Targeting fear memories: Examining pharmacological disruption in a generalized fear framework

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Labilization-reconsolidation, which relies on retrieval, has been considered an opportunity to attenuate the negative aspects of traumatic memories. A therapeutic strategy based on reconsolidation blockade is deemed more effective than current therapies relying on memory extinction. Nevertheless, extremely stressful memories frequently prove resistant to this process. Here, after inducing robust fear memory in mice through strong fear conditioning, we examined the possibility of rendering it susceptible to pharmacological modulation based on the degree of generalized fear (GF). To achieve this, we established an ordered gradient of GF, determined by the perceptual similarity between the associated context (CA) and non-associated contexts (CB, CC, CD, and CE) to the aversive event. We observed that as the exposure context became less similar to CA, the defensive pattern shifted from passive to active behaviors in both male and female mice. Subsequently, in conditioned animals, we administered propranolol after exposure to the different contexts (CA, CB, CC, CD or CE). In males, propranolol treatment resulted in reduced freezing time and enhanced risk assessment behaviors when administered following exposure to CA or CB, but not after CC, CD, or CE, compared to the control group. In females, a similar change in behavioral pattern was observed with propranolol administered after exposure to CC, but not after the other contexts. These results highlight the possibility of indirectly manipulating a robust contextual fear memory by controlling the level of generalization during recall. Additionally, it was demonstrated that the effect of propranolol on reconsolidation would not lead to a reduction in fear memory per se, but rather to its reorganization resulting in greater behavioral flexibility (from passive to active behaviors). Finally, from a clinical viewpoint, this would be of considerable relevance since following this strategy could make the treatment of psychiatric disorders associated with traumatic memory formation more effective and less stressful.