Single dose of L-dopa makes extinction memories context-independent and prevents the return of fear.

Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. Extinction, the laboratory analog of behavior therapy, does not erase conditioned fear memories but generates competing, fear-inhibitory "extinction memories" that, however, are tied to the context in which extinction occurred. Accordingly, a dominance of fear over extinction memory expression--and, thus, return of fear--is often observed if extinguished fear stimuli are encountered outside the extinction (therapy) context. We show that postextinction administration of the dopamine precursor L-dopa makes extinction memories context-independent, thus strongly reducing the return of fear in both mice and humans. Reduced fear is accompanied by decreased amygdala and enhanced ventromedial prefrontal cortex activation in both species. In humans, ventromedial prefrontal cortex activity is predicted by enhanced resting-state functional coupling of the area with the dopaminergic midbrain during the postextinction consolidation phase. Our data suggest that dopamine-dependent boosting of extinction memory consolidation is a promising avenue to improving anxiety therapy.

Converging evidence for an impact of a functional NOS gene variation on anxiety-related processes.

Being a complex phenotype with substantial heritability, anxiety and related phenotypes are characterized by a complex polygenic basis. Thereby, one candidate pathway is neuronal nitric oxide (NO) signaling, and accordingly, rodent studies have identified NO synthase (NOS-I), encoded by NOS1, as a strong molecular candidate for modulating anxiety and hippocampus-dependent learning processes. Using a multi-dimensional and -methodological replication approach, we investigated the impact of a functional promoter polymorphism (NOS1-ex1f-VNTR) on human anxiety-related phenotypes in a total of 1019 healthy controls in five different studies. Homozygous carriers of the NOS1-ex1f short-allele displayed enhanced trait anxiety, worrying and depression scores. Furthermore, short-allele carriers were characterized by increased anxious apprehension during contextual fear conditioning. While autonomous measures (fear-potentiated startle) provided only suggestive evidence for a modulatory role of NOS1-ex1f-VNTR on (contextual) fear conditioning processes, neural activation at the amygdala/anterior hippocampus junction was significantly increased in short-allele carriers during context conditioning. Notably, this could not be attributed to morphological differences. In accordance with data from a plethora of rodent studies, we here provide converging evidence from behavioral, subjective, psychophysiological and neuroimaging studies in large human cohorts that NOS-I plays an important role in anxious apprehension but provide only limited evidence for a role in (contextual) fear conditioning.

A test for the implementation-maintenance model of reappraisal.

Reappraisal has been defined as a conscious, deliberate change in the way an emotional stimulus is interpreted, initiated in order to change its emotion-eliciting character (Gross, 2002). Reappraisal can be used to down-regulate negative emotions, including anxiety (reviewed in Kalisch, 2009). There is currently a strong interest in identifying the cognitive processes and neural substrates that mediate reappraisal. We have recently proposed a model (termed implementation-maintenance model or IMMO) that conceptualizes reappraisal as a temporally extended, dynamic, and multi-componential process (Kalisch, 2009). A key tenet of IMMO is that reappraisal episodes are marked by an early phase of implementation that may comprise strategy selection and retrieval of reappraisal material into working memory, and a later phase of maintenance that may comprise working memory and performance monitoring processes. These should be supported by dissociable neural networks. We here show, using a detachment-from-threat paradigm and concurrent functional magnetic resonance imaging, that reappraisal-related brain activity shifts from left posterior to right anterior parts of the lateral frontal cortex during the course of a reappraisal episode. Our data provide first empirical evidence for the existence of two separable reappraisal stages. Implications for further model development are discussed.