Kurzfassung

Project C01:
The ability to extinguish fear protects against the development of exaggerated and generalized fears and other mental dysfunctions after trauma. For the fear-relieving effects of extinction to last, it is necessary that the extinction experience is transformed into a stable memory. We have recently shown in mice and humans that the consolidation of extinction memories can be boosted by post-extinction systemic administration of the dopamine precursor L-DOPA (Haaker et al., 2013)....Project C01:
The ability to extinguish fear protects against the development of exaggerated and generalized fears and other mental dysfunctions after trauma. For the fear-relieving effects of extinction to last, it is necessary that the extinction experience is transformed into a stable memory. We have recently shown in mice and humans that the consolidation of extinction memories can be boosted by post-extinction systemic administration of the dopamine precursor L-DOPA (Haaker et al., 2013). L-DOPA even rendered extinction memories context independent, i.e., they were expressed (fear was suppressed) outside the specific learning context of extinction, where normally return of fear (ROF) is observed. Memory boosting by dopaminergic activation may thus be a simple and robust way to augment the efficacy and/or efficiency of extinction-based programs for primary or secondary prevention, and perhaps also of programs based on the generation of other types of protective memories (see CRC Academic profile, 1.2.2.2, Challenge 3).
The behavioral effect of L-DOPA was accompanied by enhanced activation of the ventromedial prefrontal cortex (vmPFC) at the extinction expression test and, as shown in humans, by an enhanced correlation of spontaneous (“resting-state”) fMRI signal changes in the dopaminergic midbrain and the vmPFC during the memory consolidation phase after extinction. These midbrain-vmPFC correlations during consolidation predicted the enhanced vmPFC activation at test, while indices of extinction learning did not (Haaker et al., 2013). This suggests an important role for stimulus-independent, spontaneous processes during the post-learning consolidation phase in determining the long-term success of extinction. This subproject aims to better understand the neurobiology of extinction memory consolidation, with a focus on the role played by spontaneous neural activity and dopamine, and its influence on long-term extinction performance. The ultimate goal is to develop tools to make protective memories strong and stable.
In particular, we will test the contribution to extinction memory formation of spontaneous burst-firing during consolidation in vmPFC and of its modulation by dopaminergic input from the ventral tegmental area (VTA). First, in order to back-translate the human findings by Haaker et al. (2013) into the rodent model, we measure spontaneous vmPFC neuronal population activity during extinction consolidation in lightly sedated and/or awake rats using optical Calcium (Ca2+) recordings and correlate this to long-term extinction performance (Aim 1). We then determine the causal role of mesoprefrontal dopamine neurons in this process, using optogenetics (Aim 2). In humans, we extend the existing findings by comparing stimulus-driven vmPFC responses during extinction and spontaneous vmPFC activity during subsequent consolidation in fMRI, using multivariate pattern analyses, and relating this to long-term extinction performance. By this, we will test whether spontaneous vmPFC activity during consolidation might be related to the reactivation of learning experiences from preceding extinction, as one way to successful long-term memory formation (Aim 3). In Aim 4, in rodents, we bring together both strands by performing optical Ca2+ recordings and optogenetics simultaneously with fMRI in a 9.4 T small-animal scanner. We will use this to link the consolidation-related fMRI signatures determined in humans in Aim 3 with the underlying neurophysiological processes, as prepared by Aims 1 and 2. In Aim 5, these insights will then be a basis to design and understand alternative (non-pharmacological) approaches to boosting extinction memory consolidation (e.g., tDCS, behavioral manipulations), with a view to finding optimal conditions for the augmentation of preventive interventions.» weiterlesen» einklappen