mRNA translation, or protein synthesis, is a major component of the transformation of the genetic code into any cellular activity. This complicated, multistep process is divided into three phases: initiation, elongation, and termination. Initiation is the step at which the ribosome is recruited to the mRNA, and is regarded as the major rate-limiting step in translation, while elongation consists of the elongation of the polypeptide chain; both steps are frequent targets for regulation, which is defined as a change in the rate of translation of an mRNA per unit time. In the normal brain, control of translation is a key mechanism for regulation of memory and synaptic plasticity consolidation, i.e., the off-line processing of acquired information. These regulation processes may differ between different brain structures or neuronal populations. Moreover, dysregulation of translation leads to pathological brain function such as memory impairment. Both normal and abnormal function of the translation machinery is believed to lead to translational up-regulation or down-regulation of a subset of mRNAs. However, the identification of these newly synthesized proteins and determination of the rates of protein synthesis or degradation taking place in different neuronal types and compartments at different time points in the brain demand new proteomic methods and system biology approaches. Here, we discuss in detail the relationship between translation regulation and memory or synaptic plasticity consolidation while focusing on a model of cortical-dependent taste learning task and hippocampal-dependent plasticity. In addition, we describe a novel systems biology perspective to better describe consolidation.

Memory consolidation is defined temporally based on pharmacological interventions such as inhibitors of mRNA translation (molecular consolidation) or post-acquisition deactivation of specific brain regions (systems level consolidation). However, the relationship between molecular and systems consolidation are poorly understood. Molecular consolidation mechanisms involved in translation initiation and elongation have previously been studied in the cortex using taste-learning paradigms. For example, the levels of phosphorylation of eukaryotic elongation factor 2 (eEF2) were found to be correlated with taste learning in the gustatory cortex (GC), minutes following learning. In order to isolate the role of the eEF2 phosphorylation state at Thr-56 in both molecular and system consolidation, we analyzed cortical-dependent taste learning in eEF2K (the only known kinase for eEF2) ki mice, which exhibit reduced levels of eEF2 phosphorylation but normal levels of eEF2 and eEF2K. These mice exhibit clear attenuation of cortical-dependent associative, but not of incidental, taste learning. In order to gain a better understanding of the underlying mechanisms, we compared brain activity as measured by MEMRI (manganese-enhanced magnetic resonance imaging) between eEF2K ki mice and WT mice during conditioned taste aversion (CTA) learning and observed clear differences between the two but saw no differences under basal conditions. Our results demonstrate that adequate levels of phosphorylation of eEF2 are essential for cortical-dependent associative learning and suggest that malfunction of memory processing at the systems level underlies this associative memory impairment.

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Age-associated memory deterioration (and the decline in ability to acquire new information) is one of the major diseases of our era. Cognitive enhancement can be achieved by using psycho-stimulants, such as caffeine or nicotine, but very little is known about drugs that can enhance the consolidation phase of memories in the cortex, the brain structure considered to store, at least partially, long-term memories. We used cortex-dependent taste-learning paradigms to test the hypothesis that pharmacological manipulation of the translation initiation eIF2␣, which plays a role in hippocampus-dependent memory, can enhance positive or negative forms of taste memories. We found that dephosphorylation (Ser51) of eIF2␣, specifically in the cortex, is both correlated with and necessary for normal memory consolidation. To reduce eIF2␣ phosphorylation and improve memory consolidation, we pharmacologically inhibited one of the eIF2␣ kinases, PKR, which is known to be involved in brain aging and Alzheimer's disease. Systemic or local microinjection of PKR inhibitor to the gustatory cortex enhanced both positive and negative forms of taste memory in rats and mice. Our results provide clear evidence that PKR plays a major role in cortex-dependent memory consolidation and, therefore, that pharmacological inhibition of PKR is a potential target for drugs to enhance cognition. IntroductionSensory information in the mammalian brain is encoded, at least in part, in the relevant cortical area, but very little is known about pharmacological manipulations that could facilitate cortically dependent learning.From the temporal perspective, a given memory involves acquisition, consolidation, and retention phases, possibly followed by many cycles of relearning, reconsolidation, and reretention (for review, see Dudai, 2004; Alberini et al., 2006; Nader and Hardt, 2009; Alberini, 2011;Johansen et al., 2011). Memory consolidation, a process in which labile short-term memories are transformed over time into stable long-term memories, is divided into system and molecular consolidation; however, the connection between the two is not clear (Gildish et al., 2012). System consolidation is defined by the time frame in which a given brain structure (e.g., the hippocampus) is indispensable for normal memory retention, and is a very slow dynamic process (Johansen et al., 2011). Molecular consolidation is biochemically defined by the time frame in which pharmacological perturbations (e.g., by protein synthesis inhibitors) attenuate long-term but not shortterm memories.Recently, several studies, based on differing behavioral paradigms susbserved by different brain structures, demonstrated that molecular consolidation is mediated through complex regulation of mRNA translation (for reviews, see Costa-Mattioli et al., 2009a, b; Gkogkas et al., 2010; Gal-Ben-Ari and Rosenblum, 2011). As reviewed extensively (Sonenberg and Hinnebusch, 2009), translation regulation occurs during both the initiation and the elongation phases, and both phases are regulated duri...