Understanding the dynamic and destiny of memories

Abstract

Memory formation enables the retention of life experiences overtime. Based on previously acquired information, organisms can anticipate future events and adjust their behaviors to maximize survival. However, in an ever-changing environment, a memory needs to be malleable to maintain its relevance. In fact, substantial evidence suggests that a consolidated memory can become labile and susceptible to modifications after being reactivated, a process termed reconsolidation. When an extinction process takes place, a memory can also be temporarily inhibited by a second memory that carries information with opposite meaning. In addition, a memory can fade and lose its significance in a process known as forgetting. Thus, following retrieval, new life experiences can be integrated with the original memory trace to maintain its predictive value. In this review, we explore the determining factors that regulate the fate of a memory after its reactivation. We focus on three post-retrieval memory destinies (reconsolidation, extinction, and forgetting) and discuss recent rodent studies investigating the biological functions and neural mechanisms underlying each of these processes.

Keywords: Extinction; Forgetting; Memory updating; Reconsolidation; Retrieval.

Figure. 1 -. Schematic of memory destinies following retrieval.

During the initial phase of memory formation, new information is acquired and consolidated as a long-term memory. Subsequent retrieval of the consolidated memory may activate three distinct processes: i) reconsolidation is triggered after a short period of memory reactivation and a mild degree of mismatching between the original memory and the retrieval session. Reconsolidation involves an initial destabilization of the memory trace followed by memory updating through the strengthening of the original memory and the incorporation of new information; ii) extinction is triggered after a long period of memory reactivation and a high degree of mismatching between the original memory and the retrieval session. Extinction involves the formation of a new memory that inhibits the original memory trace; and iii) forgetting results from a deficit in the retrieval of the original memory. Forgetting may serve as a filter to remove unnecessary information.

Figure. 2 –. Representative model and synaptic mechanisms of retrieval-induced memory destabilization.

A) During memory retrieval, a consolidated memory that is initially in a stable state (inactive state) enters a labile state (active state) if a certain degree of mismatching occurs (i.e., prediction error). Depending on what happens during retrieval, the original memory trace can be updated into distinct forms thereby resulting in a strengthened, weakened, or modified memory. House drawings are used as an analogy for retrieval-induced memory updating. B) The transition of the original memory from an inactive to an active state after retrieval involves a series of postsynaptic mechanisms including: 1) Entrance of calcium following activation of GluN2B-containing NMDA receptor and L-type voltage-gated calcium channels (L-VGCC); 2) Activation of protein kinase CaMKII; 3) Activation of protein complexes (e.g., proteasome); 4) Degradation of scaffolding proteins (e.g., SHANK); 5) Endocytosis of calcium impermeable GluA2-containing AMPA receptors from the postsynaptic density (PSD) followed by autophagy; 6) Insertion of calcium permeable GluA1-contaning AMPA receptors in the PSD in part due to the phosphorylation of serine 845 (S845) by protein kinase A (PKA).

Figure 3 –. Schematic of the neural circuits mediating retrieval and extinction of fear memories.

Retrieval of fear-associated memories recruits reciprocal activity between PL and BLA neurons, as well as activation of CeA neurons projecting to downstream pathways that mediate fear responses. Retrieval of consolidated fear memories also activate PL neurons that project to PVT, as well as PVT neurons that project to CeA. Extinction of fear-associated memories recruits reciprocal activity between IL and BLA, as well as BLA and vHipp neurons. Both BLA projections to NAc and PL projections to IL are also recruited during extinction. In addition, hippocampal projections to PL, IL, and BLA provide contextual information during both retrieval and extinction of fear memories. Legend: PL, prelimbic cortex; IL, infralimbic cortex; NAc, nucleus accumbens, PVT, paraventricular nucleus of the thalamus, Re, nucleus reuniens, BLA, basolateral nucleus of the amygdala, CeA, central nucleus of the amygdala, dHipp, dorsal hippocampus, vHipp, ventral hippocampus.