REVIEW ARTICLE published: 05 January 2012 BEHAVIORAL NEUROSCIENCE doi: 10.3389/fnbeh.2011.00087 Molecular mechanisms underlying memory consolidation of information in the cortex

Shunit Gal-Ben-Ari 1,2 and Kobi Rosenblum1,2*

1 Department of Neurobiology, University of Haifa, Haifa, Israel 2 Center for Gene Manipulation in the Brain, University of Haifa, Haifa, Israel

Edited by: The senses of taste and odor are both chemical senses. However, whereas an organism Riccardo Brambilla, San Raffaele can detect an odor at a relatively long distance from its source, taste serves as the ultimate Scientific Institute and University, Italy proximate gatekeeper of food intake: it helps in avoiding poisons and consuming beneficial Reviewed by: Riccardo Brambilla, San Raffaele substances. The automatic reaction to a given taste has been developed during evolution Scientific Institute and University, Italy and is well adapted to conditions that may occur with high probability during the lifetime Clive R. Bramham, University of of an organism. However, in addition to this automatic reaction, animals can learn and Bergen, Norway remember , together with their positive or negative values, with high precision and *Correspondence: in light of minimal experience. This ability of mammalians to learn and remember tastes Kobi Rosenblum, Department of Neurobiology and Ethology, Center has been studied extensively in rodents through application of reasonably simple and well for Gene Manipulation in the Brain, defined behavioral paradigms.The learning process follows a temporal continuum similar to University of Haifa, Mt Carmel, Haifa those of other memories: acquisition, consolidation, retrieval, relearning, and reconsolida- 31905, Israel. tion. Moreover, inhibiting protein synthesis in the (GC) specifically affects e-mail: [email protected] the consolidation phase of taste memory, i.e., the transformation of short- to long-term memory, in keeping with the general biochemical definition of memory consolidation. This review aims to present a general background of taste learning, and to focus on recent find- ings regarding the molecular mechanisms underlying taste–memory consolidation in the GC. Specifically, the roles of neurotransmitters, neuromodulators, immediate early genes, and translation regulation are addressed.

Keywords: taste learning, consolidation, gustatory cortex, insular cortex, MAPK, ERK, translation regulation, conditioned taste aversion

INTRODUCTION Yamamoto et al., 1984, 1985; Rosenblum, 2008; Doron and Rosen- Intake of food and avoidance of poison are crucial to an organ- blum, 2010), which is defined according to its cytoarchitectonic ism’s survival in a dynamic environment. The process of deciding boundaries as the dysgranular part of the insular cortex (IC; whether food is “safe” or “hazardous” relies heavily on the gusta- Burwell, 2001). This is in line with its unique anatomical connec- tory and somatosensory systems, which are involved in evaluating tions (Figure 1), through which it receives multimodal sensory diverse properties of putative foods, such as: chemosensory, e.g., inputs, including visceral, gustatory, and somatosensory informa- modality, intensity; orosensory, e.g., texture, temperature, pun- tion from sensory thalamic nuclei (Fujita et al., 2010). However, gency; and gratification capacity (Rosenblum,2008; Carleton et al., other brain regions, such as the basolateral (Bla) and 2010). dorsal hippocampus,have been shown to be activated during novel The sense of taste differs from the other senses in two major taste processing (Yefet et al., 2006; Doron and Rosenblum, 2010), characteristics: (1) Each taste input has dual labeling, one related and also to be necessary for safe taste–memory consolidation (De to its physical (texture and temperature) and chemical features, la Cruz et al., 2008). Most of the studies of the molecular mecha- and the other to its hedonic value and safety; (2) Deciding on the nisms underlying taste memory were performed in mice and rats, safety aspects of a novel sensation, such as the taste of an unfa- therefore, the present review will focus on these studies. miliar food, involves a different temporal scale from other senses: Taste recognition on the receptor level, as well as taste reactiv- taste association with unconditioned stimulus (US) takes 1–12 h ity, as defined genetically, are beyond the scope of this review; they (Bures et al., 1998; Merhav and Rosenblum, 2008), compared with have been extensively covered elsewhere (Frank et al., 2008; Car- a few seconds for responses to other sensations. leton et al., 2010). The first objective of this review is to describe Two main strategies are used by various species, including taste-related behavior paradigms, in order to elucidate the mole- humans, in responding to various tastes: genetic programming, cular and cellular mechanisms underlying learning and memory. i.e., affinity to sweet tastes, aversion to bitter ones, and com- We then provide a detailed analysis of the currently known mole- plex learning mechanisms that involve several forebrain structures cular and cellular mechanisms of taste learning in the GC, which (Rosenblum, 2008). Modification of the basic genetic program- resides in the IC. We aim to focus mainly on studies during the ming and memories of new tastes and their values are expected last decade; previous studies have been reviewed elsewhere (Bures to be mediated, at least in part, by the gustatory cortex (GC; et al., 1998; Rosenblum, 2008).

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FIGURE 1 | Neuroanatomy of the taste system. Chemical stimuli medullary and reticular-formation neurons, which innervate the cranial motor originating in alimentary sources, upon reaching the oral cavity initiate the nuclei. The lemniscal system consists of projections of the gustatory portion processing of gustatory information (CN, central nucleus; BLA, basolateral of the NST to the secondary nucleus situated in the dorsal (PBN); this, in amygdala; NST, nucleus of ; PBN, parabrachial nucleus; pVPMpc, turn, sends axons to the pVPMpc, which ultimately relays gustatory parvocellular part of the ventralis postmedial thalamic nucleus of the information to the anterior part of the insular cortex (GC). The visceral–limbic ; GC, gustatory cortex). Taste cells, which are broadly tuned to the system refers to a collateral network of connections to the and diverse taste modalities, are innervated by VII, IX, X, which limbic areas in the forebrain, which comprises the central gustatory pathway. project to the primary gustatory nucleus in the (NST). The NST The PBN is connected to the amygdala, the hypothalamus, and the sends information to three different systems: the reflex system, the lemniscal bed-nucleus of the stria terminalis. All limbic gustatory targets are system, and the visceral–limbic system. The reflex system comprises interconnected with each other as well as with the PBN and the GC.

