo GPCR mutant collection in the rat. A pre-selected panel of 250 human GPCR homologs was screened for mutations in 813 rats, resulting in the identification of 131 non-synonymous mutations. From these, seven novel potential rat gene knockouts were established as well as 45 lines carrying missense mutations in various genes associated with or involved in human diseases. We provide extensive in silico modeling results of the missense mutations and show experimental data, suggesting loss-of-function phenotypes for several models, including Mc4r and Lpar1. Taken together, the approach used resulted not only in a set of novel gene knockouts, but also in allelic series of more subtle amino acid variants, similar as commonly observed in human disease. The mutants presented here may greatly benefit studies to understand specific GPCR function and support the development of novel therapeutic strategies