Interfering with contextual fear memories by post-reactivation administration of propranolol in mice: a series of null findings

Abstract

Post-reactivation amnesia of contextual fear memories by blockade of noradrenergic signaling has been shown to have limited replicability in rodents. This is usually attributed to several boundary conditions that gate the destabilization of memory during its retrieval. However, how these boundary conditions can be overcome, and what neural mechanisms underlie post-reactivation changes in contextual fear memory remain largely unknown. Here, we report a series of experiments in a contextual fear conditioning paradigm in mice, that were aimed at elucidating these matters. Towards this overarching goal, we first attempted to obtain a training paradigm that would consistently result in a contextual fear memory that could be destabilized upon reactivation, enabling robust amnesia by administration of propranolol. Unexpectedly, our attempts were unsuccessful to this end. Specifically, over a series of 11 experiments (including replicates) in which we varied different parameters of the fear acquisition procedure and administered propranolol or anisomycin, at best small and inconsistent effects were observed. These null findings are surprising, given that the training paradigms we implemented were previously shown to be vulnerable to post-reactivation amnestic agents. Additionally, we found that propranolol did not alter memory retrieval-induced neural activity, as measured by the number of c-Fos+ cells in the hippocampal dentate gyrus. Together, our findings illustrate the elusive nature of reactivation-dependent changes of non-human fear memory and underscore the need for better control over genetic and environmental factors that may influence behavioral outcomes of commonly used mouse strains.