BEHAVIOR PARADIGMS FOR THE MEASUREMENT OF TASTE the consolidation phase, the memory is transformed from short- LEARNING, MEMORY, AND CONSOLIDATION term memory (STM), which may last from minutes to hours, to The molecular mechanisms underlying learning and memory are long-term memory (LTM), which may last from days to a lifetime the subject of ongoing research. Although learning and memory (McGaugh, 2000; Kandel, 2001; Dudai, 2004). The time frame of are considered to be two different processes, they involve a con- the “consolidation phase” can vary within a given learning par- tinuum of events. Following a discrete event, physical changes adigm; it depends on the manipulation, and may reflect several underlying memory encoding and processing of the information different cellular and molecular processes (Figure 2). One may to be stored takes place. Ethologically, this is described as the ask whether the difference between consolidation and mainte- acquisition phase; it involves creation of an internal representa- nance of memories is an artificial one, since the processes can also tion of the novel information. This representation remains labile be regarded as continuous processing of the information by varied for some time, while the process of consolidation takes place. Dur- molecular and cellular mechanisms within a certain cortical area. ing this process the new memory becomes increasingly resistant They can also be considered in terms of temporally differential to disruption (Alberini, 2011), which can involve several types of involvement of several brain structures. intervention: behavioral (e.g., Merhav et al., 2006), pharmacolog- The next phase of memory processing is use or retrieval of ical (e.g., Rosenblum et al., 1993), or others (Bures et al., 1998). the memory, during which it is susceptible to further changes, It has been shown that the consolidation of new memory can be associated with a process of reconsolidation, which mediates its disrupted by many events, including: blocking synthesis of new restabilization. The stability of a memory depends on its age: new RNA or protein, e.g., by actimomycin D or anisomycin, respec- memories are sensitive to post-reactivation disruption, but older tively; disruption of the expression or function of specific proteins; ones are more resistant (Alberini, 2011). new learning; brain cooling; seizure, e.g., through electric shock; Ethologically, learning is usually classified into non-associative brain trauma; and regional brain lesions (Alberini, 2011). During (habituation and sensitization), associative (relationships between

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FIGURE 2 |The learning process phases: consolidation is consolidation time. The different experimental interferences with determined by type of disruption. The learning process is consolidation affect different stages of the molecular mechanisms that ethologically divided into consecutive phases of acquisition, underlie learning and memory formation. Although the same types of consolidation, retrieval, relearning, and reconsolidation. Whereas interference may be used to disrupt consolidation and reconsolidation, the acquisition, retrieval, and relearning are defined in positive terms, the time windows of sensitivity to disruption differ between the two phases of consolidation and reconsolidation phases are defined in negative terms. learning. It is therefore unclear whether the molecular processes that occur Therefore, the duration of the learning process is variable, and during consolidation are identical to the ones that occur during dependent on the type of experimental perturbation used to determine reconsolidation. amounts and events), and incidental learning (learning in the which an association is formed between a novel taste (serving as a absence of explicit external reinforcement; Gibb et al., 2006; Mor- conditioned stimulus – CS) and malaise (serving as an uncondi- ris, 2006; Miranda et al., 2008; Rosenblum, 2008; Lindquist et al., tioned stimulus – US), resulting in the animal’s subsequent avoid- 2009). Over the years, different behavioral paradigms have been ance of the novel food associated with delayed food poisoning developed in order to study the different types of learning, and (conditioned response – CR; Garcia et al., 1955; Bures et al., 1998). also to address the abovementioned temporal phases of memory The acquisition of CTA is subserved by specific brain regions, formation. including the IC and the amygdala, although their precise role in One of the most widespread taste-learning paradigms is the CTA is still unclear (Yamamoto et al., 1994; Lamprecht and Dudai, negative-learning, conditioned taste aversion (CTA) paradigm, in 1996), and it has been demonstrated that induction of neurotoxic

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lesions in the IC disrupts acquisition of CTA (Roman et al., 2006; the basolateral amygdaloid nucleus (Bla) induced N -methyl-d- Roman and Reilly, 2007). Similarly, lesions of the basolateral aspartate (NMDA)-dependent but metabotropic glutamate recep- region (Bla), but not of the central nucleus of the amygdala, selec- tor (mGluR)-independent LTP in the IC (Escobar et al., 1998, tively disrupt CTA performance (Nachman and Ashe,1974; Morris 2002; Jones et al., 1999). It is important to note that IC–LTP and et al., 1999; St Andre and Reilly, 2007). CTA is commonly used CTA both involve similar molecular mechanisms in the IC, such when a hippocampus-independent form of learning is addressed. as NMDA receptor (NMDAR) dependence, activation of ERK1/2, A widely used paradigm of positive-learning is latent inhibition and induction of immediate early genes (IEGs), including Zif268, of CTA (LI-CTA), in which an animal learns that a novel food is Fos, Arc, and Homer (Jones et al., 1999; Rodriguez-Duran et al., safe, and displays less aversion following CTA than animals sub- 2011). jected to CTA alone (Bures et al., 1998). The LI-CTA paradigm However, it remains to be more robustly proven that LTP-like involves presentation of a novel taste to an animal prior to CTA. mechanisms in the IC subserve taste learning. It was shown that Since this early experience elicits no negative consequences, the induction of LTP in the Bla–IC projection prior to CTA enhanced animal displays reduced aversion to the same taste following CTA CTA retention (Escobar and Bermudez-Rattoni, 2000). In addi- (Rosenblum et al., 1993). This modulation of behavior can be tion, it was shown that on the one hand, intracortical microinfu- attributed either to reduced strength of the association at the time sion of brain-derived neurotrophic factor (BDNF) induced LTP in of the CTA or to competition during the retrieval phase (Lubow, the Bla–IC projection of adult rats (Escobar et al., 2003), and on 1989). LI-CTA is a form of incidental learning that depends on the other hand, that intracortical microinfusion of BDNF prior to both the quantity of novel taste consumed and the functionality CTA training enhanced retention of this task (Castillo et al., 2006). of the GC (Rosenblum et al., 1993; Merhav and Rosenblum, 2008). In a follow-up study,Rodriguez-Duran et al. (2011) have shown Under certain conditions, CTA can be extinguished (Berman that when the paradigm was reversed, i.e., CTA was performed et al., 2003). Extinction reflects a decrease in the CR in the absence prior to LTP induction in the Bla–IC projection, CTA training of reinforcement of a conditioned stimulus. Behavioral evidence prevented the subsequent induction of LTP in the Bla–IC pro- indicates that extinction involves an inhibitory learning mecha- jection for at least 120 h after CTA training. In addition, they nism in which the extinguished CR reappears following presenta- showed that CTA training produced a persistent change in the tion of an unconditioned stimulus. However, studies have shown possibility of inducing subsequent LTP in the Bla–IC projection in that the memory was not erased in rats and humans (Lin et al., a protein-synthesis-dependent manner, and inferred that changes 2010). in the possibility of inducing subsequent synaptic plasticity con- Taste learning and CTA have several advantages as para- tributed to the formation and persistence of aversive memories digms for studying molecular mechanisms underlying learning (Rodriguez-Duran et al., 2011). and memory. These include: one-trial learning; strong inciden- Long-term potentiation consists of two phases on the molecu- tal learning; clear and short learning time; minimal behavioral lar level: induction, which triggers potentiation, and maintenance, manipulation, since the animals can learn in their home cage with which sustains the potentiation over time. Many molecules have very little interference from other modalities; the sensory input been shown to be involved in the induction phase of LTP, but is clearly defined, and therefore can be quantified in molecular very few have been implicated in the maintenance phase. Since terms; clearly defined cortical area(s) subserve the learning; and the working hypothesis is that LTP is the cellular mechanism high reproducibility (Bures et al., 1998; Rosenblum, 2008). underlying LTM storage,the molecular mechanisms relevant to the maintenance phase are highly important. Tothe best of our knowl- LONG-TERM POTENTIATION IN THE INSULAR CORTEX edge, to date, only a single molecule, protein kinase Mζ (PKMζ), The most studied form of neuronal adaptations is Hebbian plastic- has been found to be necessary for maintenance in both the hip- ity, which includes long-term potentiation (LTP), and its recipro- pocampus (spatial learning) and the IC (CTA): local injection of cal, long-term depression (LTD; Collingridge et al., 2004; Malenka ZIP, a PKMζ selective inhibitor, into the hippocampus resulted and Bear, 2004; Feldman, 2009; Pozo and Goda, 2010). Hallmark in reversal of LTP maintenance in vivo and loss of 1 day old spa- features of LTP are that synaptic changes are associative, rapidly tial memory (Pastalkova et al., 2006). Similarly, its injection into induced, and input specific. These features facilitate reinforce- the GC resulted in reversal of long-term CTA memory in a dose- ment of active synaptic connections with a given set of sensory dependent manner, whereas other serine/threonine protein kinase stimuli, thus eliciting an activity-induced increase in synaptic effi- inhibitors are capable of interference with long-term memory for- cacy, which is widely expressed in several pleo- and neocortical mation, but are ineffective once the memory has been established areas. Taken together, these characteristics render LTP an attrac- (Shema et al., 2009, 2011). tive model for a cellular basis for learning and memory (Bliss and Protein kinase Mζ is the brain-specific atypical protein kinase C Collingridge, 1993; Neves et al., 2008; Rosenblum, 2008; Sjostrom (PKC) isoform, which unlike full-length PKC isoforms, is a cleaved et al., 2008). form comprising the independent catalytic domain of PKCζ, and Long-term potentiation has been described in several brain is a second messenger-independent kinase. PKMζ is constitutively areas, including the hippocampus and the cortex, and in active in sustaining LTP maintenance, and studies have shown conjunction with taste learning, (Escobar et al., 1998, 2002; that it mediates synaptic potentiation specifically during the late Ramirez-Lugo et al., 2003; Chen et al., 2006; Alme et al., phase of LTP.LTP induction increases new PKMζ synthesis,leading 2007; Bramham, 2007; McGeachie et al., 2011; Rodriguez-Duran to enhanced synaptic transmission. The mechanism underlying et al., 2011). It was demonstrated that tetanic stimulation of L-LTP and spatial memory maintenance by PKMζ is thought

