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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    391—Molecular Mechanisms of Memory Consolidation

    Monday, November 11, 2013, 8:00 am - 12:00 noon

    391.01: Contextual novelty, but not prediction error, is the new information present at retrieval that controls the reconsolidation-dependent updating of an auditory fear memory in the amygdala

    Location: Halls B-H

    Univ. Wisconsin-Milwaukee, MILWAUKEE, WI

    Abstract Body: It has been widely supported that the formation of long-term fear memories requires de novo protein synthesis and increased ubiquitin-proteasome mediated protein degradation in the amygdala for their long-term storage (Jarome et al., 2011; Jarome et al., 2013; Parsons et al., 2006), a process referred to as memory consolidation. Additionally, numerous studies have shown that following retrieval there is again a need for increased protein degradation and de novo protein synthesis in the amygdala to regulate the “destabilization” and subsequent “restabilization” of the memory (Nader et al., 2000; Jarome et al., 2011; Jarome et al., 2012), a process referred to as memory reconsolidation. While several studies have shown that reconsolidation regulates the “updating” of memory content under certain conditions (Diaz Mataix et al., 2013; Lee, 2008; Sevenster et al., 2013), it is unknown what new information is being incorporated into the memory trace under normal retrieval conditions. Here, we used a molecular approach to test what the new information was that triggered memory destabilization and reconsolidation in the amygdala following the retrieval of an auditory fear memory. We found that the retrieval of an auditory fear memory increased in vitro proteasome activity at amygdala but not dorsal hippocampus synapses, suggesting that unlike contextual fear memories (Jarome et al., submitted), auditory fear memories selectively destabilize in the amygdala following retrieval. Additionally, memory retrieval resulted in a reduction in the expression of AMPA receptor subunits GluR1, GluR2 and GluR3 at amygdala synapses, while there was a selective increase in GluR1 in the hippocampus. Interestingly, training animals to 50% reinforcement did not prevent the changes in proteasome activity in the amygdala or AMPA receptor subunit expression in the amygdala and hippocampus following retrieval, but pre-exposing the animals to the retrieval conditions (auditory cue in novel context) prior to training completely alleviated the increases in proteasome activity in the amygdala and changes in AMPA receptor subunit expression in both the amygdala and hippocampus. These results suggest that under normal retrieval conditions, contextual novelty, but not prediction error, is the new information that the drives the destabilization and subsequent reconsolidation of a retrieved auditory fear memory. Additionally, these results suggest that the hippocampus is selectively engaged in the reconsolidation, but not destabilization, of a retrieved auditory fear memory, suggesting that the hippocampus may regulate this memory updating process following retrieval.

    Lay Language Summary: Our research indicates that new information present when something fear provoking is remembered controls the ability of that memory to become “updated” or modified upon recall. Importantly, manipulating this new information could even prevent the updating of memory content for an unpredictable fear event upon recall, suggesting that new environmental information may be a critical component of retrieval-dependent memory modification.
    More than 60% of all men and women experience at least one traumatic event in their lifetimes. In many cases, the traumatic experience can lead to the development of post-traumatic stress disorder (PTSD), which is an anxiety disorder that affects nearly 7% of all Americans at some point in their lifetime. One of the most promising potential therapeutic treatments for PTSD is a retrieval-based approach in which remembering or retrieving a memory leads to a brief period of time in which that memory can be modified, a process termed “reconsolidation”. However, very little is currently known about memory modification after recall and how the updating process incorporates new information.
    To test what the new information was that controlled the retrieval-dependent updating of a fear memory, we trained rats to associate an auditory cue with a shock in predictable (cue always predicted shock) or unpredictable (cue predicted shock 50% of time) conditions in a distinctive environment. The following day, we gave animals a brief reminder of the learned association (cue presentation) in a new environment or “context” (Context B) and examined the rate of protein degradation and AMPA receptor expression, two well established markers of memory vulnerability following retrieval. We focused on the amygdala, a brain region involved in the formation and storage of emotional memories. In addition, some animals were presented with the auditory cue in Context B the day prior to training. This “retrieval pre-exposure” was done to eliminate new contextual information during the reminder session given the day after training.
    We found that memory retrieval increased proteasome activity and reduced AMPA receptor expression in the amygdala, which occurred regardless of whether or not the animal was trained with a predictable or unpredictable association with shock, suggesting that the retrieved memory was temporarily vulnerable for modification. However, when we pre-exposed animals to the retrieval conditions prior to training we prevented these increases in proteasome activity and decreases in AMPA receptor expression, suggesting that the retrieved memory was no longer susceptible to modification. Surprisingly, this retrieval pre-exposure prevented the changes in proteasome activity and AMPA receptor expression in both the predictable and unpredictable conditions, suggesting that new contextual information present during retrieval was a better predictor of retrieval-induced memory vulnerability than unpredictability, which was previously suggested to be a critical component of retrieval-induced memory updating.
    These results suggest that new contextual information during memory retrieval controls the ability of both predictable and unpredictable fear memories to become modified following recall. Our results indicate that new contextual information can result in the temporary vulnerability of a fearful memory to modification following retrieval, suggesting that manipulating available environmental information during the recall of a traumatic memory could serve as a valuable tool for retrieval-based treatments for PTSD.