Boundaries on lability: Severe fear learning leads to reconsolidation-resistant memories due to noradrenergic-dependent changes in plasticity mechanisms

摘要

Severe fear learning leads to reconsolidation-resistant memories due to noradrenergic-dependent changes in plasticity mechanisms New memories go through a labile period during which they are gradually consolidated into a stable, long-term memory. Recall later on may cause the memory to return to an unstable state where it can be modified (i.e. reconsolidation). However, extreme fear learning can result in memories that are resistant to undergo reconsolidation. Our goal was to determine how severe fear learn- ing shapes memory formation into a state that is resistant to change. We hypothesize that during highly aversive experiences, unique signals trigger long-lasting molecular modifications that ensure the memory will be stored in a state that lacks the labil- ity mechanisms required to trigger reconsolidation. Using the auditory fear conditioning task, rats were trained with 1 tone- shock pairing to create mild fear memories, or 10 pairings to create strong fear memories. Later, memory was reactivated, and reconsolidation-blockade was conducted. The effectiveness of the treatment was then evaluated in a test 1 day later. One day after the test, animals were sacrificed and the amygdala, the dorsal and the ventral hippocampi were collected for western blot analysis. We found that unlike animals trained in the mild protocol, strongly trained rats were resistant to reconsolidation- blockade. At the molecular level, strong training upregulated GluA2-containing AMPAR and downregulated NR2B-containing NMDAR in the amygdala and in the dorsal hippocampus, indicat- ing limited plasticity. However, blocking b-adrenergic receptors before strong training caused memory to be formed as a mild one; it rendered memory susceptible to reconsolidation-blockade and restored GluA2 and NR2B levels towards those found in mildly trained rats. Together, these findings reveal that mild and strong fear memories are fundamentally different, with the lat- ter showing a reduction in lability mechanisms and an inability to undergo reconsolidation. Importantly, b-adrenergic activity during fear learning is critical for these outcomes, revealing that nora- drenaline shapes memory formation into a treatment-resistant state.