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to involve AMPA receptor phosphorylation and trafficking, with of in vivo microdialysis and capillary electrophoresis (Guzman- subsequent changes in the amplitude of excitatory postsynaptic Ramos et al., 2010). In their study, Guzman-Ramos et al. potential (EPSP) concomitant with dendritic translation regulated (2010) demonstrated the occurrence of an amygdala-dependent by PKMζ phosphorylation (and inhibition) of Pin1 (Sacktor,2008; dopamine and glutamate reactivation within the IC, about 45 min Vlachos et al., 2008; Navakkode et al., 2010; Parvez et al., 2010; von after the stimuli association. Furthermore, blockade of dopamin- Kraus et al., 2010; Westmark et al., 2010; Mei et al., 2011; Sajikumar ergic D1 and/or NMDARs before the off-line activity impaired and Korte, 2011). long- but not STM, which suggests dependence on protein syn- thesis (Guzman-Ramos et al., 2010). In addition, dopamine and NEUROTRANSMITTERS IN THE GUSTATORY CORTEX NMDA can synergistically activate extracellular signal-regulated INVOLVED IN TASTE LEARNING kinase (ERK)/Mitogen-activated protein kinase (MAPK) signal- The working hypothesis is that an organism relies on its sensory ing, which is necessary for the formation of long-term taste system, specifically, in the present context, the sense of taste, to memory (Kaphzan et al., 2006, 2007). create an internal representation of a given physical or chem- Activation of NMDARs has been shown to be necessary for ical stimulus. The sensory information is converted into neu- attenuation of the neophobic taste response in both the IC ronal activity that subserves the various phases of learning, i.e., (Figueroa-Guzman et al., 2006) and the Bla (Figueroa-Guzman acquisition, consolidation, and retrieval. Information regarding and Reilly, 2008). Acute microinfusions of MK-801, a non- physical/chemical properties and the significance of a given taste competitive NMDAR antagonist, into both brain regions revealed reaches the GC via several different neurotransmitters, and elicits that although there was no effect on the initial magnitude of the the release of several neurotransmitter systems in the GC, where neophobic response, attenuation of gustatory neophobia was pre- relevant receptors are expressed as well. Several molecular changes vented. Similarly, microinfusion of mGlu5-selective antagonist, in the GC have been found to be correlated with novel taste learn- 3-[2-methyl-1,3-thiazol-4yl)ethynyl]pyridine (MTEP), at 0, 1, or ing at various time points after exposure to a novel taste. The 5 μg into the rat IC or Bla prior to CTA resulted in enhanced molecules involved include acetylcholine (ACh), dopamine, nora- CTA performance in the case of the Bla, indicated by robust CTA drenaline, gamma-aminobutyric acid (GABA), glutamate, and followed by slower extinction than in control animals, in a dose- various neuropeptides (Figure 3; Rosenblum et al., 1995, 1996, dependent manner. Interestingly, MTEP microinfusion into the 1997; Berman et al., 2000; Belelovsky et al., 2005, 2009; Koh and IC resulted in less robust aversion following CTA, in addition to Bernstein, 2005; Merhav et al., 2006; Banko et al., 2007; Costa- enhanced extinction, in a dose-dependent manner (Simonyi et al., Mattioli et al., 2007; Elkobi et al., 2008; Merhav and Rosenblum, 2009). Previous studies that employed systemic administration 2008; Barki-Harrington et al.,2009b; Doron and Rosenblum,2010; of mGlu antagonists before CTA conditioning have demonstrated Sweetat et al., 2011). However, only the muscarinic-cholinergic that activation of mGlu5,but not of mGlu1 receptors,was required and NMDARs have been extensively studied with regard to their for CTA learning (Schachtman et al., 2003). In addition, attenua- roles in taste–memory acquisition, consolidation, and retention tion of CTA can be attained by microinjection of a broad-spectrum (Jones et al., 1999; Gutierrez et al., 2003; Nunez-Jaramillo et al., mGlu antagonist into the Bla (Yasoshima et al., 2000) or the IC 2008; Rosenblum, 2008). (Berman et al., 2000). mGlu5 receptors interact with NMDARs, and the two modu- GLUTAMATE late one another’s function in several brain regions in a mutually Physical and chemical taste information is transferred from the positive manner: stimulation of either receptor potentiates the oral cavity to the cortex via fast neurotransmission, mediated by other (Fowler et al., 2011). The two receptors are physically con- the neurotransmitter glutamate, the main excitatory neurotrans- nected with each other through anchor proteins: mGlu5 receptor mitter in the mammalian CNS (Rosenblum, 2008; Rondard et al., binds Homer proteins (Fagni et al., 2004), NMDAR interacts with 2011). Since the prominence of a given taste is hypothesized to postsynaptic density (PSD)-95, and Homer and PSD-95 can be be mediated via activation of the neuromodulatory system (e.g., clustered by Shank – all three of which are PSD proteins (Nais- Kaphzan et al., 2006), it is possible that the interaction between the bitt et al., 1999; Tu et al., 1999). NMDA and mGlu5 can act two systems produces a long-term taste–memory trace; it is also synergistically to activate a number of proteins such as MAPKs, likely that it coincides on specific neurons and probably molecules calcium/calmodulin-dependent protein kinase II (CaMKII), and that can serve as coincidence detectors of the sensory input and its CREB (Mao and Wang, 2002; Yang et al., 2004). meaning (Kaphzan et al., 2006). A plethora of studies using genetic, pharmacological, physi- The glutamate receptor family comprises four types of ological, and biochemical approaches have indicated the critical receptors: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propi- roles played by mGlu5 and NMDA in both the IC and the hip- onic acid (AMPA), N -methyl-d-aspartic acid (NMDA), kainate, pocampus in acquisition and consolidation, but not retrieval, and mGluRs. AMPA, NMDA, and kainate receptors are ionotropic of memory of aversive tasks, specifically in avoidance learning receptors, i.e., they can produce complex fast ion influx-mediated and CTA (Schachtman et al., 2003; Cui et al., 2005; Gravius changes in the neuron, whereas mGluRs produce slow sec- et al., 2005; Izquierdo et al., 2006; Simonyi et al., 2007, 2009; ond messenger-mediated changes in the neuron by activating Barki-Harrington et al., 2009a; Nunez-Jaramillo et al., 2010). G-protein-coupled receptors (GPCRs; Rondard et al., 2011). In a recent follow-up study employing co-administration of an Glutamate and dopamine have been implicated in off-line mGlu5-receptor-positive allosteric modulator, 3-cyano-N -(1,3- processing and memory consolidation following CTA, by means diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB),and an NMDAR

