Patterning valence specific amygdala memory by DTA and VTA

Emotional memories help to learn from important experiences, good or bad, to avoid future threats or seize rewards. In this process, the brain associates predictive stimuli to positive or negative outcomes. Dysfunction in formation or recall of these emotional memories are linked to a variety of psychiatric conditions, from post-traumatic stress disorder (PTSD) to addiction. However, despite the clinical importance, the underlying neuronal mechanisms writing and discriminating such positive or negative experiences into brain networks are largely unknown. Previous research suggests that events subjectively perceived as important (good or bad) both increase dopamine, which in turn instructs the amygdala to learn. Here, we hypothesize that emotional memories are reinforced by dedicated dopamine systems in the dorsal tegmental (DTA) and ventral tegmental (VTA) areas, which write positive or negative associations into amygdala memory, respectively. To investigate this experimentally, we model emotional learning as Pavlovian conditioning in the laboratory. In these behavioral assays, the brain associates tone cues with food reward or aversive events. During these behaviors, the Haubensak Laboratory at the Research Institute of Molecular Pathology (IMP) will perform deep brain imaging of neuronal activity in DTA, VTA and amygdala networks to investigate how these elements process negative and positive experiences. The Lessmann Laboratory at the Otto-von-Guericke University of Magdeburg (OVGU) will investigate how these experiences together with dopamine signaling rewires the synaptic connectivity in the amygdala that underlies memory formation. Jointly, this research will allow to investigate two alternate hypotheses. As working hypothesis, we propose that the DTA is activated upon negative experiences, which projects to and strengthens synapses on a dedicated local amygdala fear circuit via a dopamine 1 receptor. Positive experiences, in contrast, activate the VTA, which projects to and strengthens synapses on a different local amygdala reward circuit using a so-called dopamine 2 receptor. Thus, positive and negative experiences are stored and discriminated by dedicated dopamine subsystems and amygdala local circuits (valence specific model). Alternatively, we hypothesize that negative and positive experiences might require DTA and VTA acting synergistically using the same type of local amygdala circuits but distributed along a gradient within the amygdala network (valence distributed model). Taken together, our research program is the first to directly probe two alternative models of how the brain stores and discriminates opposing emotional memories in its neuronal networks. This research will then provide a framework for understanding how it does so using dopamine as a general messenger for both, negative and positive reinforcement learning. This initiative will also contribute a mechanistic framework for understanding of dopamine- and amygdala- circuitries in psychiatric conditions, like PTSD, addiction and Parkinson associated mood changes. 1