Elucidating the role of dopamine signaling in the extended amygdala in the generalization of fear responses – DOPAFEAR

The learning of appropriate defensive behavioral responses to threatening situations relies on highly sophisticated mechanisms requiring a fine balance between memory specificity and generalization. While the memory specificity enables accurate behavioral responses when aversive predicting cues are presented, generalization allows some level of flexibility by enabling the rapid deployment of appropriate defensive strategies during novel encounters of cues resembling those predicting threat. However, in some cases generalization of threat responses is exacerbated, resulting in strong defensive reactions to other stimuli that resemble aspects of a learned threat. This overgeneralization, which constitutes a core feature of anxiety disorders, result in part from usurped activity of neural circuits localized within a neuronal continuum called the central extended amygdala comprising the central nucleus of the amygdala (CEA) and the lateral part of bed nucleus of the stria terminalis (BNST). Of interest, we recently uncovered that dopamine controls generalization through concomitant activation of dopamine D2 type receptors (D2R) in both the CEA and BNST. Although further evidences support the hypothesis that aberrant dopamine signaling leads to maladaptive threat processing and generalization, the neural circuit and molecular mechanisms by which dopamine control generalization are far from being fully elucidated. By combining chemogenetic- and optogenetic-mediated silencing and activation manipulations, cell-type specific high-throughput sequencing and behavior, our research proposal aims to identify the neural circuit of the extended amygdala in which dopamine D2 signaling acts and to decipher the molecular mechanisms engaged by DA with this circuit to control threat processing and prevent overgeneralization of conditioned threat responses. To do so, we propose 1) to identify in which neural population DA D2R act to control fear generalization, 2) to test whether overgeneralization of threat processing is causally linked to altered plasticity of CEA and BNST D2R-expressing neurons and 3) to perform cell-specific profiling of mRNAs dysregulated in mice displaying generalized fear responses and evaluate the functional implication of identified candidates on development of aberrant threat processing leading to generalization. By providing a better understanding of neural circuits and molecular mechanisms controlling generalization, this research proposal should enable the development of new and more specific therapeutic approaches to anxiety disorders.