Invited ReviewMolecular signatures and mechanisms of long-lasting memory consolidation and storage
Introduction
Long-term memory (LTM) is conventionally defined as that lasting more than several hours and there is a vast amount of information regarding the participation of many biochemical pathways and brain circuits in LTM formation. In 1900, Muller and Pilzecker (1900) proposed that formation of permanent memory takes time and that during this time, memory remains vulnerable to disruption. The process of developing stable memory is referred to as “consolidation” (McGaugh, 1966, McGaugh, 2000). A dominant idea that emerged two decades ago is that memory consolidation comprises two stages or phases: the initial stage, called cellular or synaptic consolidation, is fast, lasting from several hours to a couple of days. This process is thought to take place at synapses of the neuronal circuits encoding the experience-dependent internal representation such as the hippocampus and related non-cortical structures (Dudai, 2002). Cellular consolidation involves the activation of transcription factors to modulate gene expression, as well as synthesis, posttranslational modification and reorganization of proteins at synapses and soma, which finally ends in synaptic remodeling that makes the memory trace stable and precise (Alberini, 2009, Lamprecht and LeDoux, 2004, Morris, 2006, Ruediger et al., 2011). In other words, cellular consolidation has been defined as the transition of memory from protein synthesis and gene expression-dependence to independence in specific brain regions involved in acquisition of a particular learning experience (Medina, Bekinschtein, Cammarota, & Izquierdo, 2008).
The second phase is slower, and entails the participation of neocortical regions and their interactions with medial temporal lobe structures reorganizing the recently learned material (Squire, 1992) by gradually binding together the multiple cortical regions that store memory for a whole event. This phase is called systems-level consolidation and lasts several days to weeks or months in most learning tasks studied so far (Frankland & Bontempi, 2005). Systems consolidation is usually referred to as the process by which memory becomes independent of the hippocampus.
The standard model of memory consolidation posits that the hippocampus is primarily involved in consolidating and recalling recent episodic-like memories while some cortical regions, including prelimbic, orbitofrontal, and anterior cingulate areas, are mostly implicated in remote memory processing (Frankland et al., 2004, Lesburgueres et al., 2011, Maviel et al., 2004, Shan et al., 2008). However, strong alternative hypotheses emerged in the last few years stating that some cortical regions outside the temporal lobe have indeed a role in the very first moments of memory formation and participate in recalling both recent and remote memories (Einarsson & Nader, 2012; Katche et al., 2013; Leon et al., 2010, Tse et al., 2011).
Although much is known about LTM consolidation, what puts the “long” in LTM is its persistence over time. Most of the acquired information is bound to disappear or may leave an undetectable trace. In addition, and although it is not the subject matter of this review, it is essential to point here that recent findings strongly suggest that behavioral and neurohumoral conditions at the moment of memory retrieval could play a key role in modifying already consolidated memories or, conversely, helping to strength the reactivated memory trace or keep it stable for longer periods of time through a protein synthesis-dependent reconsolidation process. Moreover, quite recently it has been shown that, as happens during memory consolidation (see below), administration of protein synthesis inhibitors late after reactivation hampers the persistence of fear memory (Nakayama et al., 2013). Therefore, the matter of memory persistence is central in understanding the neurobiology of learning and memory.
The main goal of this review article is to describe what has been published about long-lasting molecular changes in memory processing, and specifically this article deals with those molecular mechanisms involved in long-lasting LTM. Therefore, we will focus on cellular consolidation mechanisms in hippocampus and related brain regions (including some cortical areas) involved in late posttraining consolidation periods that lead to persistent memories. Several of long-lasting molecular changes shown below are good examples of molecular changes that seem to last well beyond times suggested for the formation of memory. Unraveling the functional role of these molecular signatures is, in most cases, in progress and permits us to envision new ways of thinking memory consolidation.
Section snippets
Glutamate receptors and protein kinases
The first study that demonstrated a long-lasting process in the hippocampus required for LTM consolidation is that of Riedel et al. (1999). They demonstrated that ongoing activity in the hippocampus is required for spatial memory consolidation during several days after training rats in a water maze. Consistent with this there are some reports demonstrating that different types of glutamate receptors undergo long-lasting changes and/or are needed at very late posttraining time points in the
Concluding remarks
The findings reviewed in this article suggest that long-lasting memory processing is associated with a plethora of late posttraining changes in several brain regions. The studies on a critical phase involved in persistence of LTM storage that we commented here open a potential avenue of research on the mechanisms of late memory consolidation. For instance, is this process the end of the cellular consolidation phase? Is this phase a necessary link between cellular and system consolidation? Is
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One single physical exercise session improves memory persistence by hippocampal activation of D1 dopamine receptors and PKA signaling in rats
2021, Brain ResearchCitation Excerpt :Protein synthesis and regulation of several biochemical pathways are required to transform information previously acquired into an LTM trace stable and precise (Bekinschtein et al., 2010, 2008, 2007; Katche et al., 2013). Most studies measured the LTM 24 h after learning to evaluate different tools and mechanisms that can improve memory consolidation; however, LTM persistence over time is not fully understood (Bekinschtein et al., 2007; Katche et al., 2013). The positive influence of physical exercise on memory is a topic of continuous interest.