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FIGURE 3 | Molecular mechanisms underlying taste learning explored. A, neuromodulators/glutamate; B, receptors; C, scaffold proteins; D, in the gustatory cortex: schematic simplified representation signal transduction and hub molecules; E, translation regulation; F, assuming the different molecular events take place within transcription. Key: neuromodulators – white hexagon; glutamate – white the same neuron. Glutamate/neuromodulators (Ach, dopamine) ellipse; receptors of neurotransmitters/neuromodulators – blue; reach the postsynaptic site and affect the neuron through specific representatives of major protein kinases and phosphatases that may have receptors (NMDAR, AMPAR, mGluR, muscarinic receptors, dopamine short-term (CamKIIα) or long-term effects-green; protein translation receptors, e.g., D1). The receptors are linked to scaffold proteins that form the machinery – purple; transcription factors – coral; immediate early genes – red; postsynaptic density (PSD), e.g., MAGUKs, Shank, Homer. MAGUKs are second messenger – orange. *CaMKII is known to phosphorylate PSD-95 and linked through distal scaffolding proteins (DSP) to CamKII. The complexes of SAP-97, but it remains to be clarified whether it phosphorylates PSD-93 and receptors and PSD proteins activate signal transduction and hub molecules, SAP-102 as well. In addition, CamKII is well known to activate cytoplasmic which in turn activate transcription and translation regulation. This chain of polyadenylation element binding protein (CPEB) in other brain regions and in events, according to our current understanding, results in a new cellular connection with other forms of learning, thereby affecting protein translation. steady state. It is currently unknown whether all molecular processes **The BDNF pathway has been simplified; other proteins participate in this depicted occur within a single neuron – a question that remains to be further pathway. antagonist, MK-801, it was shown that NMDA and mGlu5 inter- There is ample evidence in the literature for the importance of acted functionally in CTA-conditioned rats. Whereas CDPPB NMDAR, specifically its regulatory NR2B subunit, in taste learn- administered by itself prior to the conditioning trial had no effect ing. For example, CTA conditioning-induced long-lasting tyro- on CTA or hippocampus-dependent step-down inhibition, co- sine phosphorylation of NR2B specifically in the IC (Rosenblum administration of the two compounds resulted in attenuation of et al., 1995). Furthermore, local administration of (2R)-amino-5- learning deficits in both tasks (Fowler et al., 2011). phosphonovaleric acid (APV), a reversibly selective competitive

