The role of exogenously administered murine amyloid-beta in disrupting different phases of the learning process: from consolidation to extinction

Abstract

The presence of soluble Aß oligomers alters synaptic function and is implicated in cognitive dysfunction. Furthermore, established research in rodents indicates that intracerebroventricular (ICV) injections of human Aß alters both the acquisition and consolidation of associative memories, but little is understood about how oligomeric Aß impacts the retrieval of those memories, or their extinction. Murine and human Aß differ by three amino acids (R5G, Y10F, H13R) which alter aggregation efficacy and diminish toxicity. The purpose of the present experiments was to determine how oligomeric murine Aß impacts the consolidation, retrieval, and extinction of associative memories. Using a contextual fear-conditioning (CFC) paradigm, five experiments were carried out to disentangle which phase of learning, consolidation and/or retrieval is impacted in the presence of murine Aß oligomers.^

In Experiments 1, 2, and 3, animals received an injection of Aß or sterile saline immediately following training, or 2 or 6 hours post-training, and were tested in the same context 42-48 hours later. Results indicate that Aß infusions within 2 hours of training lead to decreased freezing behavior, indicating that murine Aß disrupted the consolidation and possibly the retrieval of the context-shock pairing. In Experiment 4, animals were trained in CFC and received injections of Aß or sterile saline 46 hours later. Two hours after infusions, freezing behavior was assessed in the same context. Results from Experiment 3 revealed that Aß infusions 2 hours prior to testing had no impact on freezing behavior. Together these results indicate that Aß is disrupting the consolidation of new memories, but is not impacting the recovery of previously consolidated information.^

Experiment 5 investigated the ability of murine Aß to disrupt the extinction of learned fear. This study utilized a LPS-induced Aß production protocol previously utilized in our laboratory. Findings revealed that murine Aß is also capable of disrupting, or at least delaying extinction learning. This research suggests that despite differences between murine and human Aß, the functional outcomes on memory are strikingly similar. Thus, models utilizing endogenous or exogenous mAß in non-transgenic animals can be useful in examining the role of Aß in memory processes and the subtle ways in which Aß oligomers alter synaptic functioning.