In daily life, memories are intertwined events. Little is known about the mechanisms involved in their interactions. Using two hippocampus-dependent (spatial object recognition and contextual fear conditioning) and one hippocampus-independent (conditioned taste aversion) learning tasks, we show that in rats subjected to weak training protocols that induce solely short term memory (STM), long term memory (LTM) is promoted and formed only if training sessions took place in contingence with a novel, but not familiar, experience occurring during a critical time window around training. This process requires newly synthesized proteins induced by novelty and reveals a general mechanism of LTM formation that begins with the setting of a ''learning tag'' established by a weak training. These findings represent the first comprehensive set of evidences indicating the existence of a behavioral tagging process that in analogy to the synaptic tagging and capture process, need the creation of a transient, protein synthesis-independent, and input specific tag.hippocampus ͉ insular cortex ͉ memory consolidation ͉ protein synthesis ͉ novelty A cquisition of new information can be stored into at least two temporally and mechanistically different memory types: a short-term (STM) and a long-term memory (LTM). It is well known that in order for LTM to be established, synaptic changes must be stabilized by the action of newly synthesized proteins (1). This process of memory trace consolidation takes place in the brain areas where such forms of learning and memory are likely to reside. Surprisingly, recent evidence demonstrated that the supply of newly synthesized proteins may also derived from another behavioral event occurring in a relatively long-lasting associative time window, helping to promote LTM for a weak learning task that otherwise would only induce STM (2).Current models, based on seminal ideas, propose that memories are stored by stable changes in synaptic weight modifying the activity of specific neuronal circuits (3-5). Therefore, those specific synapses activated by a given learning will require the supply of new plasticity-related proteins (PRPs) for LTM to be formed. As a consequence, there should be a mechanism that restricts the action of PRPs to recently activated synapses but not to others. To address this biological problem, it was suggested that a transient local synaptic tag is established at those recently activated synapses where PRPs are specifically captured. This idea was originally postulated by Frey and Morris (6) and it is now known as the synaptic tagging and capture (STC) hypothesis (7-9). In their seminal work they showed that early-LTP, a transient form of LTP that is induced by a weak stimulus, could be extended to late-LTP, a more persistent form of LTP, if the weak and the strong stimuli were applied in a relatively long-lasting associative time window on different synapses of the same neuron. Frey and colleagues also found that an hippocampal LTP can be reinforced by exposing rats to a novelty ...

Long-term memory (LTM) consolidation requires the synthesis of plasticity-related proteins (PRPs). In addition, we have shown recently that LTM formation also requires the setting of a "learning tag" able to capture those PRPs. Weak training, which results only in short-term memory, can set a tag to use PRPs derived from a temporal-spatial closely related event to promote LTM formation. Here, we studied the involvement of glutamatergic, dopaminergic, and noradrenergic inputs on the setting of an inhibitory avoidance (IA) learning tag and the synthesis of PRPs. Rats explored an open field (PRP donor) followed by weak (tag inducer) or strong (tag inducer plus PRP donor) IA training. Throughout pharmacological interventions around open-field and/or IA sessions, we found that hippocampal dopamine D1/D5-and β-adrenergic receptors are specifically required to induce PRP synthesis. Moreover, activation of the glutamatergic NMDA receptors is required for setting the learning tags, and this machinery further required α-Ca 2+ /calmodulin-dependent protein kinase II and PKA but not ERK1/2 activity. Together, the present findings emphasize an essential role of the induction of PRPs and learning tags for LTM formation. The existence of only the PRP or the tag was insufficient for stabilization of the mnemonic trace.synaptic tagging | CA1 | dentate gyrus I t is widely accepted that certain forms of long-term memory (LTM) require the synthesis of plasticity-related proteins (PRPs). These proteins generally are synthesized by a proper salient experience that will be finally remembered. However, a transient event, which normally produces only short-term memory (STM), also can use PRPs provided by another associated event to stabilize its mnemonic trace into LTM (1). This process has been named "behavioral tagging" and depends on the setting of a learning tag by the transient event and also on PRPs, synthesized by associated strong events, which will be captured later by tags resulting in LTM (2).We use a protocol of two consecutive behavioral tasks, where the event that provides PRPs (exploration of a novel open field, OF) is independent from the event that establishes a learning tag [a weak training in an inhibitory avoidance (wIA) that normally results in IA-STM)]. Using this protocol, we recently demonstrated that IA-LTM can be promoted by OF exploration throughout a mechanism that requires newly synthesized proteins and depends on the activation of dopamine D1/D5 receptors in the dorsal hippocampus (dHP) (1). This finding is in accordance with results showing that the ventral tegmental area releases dopamine in the hippocampus to process the novelty signal (3). Here, we studied whether the activation of D1/D5 receptors is required for PRP synthesis induced by novelty. Because novelty detection also is accompanied by increased hippocampal noradrenergic activity driven by enhanced firing of the locus coeruleus (4-6), we also studied the possible role of this neurotransmitter system in PRP synthesis involved in IA-LTM.Based on ...

Similar molecular machinery is activated in neurons following an electrical stimulus that induces synaptic changes and after learning sessions that trigger memory formation. Then, to achieve perdurability of these processes protein synthesis is required for the reinforcement of the changes induced in the network. The synaptic tagging and capture theory provided a strong framework to explain synaptic specificity and persistence of electrophysiological induced plastic changes. Ten years later, the behavioral tagging hypothesis (BT) made use of the same argument, applying it to learning and memory models. The hypothesis postulates that the formation of lasting memories relies on at least two processes: the setting of a learning tag and the synthesis of plasticity related proteins, which once captured at tagged sites allow memory consolidation. BT explains how weak events, only capable of inducing transient forms of memories, can result in lasting memories when occurring close in time with other behaviorally relevant experiences that provide proteins. In this review, we detail the findings supporting the existence of BT process in rodents, leading to the consolidation, persistence, and interference of a memory. We focus on the molecular machinery taking place in these processes and describe the experimental data supporting the BT in humans.