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inhibitor of NMDAR, to the IC prior to CTA conditioning demonstrated that carbachol, a cholinergic agonist, increased the impaired CTA memory in a brain-region- and time-dependent amplitude of unitary inhibitory postsynaptic currents (uIPSCs) manner (Rosenblum et al., 1995, 1996, 1997). In addition, whereas in interneuron-to-interneuron synapses with higher paired-pulse exposure to a novel taste, e.g., saccharin, increased phosphoryla- ratios. However, the same compound induced dose-dependent tion in the NMDAR subunits, repeated doses of saccharin at the suppression of uIPSCs in fast spiking of pyramidal cell synapses. same concentration, which rendered the taste familiar, led to a dra- This attenuation was mitigated by atropine, a muscarinic ACh matic decrease in the levels of serine phosphorylation of NR2A and receptor antagonist (Yamamoto et al., 2010), and the authors NR2B subunits (Nunez-Jaramillo et al., 2008). inferred that “carbachol facilitates GABA release in interneuron NR2B phosphorylation in the IC is not only correlated with synapses with lower release probability, and cholinergic modula- but is necessary for taste learning, as has been demonstrated tion of GABAergic synaptic transmission is differentially regulated through pharmacological and genetic approaches: local admin- depending on postsynaptic neuron subtypes.” It is important to istration of the tyrosine kinase inhibitor, genistein, to the IC note that neurons projecting from one brain-region involved in prevented the increase in phosphorylation of NR2B on tyrosine taste learning to another (Figure 1) are inherently excitatory, how- 1472, and attenuated taste–memory formation (Barki-Harrington ever, neurons within a certain brain region may be inhibitory et al., 2009b). Additionally, whereas novel taste exposure has been as well. The roles of inhibitory cortical neurons are yet to be recently demonstrated to induce intracellular redistribution of determined. NR2A and NR2B subunits in the IC (Nunez-Jaramillo et al., 2008), microinjection of genistein to the IC altered this learning-induced POSTSYNAPTIC DENSITY-95 distribution pattern of NMDAR, highlighting the importance of Postsynaptic density-95 (PSD-95), a membrane-associated guany- NR2B tyrosine phosphorylation after learning in determination late kinase (MAGUK), is the major scaffolding protein in the of NMDAR distribution (Barki-Harrington et al., 2009b). excitatory PSD and a potent regulator of synaptic strength (Chen In another study, transgenic (Tg) mice over-expressing the et al., 2011). It has been recently shown that 3 h following novel NR2B subunit specifically in the forebrain (which includes the IC) taste learning, expression levels of this protein were specifically were shown to have enhanced CTA, as well as slower extinction elevated in the GC. This elevation has been shown to be necessary rates, although aversion levels were similar in Tg and wild-type for acquisition of novel taste memory, but not for its retrieval, and (Wt) mice 30 days after the CTA conditioning. However, under it has not been observed in response to a familiar taste (Elkobi the LI-CTA paradigm, the Tg mice did not differ from Wt mice et al., 2008). Moreover, there was a correlative increase in PSD-95 in their aversion levels, and in a paradigm of two-taste LI-CTA association with tyrosine-phosphorylated NR2B following novel (second order conditioning, in which the mice are exposed to taste learning (Barki-Harrington et al., 2009b). A study concerning both novel and familiar tastes) the Tg mice showed attenuation of spatial learning, which is both hippocampus- and IC-dependent, enhanced CTA (Li et al., 2010). has shown that water-maze training induced a translocation of NMDARs and PSD-95 to lipid raft membrane microdomains, GABA AND ACh concomitant with increased NR2B phosphorylation at tyrosine Although the involvement of glutamate receptors in the process- 1472 in the rat IC (Delint-Ramirez et al., 2008), similarly to ing of taste learning in the GC has been extensively studied, novel taste learning, as mentioned above (Barki-Harrington et al., other neurotransmitters have been implicated as well. Novel tastes 2009b). have been shown to increase ACh levels in the rat IC, whereas a PSD-95 and other MAGUK family proteins, SAP-97 and PSD- familiar taste did not (Miranda et al., 2000). Furthermore, phar- 93, have been shown to interact with NMDAR, thereby regulating macological inactivation of the nucleus basalis magnocellularis, a its function, e.g., all three inhibited NR2B-mediated endocyto- cholinergic and GABAergic source in the basal forebrain, impaired sis (Lavezzari et al., 2003). The MAGUK family proteins have CTA acquisition (Miranda and Bermudez-Rattoni, 1999). How- been shown to mediate NMDAR clustering and/or trafficking by ever, retrieval was not impaired by this manipulation. In addition, association with NMDAR NR2 subunits via their C-terminal glu- cholinergic activity mediated by muscarinic receptors in the IC tamate serine (aspartate/glutamate) valine motifs. In addition, the has been shown to be necessary for acquisition and consolida- MAGUK proteins interacted differentially with different NMDAR tion of contextual memory of inhibitory avoidance (Miranda and subtypes, comprised of differing receptor subunit combination Bermudez-Rattoni, 2007). (Cousins et al., 2008). Specifically, PSD-95 interacted with both Inhibitory GABAergic interneurons have been recently demon- NR2A and NR2B (Kornau et al., 1995), and this interaction could strated to be activated in response to novel taste learning in be modulated by either serine or tyrosine phosphorylation. a layer-specific manner hours after taste learning, which sug- For example, CaMKII phosphorylated PSD-95 on serine gests that these neurons are involved not only in acquisition, but residue, causing dissociation of NR2A, but not of NR2B from the also in off-line processing and consolidation of taste informa- NMDA–PSD-95 complex. In addition, PSD-95 itself functioned tion (Doron and Rosenblum, 2010). Electrophysiological studies as a negative regulator of the tyrosine kinase Src, for which it in anesthetized rats revealed that excitatory propagation in the IC served as a contact point to the NMDAR, thus enabling its reg- was primarily regulated by AMPA and GABAA receptors (Fujita ulation (Kalia et al., 2006). Moreover, phosphorylation of NR2A et al.,2010). Another electrophysiological study in rat-cortex slices, and NR2B and their associated proteins by Src or Fyn was found which employed multiple-whole-cell patch-clamp recording from in some cases to enhance their association with PSD-95 (Rong layer V GABAergic interneurons and pyramidal cells of rat IC, et al., 2001; Zalewska et al., 2005). Other tyrosine kinases shown

