Abstract:

Retrieval of long-term memories can induce a destabilization process that returns them into a labile state, and then the labile state will be followed by a reconsolidation process that helps memories to restabilize and maintain their relevance. The reconsolidation process can be interfered by electroconvulsive shock, pharmacological treatment or behavioral training to update the original memories. Disrupting memory reconsolidation could become an approach tackling maladaptive memory. However, some boundary conditions such as training strength and memory age may prevent memory destabilization. Memory destabilization is the prerequisite for reconsolidation to occur. Therefore, they make reconsolidation-based interventions invalid. This may be taken as a potential stumbling block for reconsolidation-based interventions: in clinical practice, old and strong maladaptive memories are the norm rather than the exception. Therefore, overcoming the boundary conditions has become an urgent problem, and it is also one of the hotspots in the field of reconsolidation in recent years. It is because boundary conditions hinder the memory destabilization that memory can’t experience reconsolidation. Therefore, this paper first summarized and analyzed the molecules involved in memory destabilization and their respective roles in memory destabilization. Among the boundary conditions, memory strength is the most studied. Therefore, combining the molecules of memory destabilization and a series of experimental evidences about the effect of memory strength on memory reconsolidation, we inferred that the molecular path of memory strength hindering memory destabilization may be: as the memory strength increases, the noradrenergic projection from locus coeruleus to amygdala will be enhanced, and then the expression levels of NR2B and GluA2 in basolateral amygdala, the key molecules of memory destabilization, will be changed through this projection, and thus memory destabilization will be inhibited. Boundary conditions can affect the activities of key molecules involved in memory destabilization, thus hindering memory reconsolidation. This suggests that, in turn, pharmacological manipulation of the molecules involved in memory destabilization before memory activation can overcome the barrier of memory destabilization caused by the boundary conditions formed during memory coding. Previous animal experiments have shown that NMDAR, one of the key molecules involved in memory destabilization, was pharmacologically regulated before memory activation, which successfully promoted memory destabilization and overcome the boundary conditions. It can be seen that the boundary conditions are not absolute. All the molecules involved in memory destabilization are expected to be the target molecules to overcome the boundary conditions. The role of other molecules involved in memory destabilization, except NMDAR, in overcoming the boundary conditions is still unknown and needs to be further explored. The effect of these molecules in overcoming the boundary conditions may be different, and the clinical application potential is also different, which requires a lot of comparative experiments to select the best target molecules. Future research can further explore more and better methods to promote memory destabilization and overcome boundary conditions, and enhance the clinical application potential of reconsolidation-based interventions.

Key words: memory reconsolidation, memory destabilization, boundary conditions, ubiquitin - proteasome system, autophagy