Abstract■ The pFC is critical for cognitive flexibility (i.e., our ability to flexibly adjust behavior to changing environmental demands), but also for cognitive stability (i.e., our ability to follow behavioral plans in the face of distraction). Behavioral research suggests that individuals differ in their cognitive flexibility and stability, and neurocomputational theories of working memory relate this variability to the concept of attractor stability in recurrently connected neural networks. We introduce a novel task paradigm to simultaneously assess flexible switching between task rules (cognitive flexibility) and task performance in the presence of irrelevant distractors (cognitive stability) and to furthermore assess the individual "spontaneous switching rate" in response to ambiguous stimuli to quantify the individual dispositional cognitive flexibility in a theoretically motivated way (i.e., as a proxy for attractor stabi-

There has been significant controversy whether stressful life events (SLEs) experienced over the lifespan may elevate the risk of depression in individuals who are homozygous for the short (S) allele of the repeat length polymorphism (5-HTTLPR) in the regulatory region of the serotonin transporter gene (SLC6A4), compared with individuals homozygous for the long (L) allele. On the basis of the hypothesis that age may be a critical variable, by which such a gene-by-environment interaction may be present in younger adults, but not in older adults and in children, aim of this study was to investigate the role of 5-HTTLPR and SLEs on the endocrine stress response in multiple age cohorts. A total of 115 children (8-12 years), 106 younger adults (18-31 years), and 99 older adults (54-68 years) were subjected to the Trier Social Stress Test (TSST) and structured interviews on SLEs. The TSST induced significant endocrine stress responses in all groups. There was a main effect of genotype in younger and older adults with individuals homozygous for the more active L allele showing a significantly larger cortisol response to the TSST than individuals carrying at least one of the low-expressing S alleles. As predicted, there was a significant interaction of 5-HTTLPR genotype and SLEs, but this interaction was only significant in younger adults and only when the measured SLEs had occurred during the first 5 years of life, suggesting that both age and the specific type of SLE has a role in whether a significant gene-environment interaction is observed.

Anxiety-related behaviors are closely linked to neural circuits relaying fear-specific information to the amygdala. Many of these circuits, like those underlying processing of innate fear, are remarkably well understood. Recent imaging studies have contributed to this knowledge by discriminating more detailed corticoamygdalar associations mediating processing fear and anxiety. However, little is known about the underlying molecular mechanisms. We used the acoustic startle paradigm to investigate the impact of molecular genetic variation of serotonergic function on the acoustic startle response and its fear potentiation. Startle magnitudes to noise bursts as measured with the eye blink response were recorded in 66 healthy volunteers under four conditions: presenting unpleasant and pleasant affective pictures as well as neutral pictures, and presenting the startle stimulus without additional stimuli as a baseline. Subjects were genotyped for functional polymorphism in the transcriptional control region of the serotonin transporter gene (5-hydroxytryptamine transporter gene-linked region: 5-HTTLPR). Analyses of variance revealed a significant effect of 5-HTTLPR on overall startle responses across conditions. Carriers of the short (s) allele exhibited stronger startle responses than l/l homozygotes. However, we could not confirm our hypothesis of enhanced fear potentiation of the startle in s allele carriers. In conclusion, the results provide first evidence that the startle response is sensitive to genetic variation in the serotonin pathway. Despite some issues remaining to be resolved, the startle paradigm may provide a valuable endophenotype of fear processing and underlying serotonergic influences.

Remembering delayed intentions can be highly demanding. Accuracy in laboratory paradigms assessing prospective memory (PM) is typically well below ceiling, and failure to remember intended behaviors after a delay is a common occurrence in everyday life. However, relatively little is known of the potential differences in brain activity that distinguish successful versus unsuccessful PM. In this fMRI study, participants repeatedly encoded, stored, and then had the opportunity to retrieve intended behaviors while engaged in a distracting ongoing task. This yielded a success rate of approximately two thirds. Overall levels of brain activity distinguished successful versus unsuccessful trials at all three stages (encoding, storage, and retrieval), suggesting multiple neural determinants of PM success. In addition, the voxelwise similarity between patterns of brain activity at encoding and retrieval was greater for successful than unsuccessful trials. This was true even in posterior cingulate, which showed opposite patterns of signal change between encoding and retrieval. Thus, successful realization of delayed intentions may be associated with reinstatement of encoding context at the time of retrieval.