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to interact with PSD-95 include c-Abl and Pyk2: the former regu- resulted in inhibition of ERK1/2, as well as attenuation of CTA lated synaptic clustering of PSD-95 (de Arce et al., 2010); the latter (Rosenblum, 2008) and blockade of learning-induced elevation of underwent PSD-95-induced postsynaptic clustering and activa- PSD-95 3 h following taste learning (Elkobi et al., 2008). tion (Bartos et al., 2010). It has been suggested that the role of the The various MAPKs are activated within differing time periods PSD-95–NMDA complex is to protect NR2 subunits from under- after novel taste learning; ERK activation appears to begin a few going cleavage by calcium-dependent proteases, and thereby to minutes up to 1 h following novel taste consumption (Rosenblum, provide a mechanism for regulating NMDAR expression (Dong 2008). It has been shown that novel taste consolidation requires et al., 2004). the elevation of ERK1/2 activity in the IC 20 min after taste con- sumption. However, JNK1/2 was activated 1 h after novel taste THE ROLE OF THE MAPK/ERK PATHWAY IN THE GUSTATORY learning, whereas p38 was not modified at any of the examined CORTEX time points (Berman et al., 1998). Interestingly, the time scale of Mitogen-activated protein kinases are a family of serine/threonine ERK activation was species-specific; it was shown to differ between kinases implicated in regulation of cell proliferation and differenti- mice and rats (Swank and Sweatt, 2001). ERK expression following ation (Seger and Krebs, 1995; Belelovsky et al., 2007). Three major taste learning is not only time-restricted, but also space-restricted; groups of MAPKs have been identified in mammalian cells: extra- it was activated in the GC, but not in the hippocampus, after cellular signal-regulated kinase (ERK), c-jun N-terminal kinase the same length of time following learning (Yefet et al., 2006). (JNK), and p38 MAP kinase. High levels of the ERK isoforms, The various MAPKs also differed in BDNF-induced activation: ERK1 (p44 MAPK) and ERK2 (p42 MAPK), have been detected in intrahippocampal microinfusion of BDNF that aimed to induce neurons in the mature CNS (Fiore et al., 1993). ERK activity has LTP resulted in rapid phosphorylation of ERK and p38, but not of been shown to be crucial for several forms of learning and mem- JNK (Ying et al., 2002). These effects were observed in the dentate ory, including fear conditioning, CTA memory, spatial memory, gyrus, but not in other examined hippocampal regions, and were step-down inhibitory avoidance, and object recognition memory. shown to be MEK–ERK-dependent. In a study in which several pharmacological agents were locally Whereas the upstream regulation of ERK in the GC is well injected into the rat IC, it was found that NMDARs, mGluRs, studied, our knowledge regarding its downstream targets remains muscarinic, beta-adrenergic, and dopaminergic receptors were fragmentary. MAPK substrate, ELK-1, a transcription factor regu- all implicated in acquisition of the new taste memory, but not lating immediate early expression of genes via the serum response in its retrieval, although these neurotransmitter/neuromodulator element (SRE) DNA consensus site (Besnard et al., 2011), has been systems differed in their role in acquisition. In addition, it was shown to be phosphorylated in a time frame similar to that of demonstrated that of all the receptors studied, only NMDA and ERK activation after novel taste learning, and neurotransmitters muscarinic receptors specifically mediated taste-dependent acti- required for induction of LTM are also required for ELK-1 phos- vation of ERK1–2, whereas dopaminergic receptors regulated the phorylation in the GC in response to taste learning (Berman et al., basal level of ERK1–2 activation (Berman et al., 2000). Several 2003). Further studies are needed to identify other possible targets studies have demonstrated the differential role of ERK1 and 2 in of ERK and their mechanisms of action underlying taste processing cell growth and proliferation and synaptic plasticity. For exam- in the GC. ple, ERK1 knockout mice displayed enhancement of striatum- dependent long-term memory, in conjunction with facilitation of THE ROLE OF TRANSLATION REGULATION IN LTP in the nucleus accumbens, indicating the importance of ERK2 TASTE–MEMORY CONSOLIDATION (Mazzucchelli et al., 2002; Vantaggiato et al., 2006). The distinctive biochemical characteristic of memory consolida- ERK activation occurs downstream to neurotransmitter release tion is its dependence on synthesis of functional proteins in the and activation of the forebrain cholinergic neurons during and relevant brain regions (Davis and Squire, 1984). Indeed, local immediately after acquisition of an inhibitory avoidance response. application of anisomycin,a protein-synthesis inhibitor,to specific ERK plays a major role in learning, by promoting cellular integra- brain regions affected CTA in a dose-, site-, and time-dependent tion of divergent downstream effectors that may trigger differing manner (Rosenblum et al., 1993; Meiri and Rosenblum, 1998). responses, depending upon which subsets of scaffolding anchors, For instance, local application of anisomycin to the GC atten- target proteins,and regulatory phosphatases are involved (Giovan- uated CTA and taste learning under the LI paradigm (Rosen- nini, 2006). MEK–ERK, the upstream kinase of ERK, is a crucial blum et al., 1993); however, the same treatment had no effect signal transduction cascade in synaptic plasticity and memory on STM (Houpt and Berlin, 1999), which suggests that short-term consolidation (Sweatt, 2001), and its inhibition affected both early taste memory is independent of protein synthesis. Temporally, and late phases of LTP in the hippocampus (Rosenblum et al., taste learning is sensitive to protein-synthesis inhibitor(s) from 2002). just before learning until up to 100 min afterward (Rosenblum, Extracellular signal-regulated kinase activation was shown to 2008). In addition, extinction of CTA is dependent on func- be correlated with novel taste learning, although the amount of tional protein synthesis in the prefrontal cortex (Akirav et al., protein remained unchanged (Berman et al., 1998; Belelovsky 2006). It is generally accepted that protein translation affects et al., 2005). In addition, the expression of LTP in the GC was LTM consolidation by modulation of synaptic strength, since ERK-dependent, and operated in a positive feedback mode (Jones protein-synthesis inhibitors prevented transformation of early et al., 1999). In a recent study, it was shown that bilateral injection LTP to late LTP.However,other modifications of intrinsic neuronal of U0126, a specific MEK inhibitor, to the GC prior to learning properties also subserve learning-related behavioral changes. For

