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These studies have asked: What regulatory mechanisms of transcription are involved in long-term memory formation? Most of these mechanisms are conserved in the mammalian brain where the CREB-dependent pathway has also been shown to be necessary for long-term memory formation and long-term synaptic plasticity (Benito and Barco 2010; Barco and Marie 2011). CREB refers to the activator isoform, but the CREB family of transcription factors includes several members (such as CREB-2 and activating transcription factor [ATF-4]) that can act as inhibitors of transcription.
Can these changes in gene expression by themselves explain the long persistence of memories? 2002; Yin and Tully 2006; Alberini 2009; Kandel 2012). Moreover, the overexpression of CREB promotes long-term memory storage from protocols that otherwise only induce short-term memory indicating its proactive role (Josselyn et al. Thus, its specific contribution to long-term memory formation is defined by the orchestrated regulation of the context in which CREB functions. This indicates an intimate functional link between the two families of transcription regulators. The biological implication of the contribution of a cascade of gene expression is that it governs a complex cellular function through a controlled and specific amplification of the initial signal.
Are these changes in gene expression transient or do they last for weeks, months, or even years paralleling memory storage? Although CREB represents one of the earliest identified transcription factors required for long-term memory formation, transcription regulation is a complex mechanism that involves the interactions of several transcription factors that can activate or inhibit transcription, cofactors, and general transcription proteins as well as chromatin-modifying proteins.
This central issue has attracted the attention of many neuroscientists in the last two decades and has been investigated in in vitro models and a variety of behavioral paradigms in invertebrates as well as in mammals. In fact, CREB, like many other transcription factors, is expressed in many cell types throughout the organism, is regulated by several intracellular pathways, and is involved in several processes through different protein/chromatin complexes.
In this article, we provide an overview of the mechanisms contributing to this transcriptional regulation underlying long-term memory formation.
The ability to form long-term memories and to store them for periods ranging from days to weeks to a whole lifetime is one of the brain functions most critical for adaptation and survival.
Without the ability to store information about our experiences for the long term, our lives would be a series of disconnected fragments.
It was long believed that the molecular/cellular phase of memory consolidation occurs only once, following training.In this review, we summarize some of the current answers to these questions. These cellular mechanisms include long-lasting changes of the strength of synaptic connections in long-term facilitation (LTF) in the invertebrate , and long-term potentiation (LTP) and long-term depression (LTD) in mammalian brain cells (Lynch 2004), thus strengthening the conclusion that transcription and gene expression are essential and general mechanisms necessary for stabilizing functions supported by long-term plasticity. One gene controlled by and downstream from CREB activation in the context of learning or long-term plasticity is the CCAAT enhancer–binding protein (C/EBP), an immediate early gene (IEG) whose disruption or overexpression, like that of CREB, blocks or promotes long-term synaptic plasticity and long-term memory consolidation, respectively (Alberini et al. In fact, through specificity and cooperativity, gene-expression cascades lead to precise concerted actions.Given the large number of studies, we will only be able to describe examples of (1) the major classes of transcription factors that play a critical role in both posttraining and postretrieval transcriptional regulation; (2) the target sequences regulated, including effector genes; and (3) the noncoding RNAs that have recently been found to regulate transcription and that can lead to chromatin, DNA, and RNA modifications that act in concert with transcription factors to regulate transcription important for memory consolidation. As in consolidation, the necessity of m RNA transcription in reconsolidation has been observed in many species ranging from invertebrates like to mammals (Sangha et al. Since the initial studies of the 1990s on the identification of transcription factors required for long-term plasticity and memory, it has emerged that one of the gene expression pathways required across species, types of memories, and memory systems for long-term plasticity and memory consolidation is that activated by c AMP-dependent mechanisms and mediated by members of the family known as c AMP-response element-binding proteins (CREB) (Dash et al. Other transcription factors regulated as IEGs include the c-Fos and the zinc-finger protein Zif268 (also known as early growth response protein [EGR]-1).Consolidation is manifest not only in behavior, but also in the cellular and molecular mechanisms contributing to long-term synaptic plasticity (Kandel 2001, 2014; Alberini 2009). In addition, through a subsequent process called system consolidation, the initial critical role of the hippocampus continues for up to weeks in mice and even up to years in humans, although, over time, it can become dispensable (Squire et al. As a result, memory loss can still occur weeks after training in animals, and even years in humans, when the hippocampus is either inactivated or ablated.Although it was long believed that molecular consolidation is completed rapidly, within a few hours, it recently emerged that in vivo it continues for at least 24 h, a temporal window in which circadian rhythms and sleep may make an important contribution (Eckel-Mahan and Storm 2009; Wang et al. For example, in the hippocampus, a brain region critical for the formation of long-term contextual, spatial, and episodic memories, the gene expression–dependent phase necessary for the consolidation of inhibitory avoidance memory in rats lasts for more than 24 h, and seems to be completed by 48 h after training (Taubenfeld et al. At the end of this phase of system consolidation, memories become insensitive to disruption by either pharmacological or molecular manipulations or hippocampal disruption/inactivation, and are therefore considered consolidated at the system level.
What are the genes transcribed in response to the experience and what are their functions? 2014), indicating its general and evolutionarily conserved role in the fragile phases of memory. In the invertebrates , the activation of the cascade c AMP-protein kinase A (PKA)-CREB is critical for plasticity and memory formation (Yin et al. Specifically, c AMP-PKA activation initiates short-term synaptic changes that subsequently link via nuclear translocation of PKA, ERK, and perhaps other kinases to the activation and recruitment of CREB proteins and gene transcription (Bacskai et al. Hence, CREB, although essential, is one of several transcriptional events required for memory consolidation and reconsolidation. One important aspect of this functional link is that via C/EBP, CREB controls a transcriptional cascade (Goelet et al. The result is a stable and long-lasting functional change that, at the same time, maintains flexibility and dynamism.