Mecanismos dependentes de TrkC como alvo no resgate do medo patológico: validação de novos agonistas.

In this project we aim to investigate how TrkC signaling modulates the activity of amygdala fear and extinction engrams, and therefore dissect the mechanisms behind its contribution to the extinction of fear memories. We hypothesize that activation of TrkC in the amygdala fear and/or extinction neurons leads to changes in neuronal activity thereby contributing either to a weakening of the fear engram or to a potentiation of the extinction engram (or both). Moreover, we propose to validate the efficacy of novel small molecule TrkC agonists on fear extinction behavior and the underlying neural mechanisms. We envision the development of a mechanism-based therapy that combines exposure therapy together with pharmacological activation of TrkC to combat anxiety disorders. To address this hypothesis, the following objectives are proposed: 1) We will evaluate the formation and ‘size’ of amygdala fear and extinction engrams in our rodent model of interindividual variation in fear extinction (EXT-success versus EXT-failure); and test whether activation of TrkC signaling selectively in the amygdalar fear engram or in the extinction engram is sufficient to promote fear extinction in EXT-failure mice, corroborating its potential in rescuing maladaptive fear; 2) We will assess, in vivo, the activity pattern of amygdala fear and extinction engram neurons in EXT-success and EXT-failure mice, and how activation of TrkC signaling in these neurons modulates their activity; 3) Finally, we will test the effects of newly developed small molecule agonists of TrkC in our mouse model of interindividual variation in fear extinction, as well as their effects in the underlying neural substrates. The validation of such compounds will be of clinical value for drug development and pharmacological intervention in diseases of maladaptive fear. In this project, we expect to dissect the neural mechanisms of action of TrkC signaling in the processing of fear extinction, and validate novel small molecule TrkC agonists for therapeutic intervention in disorders of maladaptive fear.