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example, learning-induced reduction in the postburst after hyper- The suggested mechanism could perform a switch-like function in polarization (AHP) lasts for days after completion of training, expressing a specific set of mRNAs within a restricted time window and is implicated in maintenance of learned skills. It has been in a cellular microdomain/s such as the synapse. recently demonstrated that synaptic activation-induced short- term postburst AHP reduction in hippocampal and pyramidal MAMMALIAN TARGET OF RAPAMYCIN neurons could be transformed to a protein-synthesis-dependent Some of the correlative changes that follow novel taste or long-term AHP reduction that persisted for long time periods CTA paradigms have been observed in proteins that are either (Cohen-Matsliah et al., 2010). Such learning-induced AHP reduc- direct or indirect targets of the mammalian target of rapamycin tion has been shown to be maintained by persistent activation (mTOR), also known as FKBP-12-rapamycin-associated protein of PKC and ERK in piriform cortex neurons (Seroussi et al., (FRAP), which consists of two TOR complexes (TORC) that dif- 2002; Cohen-Matsliah et al., 2007), but has been found to be fer in rapamycin sensitivity. TORC1 mediated rapamycin-sensitive CaMKII-independent (Liraz et al., 2009). TOR-shared signaling to the translation machinery, the transcrip- Translation consists of three phases: initiation, elongation, and tion apparatus, and other targets (Loewith et al., 2002; Hay and termination. Of these, the initiation phase is the most tightly Sonenberg, 2004), and its blockade by rapamycin interfered with regulated, and is affected by phosphorylation of initiation fac- translation of specific subpopulations of mRNA (Raught et al., tors (IFs) and ribosomal proteins (Proud, 2000). Initiation in 2001). Downstream targets of mTOR include ribosomal protein eukaryotes serves as the rate-limiting step in protein synthesis, kinase (S6K1) and EF 1A and 2 (eEF1A and eEF2), which are and therefore serves as an important target for translational con- mostly involved in ribosome recruitment to mRNA, and regula- trol (Costa-Mattioli et al., 2009). There is considerable evidence in tion of both the initiation and elongation phases of translation the literature that increased initiation results in enhanced learning, (Hay and Sonenberg, 2004). and vice versa. In knockout mice lacking the translation repres- There is considerable evidence for the importance of the sor eukaryotic initiation factor 4E-binding protein (4EBP2; Banko mTOR pathway in various forms of synaptic plasticity. In Aplysia, et al., 2007) or with reduced phosphorylation of eukaryotic initi- rapamycin application prevented long-term facilitation (Casadio ation factor 2α (eIF2α; Costa-Mattioli et al., 2007), and therefore et al., 1999), and in the rat hippocampal CA1 region, rapamycin with enhanced initiation, no differences in taste recognition in blocked high-frequency stimulation (HFS) and BDNF-induced parallel to enhanced CTA learning were observed; furthermore, LTP (Tang et al., 2002). In addition, mTOR-dependent activation other types of learning and plasticity in the consolidation phase of dendritic S6K1 was shown to be necessary for the induc- were enhanced as well. Conversely, knockout mice lacking either tion phase of protein-synthesis-dependent synaptic plasticity S6K1 or S6K2, characterized by reduced initiation rates, exhibited (Cammalleri et al., 2003). impaired taste learning (Antion et al., 2008). In a model analo- It has been recently shown that following novel taste learn- gous to CTA in the chick, eukaryotic translation initiation factor ing, two temporal waves of mTOR activation occurred in the GC 2B (eIF2B) was found to be both correlated with and necessary for (Belelovsky et al., 2009). Furthermore, it was shown that PSD-95 taste–memory consolidation (Tirosh et al., 2007). elevation in the GC 3 h following taste learning, which is neces- The second phase of translation, elongation, requires activ- sary for LTM (Elkobi et al., 2008), was prevented following local ity of elongation factors (EFs). Eukaryotic elongation factor 2 application of rapamycin to the GC. Another study has shown, by (eEF2) mediated ribosomal translocation (Ryazanov and Davy- means of HFS, an interesting interplay between ERK and mTOR dova, 1989) and was phosphorylated on Thr56 by a spe- pathways induced at CA3–CA1 synapses: whereas HFS induced cific Ca2+/calmodulin-dependent kinase. Phosphorylation of this LTP as well as translational proteins regulated by mTOR, the for- kinase inhibited its activity and led to general inhibition of protein mer induction was blocked by use of ERK inhibitors (Tsokas et al., synthesis (Nairn and Palfrey, 1987). It has been shown that follow- 2007). Moreover, this study showed ERK to be not only correlated ing novel taste learning,eEF2 phosphorylation was increased in the with, but necessary for mTOR stimulation by HFS via interac- GC, indicating attenuation of translation elongation (Belelovsky tion with phosphoinositide-dependent kinase 1 (PDK1) and Akt, et al., 2005). This finding, which is counter-intuitive, implies that which are upstream to mTOR. the situation is more complex than implied by the simple model Other studies that used genetic and pharmacological of “the more IFs, the better the taste learning” (Rosenblum, 2008). approaches in the CA1 region of the hippocampus showed that Nevertheless, there was increased initiation in the same samples, activation of mTORC1 facilitated initiation of protein transla- manifested as increased phosphorylation levels of ERK and S6K1 tion through phosphorylation and inhibition of eukaryotic initi- (Belelovsky et al., 2005). ation factor 4E (eIF4E)-binding proteins (4E-BP), which inhibit Therefore, we have proposed a putative mechanism, by which complex formation. Phosphorylation of eIF4E on Ser209 is ERK- increased initiation concomitant with decreased elongation in dependent and was closely linked with translation of specific the same neurons in the GC might increase expression levels of mRNA subpopulations (Panja et al., 2009). Thus, it is currently mRNAs that are poorly initiated. This was reflected, for example, accepted that ERK and mTORC1 synergistically regulate eIF4E and in the case of phosphorylation of the α subunit of eIF2 (eIF2 α), translation initiation in LTM and synaptic plasticity. It has been which, in turn, led to suppression of general translation (Hinneb- recently shown that Pin1 inhibited protein-synthesis induced by usch et al., 2000), concomitant with stimulation of translation of glutamatergic signaling, and it was suggested that eIF4E and 4E- ATF4 (Lu et al., 2004;Vattem and Wek,2004), which is required for BP1/2 mediated an increase in dendritic translation induced by late phase LTP and LTM (Bartsch et al., 1995; Chen et al., 2003). Pin 1 inhibition (Westmark et al., 2010).

