Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - Remote memory traces (Cellular and molecular mechanisms of remote fear attenuation)

Teaser

In this project, we are interested in elucidating the neuronal subpopulations and the underlying molecular mechanisms of remote fear memory extinction. Despite an elevated lifetime prevalence of related fear and anxiety disorders, effective treatments for long-lasting, i.e...

Summary

In this project, we are interested in elucidating the neuronal subpopulations and the underlying molecular mechanisms of remote fear memory extinction. Despite an elevated lifetime prevalence of related fear and anxiety disorders, effective treatments for long-lasting, i.e. remote, traumatic memories are scarce and the mechanisms behind successful memory attenuation poorly understood. To this end, we are using a combination of transgenic mouse models to visualise cells implicated in remote memory storage and attenuation, in combination with approaches to alter neuronal activity and with cell type-specific molecular analyses. In particular, we hypothesize that successful attenuation of traumatic memories engages a fundamental change in cell populations initially activated by the traumatic exposure, i.e., within the same « memory trace ». The objectives are to first identify the cells responsible for remote fear memory attenuation, and second, to identify the molecular mechanisms within these cells that drive remote fear memory attenuation.

Work performed

For the reporting period, we have successfully established the double labeling procedure for our project. Thus, we can now permanently tag remote fear memory recall-induced neurons and re-label them by remote fear memory extinction-induced neurons, in case there is an overlap. With this tool in hand, we have now quantified the overlap of remote fear memory recall-induced and remote fear memory extinction-induced neurons in brain areas relevant for remote memory storage and extinction, such as the hippocampus, amygdala and cortex. The results indicate that the successful attenuation of remote fear memories correlates with a significant reactivation of recall-induced cells in the hippocampus hippocampal area CA1 and the dentate gyrus, but not in CA3. In the cortex, in the infralimbic area, but not in the anterior cingulate area or in the prelimbic area. In the amygdala, in the basolateral part, but not in the central part. What is more, when we chemogenetically block the activity of recall-induced neurons in DG, but not in CA3, using the Daun02 inactivation method, the degree of fear memory attenuation is impaired. Furthermore, when we chemogenetically activate recall-induced neurons, attenuation is facilitated. These results stipulate that a loss-of-function of the original memory trace of fear is detrimental for fear attenuation, which in turn favours the notion that the original memory trace of fear has been updated, i.e., relearned towards safety likely via reconsolidation-updating mechanisms, rather than having been suppressed via extinction learning.

Final results

For the remaining part of the project, we expect to identify the molecular mechanisms inside the neuronal populations that lead to effective memory attenuation of remote traumatic memories.