The Behavioral Tagging Hypothesis and Its Implications for Long-Term Memory Formation

MONCADA, DIEGO; BALLARINI, FABRICIO; MARTÍNEZ, MARÍA C.; VIOLA, HAYDÉE

Synaptic Tagging and Capture: From Synapses to Behaviour

Springer

Año: 2014; p. 231 - 259

Abstract Memories are experience-dependent internal representations of the world that can last from short periods of time to a whole life. The formation of longterm memories relies on several biochemical changes, which inducing modifications in the synaptic effi ciency change the way the neurons communicate each other. Interestingly, the formation of a lasting memory does not entirely depend on learning itself; different events occurring before or after a particular experience can affect its processing, impairing, improving, or even inducing lasting memories. The overlapping of neuronal networks involved in the processing of different types oflearning might explain why different experiences interact at neuronal level. However, how and where this does really happen is an issue of study. In 1997, the Synaptic Tagging and Capture (STC) hypothesis provided a strong framework to explain how synaptic specifi city can be achieved when inducing long-lasting changes in electrophysiological models of functional plasticity. Ten years later, an analogous argument was used in learning and memory models to postulate the Behavioral Tagging hypothesis. This framework provided solid explanation of how weak events, only capable of inducing transient forms of memories, can result in lasting memories when occurring in the context of other behaviorally relevant experiences. The hypothesis postulates that the formation of lasting memories rely on at least two parallel processes: the setting of a learning tag that determines whichmemory could be stored and were; and the synthesis of plasticity-related proteins, which once captured at tagged sites will allow the consolidation of a memory for long periods of time. Therefore a weak learning, only able to induce transient forms of memories but also capable of setting a learning tag, could be benefi ted from the proteins synthesized by a different strong event, processed in the same areas, by using them to consolidate its own lasting memory. In this chapter we will detail the postulates and predictions of the Behavioral Tagging hypothesis, deepen the mechanisms involved in the setting of the tag and the synthesis of proteins, and revise the universe of experiments performed from rodents to humans in order to discuss its implications on learning and memory processing. 1- Introduction: Memory formation is the process that enables the retention of information about the world, acquired during learning. This cognitive function is responsible for remembering events, facts, situations, places, objects and motor skills2. All this information constitutes the acquis of learning and memories of an individual, defining who he/she/it is and also offering a plethora of behaviors according to the circumstances that had been learned in past experiences. However, not all the information that we acquire is stored for long-term periods. The notion that multiple forms of memory exist, was expressed by3 and others, who distinguished between primary and secondary memory, currently call short- (STM) and long-term memory (LTM)4. A typical feature of memory is that learning does not instantaneously induce a LTM trace; instead it takes time to be fixed. This centennial observation was reported by Müller and Pilzecker through the proposal of the perseveration-consolidation hypothesis of memory5,6. They performed list-learning experiments in humans founding that memory of newly learned information was disrupted by the learning of other information shortly after the original one. These results suggested that processes underlying new memories initially persist in a fragile state and consolidate over time7,8. Consequently, memory is vulnerable for a certain period of time after learning, enabling endogenous processes activated by an experience, or even by another one, to modulate its strength7. In this regard, behavioral, hormonal and neural influences acting during this fragile period can regulate memory consolidation, improving or impairing it. Thus, stress, arousal, motivation and reward can profoundly affect memory formation9-13. This chapter will describe in detail the action of a novel experience over the formation of an independent LTM, making emphasis in the mechanism involved in this process. Over the past decades, many molecular and cellular mechanisms underlying the formation and stabilization of LTM were well characterized7,14,15. We now understand in considerable detail the molecular machinery involved in the process of ?cellular or synaptic consolidation? occurring within the first hours after the encoding of information8. One surprising finding is the remarkable degree of conservation of memory mechanisms in different brain regions within a species and across species widely separated by evolution16. Among the components of this molecular machinery it was found necessary the activation of synaptic neurotransmitter receptors, protein kinases, transcription factors and gene transcription17-21. In particular, the finding that protein synthesis inhibitors did not prevent the learning and the expression of STM supports the view that protein synthesis is required only for consolidation of LTM22-26. This introduction led us to conceptualize that memories are experience-dependent internal representations of the world27, build by biochemical changes taking place over an extended period of time after learning. However, how these representations are codified, where they take place in our brain and if the biochemical changes associated with LTM formation have selective functions, it will be discussed bellow. It is expected of memories to be encoded in spatiotemporal states of neuronal circuits. It is widely accepted that neural activity induced by learning triggers changes in the strength of synaptic  connections within the brain. Synaptic Plasticity and Memory (SPM) hypothesis, states that an activity-dependent plastic change is induced at the appropriate synapses during memory formation. The plastic changes must occur in those brain areas were memory is being processed and are both necessary and sufficient for the storage of the information28. The most relevant aspect of a memory trace is that those changes in behavior, occurring as a consequence of a learning experience, persist in time. In this way, a model of synaptic plasticity where brief stimulations of a neural pathway induce long-lasting changes in the synapses was postulated as one plausible clue of the mechanisms underlying the formation of lasting memories. These changes in the synapses? efficacy involve either up- or down-regulation of synaptic strength and, in the case of persisting for more than one hour, they are referred as long-term potentiation (LTP) or depression (LTD) respectively. Then, where does the synaptic plasticity related to LTM formation occur? Different kind of learning are processed by different brain areas29, resulting the substrate of the memories distributed along different and/or overlapped regions of the brain depending on their nature (Procedural, Emotional, Spatial, Declarative, etc.). Therefore rather than being processed and stored at single neuron levels, particular memories may be thought to be distributed across multiple neurons and synapses in networks that could involve more than one particular brain area. Then, how can be achieved the synaptic specificity related to a particular memory? How can the neuronal machinery assures the delivery of proteins to those sites were plasticity should be held? Using models of synaptic plasticity, Frey and Morris30 postulated the hypothesis of ?Synaptic tagging and capture? (STC) able to explain how the system could obtain the input specificity in functional plasticity processes. The STC hypothesis declares that LTP involves the local tagging of synapses at the moment of induction. Then, those tags can capture plasticity-related proteins (PRPs) synthesized in the soma or local dendritic domains, allowing the stabilization of the potentiation for long periods of time. The STC hypothesis opened a new approach to think the process of LTM formation, letting us to propose that learning could signal the sites related to memory plasticity, where PRPs will be capture in order to allow its consolidation. In this context, signaling what information to store and where to do it seems as important as the synthesis of PRPs, to allow the formation of a lasting memory. In this frame, we display a remaining question: could these processes be dissected? Are PRPs always synthesized as a consequence of learning? Do different biochemical changes induced by learning have different function? Are some of them specifically related to establish a mark and others to trigger the synthesis of PRPs? These topics will be developed along this chapter.