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It is important to note that other mechanisms have been impli- A recent study has elegantly exploited the fact that Arc and cated in translational control of long-lasting synaptic plasticity and Homer1a show differential temporal expression patterns in acti- memory, e.g., micro-RNA regulation (miRNA), and it is highly vated neurons (Guzowski et al., 2001): it was used to mark neu- likely that they participate, at least in part, in taste learning as well. ronal ensembles in the GC and Bla that participated in processing However, it remains to be clarified whether this is indeed the case. novel taste information. Using in situ hybridization, Saddoris et al. (2009) showed that repeated exposure to a novel taste IMMEDIATE EARLY GENES AND CONVERGENCE OF CS/US (sucrose) within the time frame required for temporal differen- Immediate early genes, activated transiently and rapidly by vari- tiation of Arc/Homer1a resulted in increased IEG activity, as well ous cellular stimuli, are regulated at the transcription level. They as increased overlap of activated neuronal populations in the GC. provide a first response to these stimuli, in advance of protein In addition, they showed that odor cues associated with sucrose, synthesis. Many of the IEGs are transcription factors or other but not with water, elicited potentiation of IEG activity in the GC DNA-binding proteins (Plath et al., 2006). Expression levels of similar to that of sucrose itself, independently of Bla. Such cell IEGs have been shown to increase in neuronal populations that populations, responsive to both CS (taste) and US (odor), are held subserve stimulus encoding in response to various kinds of behav- to be critical for further plasticity. iors (Campeau et al., 1991; Guzowski et al., 2005; Mattson et al., Another study employed compartmental analysis of temporal 2008; Koya et al., 2009). Several such IEGs have been implicated in gene transcription fluorescence in situ hybridization (catFISH) for taste memory, including cFOS, Activity-regulated cytoskeleton- Arc, relying on complete translocation of Arc from the nucleus to associated protein (Arc/Arg3.1), Homer, and BDNF (Saddoris the cytoplasm over 30 min. This study, which applied Arc catFISH et al., 2009; Doron and Rosenblum, 2010), and have been shown following a sucrose-conditioned odor preference test involving to be elevated following other forms of learning as well. The afore- nine odor-taste pairings, showed, in contrast to the findings of mentioned IEGs belong to a subclass termed effector neuronal Saddoris et al. (2009), that such a flavor experience paradigm IEGs, which mediate NMDAR-regulated phenotypic changes in induced a fourfold increase in the percentage of cells activated the brain (Kaufmann and Worley, 1999). Many of these have been by both taste and odor stimulations in the Bla, but not in the IC immunohistochemically detected in dendrites (Lyford et al., 1995; (Desgranges et al., 2010). Furthermore, the authors showed that Tsui et al., 1996). in odor-conditioned rats the number of cells responsive to one stimulus was unchanged. An earlier study, which used catFISH ARC AND HOMER for Arc as well, also found that following CTA, specific Bla neu- Arc and Homer are NMDAR-dependent markers for plasticity ronal populations were responsive to both CS and US (Barot et al., (Guzowski et al., 2001). Arc has been shown to play an impor- 2008). Furthermore, this study demonstrated that when the LI- tant role in consolidation of synaptic plasticity and memories CTA paradigm was used, no coincident activation was detected. as an effector molecule downstream of many signaling pathways The identity of the cells expressing coincident activation remains (Shepherd and Bear, 2011). It mediates synaptic homeostatic scal- to be further characterized. ing of AMPA receptors, via a mechanism of interaction with the endocytosis machinery which, in turn, regulates AMPA receptor BRAIN-DERIVED NEUROTROPHIC FACTOR trafficking (Chowdhury et al., 2006; Plath et al., 2006; Shepherd Brain-derived neurotrophic factor has emerged as a potent medi- et al.,2006).Additionally,Arc affects cytoskeletal dynamics,as local ator both of synaptic plasticity on the cellular level, and of the injection of Arc antisense into the dentate gyrus 2 h following LTP interaction of an organism with its environment on the behavioral induction resulted in reversal of LTP,as well as dephosphorylation level (Moguel-Gonzalez et al., 2008). Along with its tyrosine kinase of actin depolymerization factor/cofilin, and loss of nascent fila- receptor TrkB, BDNF plays a critical role in activity-dependent mentous actin (F-actin) at synaptic sites (Messaoudi et al., 2007; plasticity processes, such as LTP,learning, and memory (Ma et al., Bramham et al., 2010). In turn, these changes are instrumental in 2011). Several studies have examined the effect of BDNF in the regulation of spine morphology by increasing spine density (Pee- CTA paradigm. As mentioned above, BDNF-induced enhance- bles et al., 2010). A recent electrophysiological study has shown ment of CTA retention (Castillo et al., 2006), and this effect that Arc synthesis was regulated by ERK–MNK signaling dur- recently has been demonstrated to be dependent on activation ing LTP consolidation in the dentate gyrus in live rats. Although of MAPK and phosphatidylinositol-3-kinase (PI-3K) in the IC mTORC1 is activated following HFS stimulation, its pharmaco- (Castillo and Escobar, 2011). Furthermore, local administration of logical inhibition revealed that it is not essential for Arc synthesis BDNF into the IC immediately after similar anisomycin adminis- and LTP (Panja et al., 2009). tration performed prior to CTA training has been shown to reverse Homer1 is a PSD scaffolding protein, involved in the regulation the anisomycin-induced CTA memory deficits almost to control of synaptic metabotropic receptor function; it has been implicated levels. Taken together, these results imply that BDNF is a protein- in structural changes occurring at synapses during long-lasting synthesis-dependent memory enhancer (Moguel-Gonzalez et al., neuronal plasticity and development (Xiao et al., 1998). Both Arc 2008). and Zif268 are required for generation of mRNA-dependent LTP. Although BDNF is an IEG, the time scale of its mRNA expres- Additionally, intrahippocampal microinfusion of BDNF resulted sion is somewhat longer than those of Arc or Homer. For instance, in selective upregulation of Arc mRNA and protein, in addition to BDNF mRNA expression in the rat IC peaked 6 h after CTA, and rapid and extensive delivery of Arc mRNA transcripts to granule began to return to base level after 8 h (Ma et al., 2011). Sur- cell dendrites (Ying et al., 2002). prisingly, this study found that BDNF levels in the Bla remained

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unchanged, but an increase was observed in the central nuclei of and retrieval are well defined in time. However, the consolidation the amygdala (CeA),peaking at 4 h. The authors showed that phos- phase is defined mainly in negative rather than positive terms; it is phorylated TrkB levels were elevated in the CeA long before the sensitive to various disruptions at different time points following CTA-induced BDNF synthesis started, indicating a rapid activity- acquisition, and the connections between the various molecu- dependent BDNF release, presumably independent of protein lar entities involved in the process of taste learning are not well synthesis. These data suggest that BDNF secretion and synthe- described. In Figure 3 we outline some of the processes known to sis may be spatially and temporally involved in CTA memory be taking place in the GC following novel taste learning. This off- formation. These authors also demonstrated that BDNF secre- line processing of information in the brain may represent a more tion and synthesis were necessary for STM and LTM, respectively, continuous rather than a phasic process. However,the mechanisms and, in addition, that BDNF injected into the CeA enhanced the and molecular/cellular participants in these processes are yet to be CTA memory. Furthermore, in another study it was shown that identified (Figure 3). It is clear that in order to better understand a human naturally occurring polymorphic variant of BDNF in the consolidation or off-line processes, it is necessary to enhance knock-in mice (Val66Met) caused impairments in CTA extinc- the measurements of the biochemical factors that are correlated tion, but not in its acquisition or retention, whereas in humans, with and necessary for taste learning, and to improve their reso- homozygosity to this variant is associated with altered hippocam- lution to a few cubic micrometers or to cellular/subcellular levels. pal volume, hippocampal-dependent memory impairment, and The tools for this kind of in vivo single-cell analysis have been susceptibility to neuropsychiatric disorders. On the cellular level, dramatically improved recently, and will be used to obtain better this polymorphism was associated with alterations in intracellu- descriptions of the molecular and cellular mechanisms underlying lar trafficking and activity-dependent secretion of Wt BDNF in learning and memorizing processes. Moreover, we and others will neurosecretory cells and cortical neurons (Yu et al., 2009). aim to identify the specific circuit or neuronal ensemble involved in creation and maintenance of any given memory and its value. FUTURE DIRECTIONS Other aims, more specific to the taste system, will be to under- In all, a more thorough understanding of the molecular mech- stand the neuronal mechanisms underlying the taste–memory anisms underlying taste memory and of the functioning of the condition of waiting “on hold” for many hours, with its physi- corresponding regulatory processes in relevant neurons that sub- cal and chemical information as a conditioned stimulus, pending serve taste-learning processing circuits should help to elucidate arrival of the unconditioned stimulus or the digestive information many important basic aspects of neuronal function. The main that will enable the taste to be tagged as safe or dangerous. This spe- future questions and the directions of future research might be cific and unique ability of taste-learning beautifully represents the more general in their nature, reflecting the potential development flexibility of the neuronal system underlying learning and memory of knowledge and understanding in the field of biological mech- processes, and can also teach us about the limits of the neuronal anisms of learning and memory, or they might address questions systems abilities to create simple and associative memories. specific to the taste systems in the mammalian/. For example, dissection of the temporal dynamics of any mem- ACKNOWLEDGMENTS ory – acquisition/consolidation and the establishment of remote This work was supported by DIP (RO 3971/1-1), ISF (1305/08), memory retrieval, relearning, and reconsolidation – which was and European Union Seventh Framework Program EUROSPIN outlined in Figure 2 can be misleading. It is clear that acquisition (Contract HEALTH-F2-2009-241498)grants for Kobi Rosenblum.

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