Young Dr. The mechanism of memory remains one of the great unsolved problems of biology. Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today. The discovery of activity-induced long-term potentiation LTP and long-term depression LTD of central synapses in the s and 80s further sparked the interest of a whole generation of neurobiologists in studying synaptic plasticity and its relationship to memory. There is now general consensus that persistent modification of the synaptic strength via LTP and LTD of pre-existing connections represents a primary mechanism for the formation of memory engrams.

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Young Dr. The mechanism of memory remains one of the great unsolved problems of biology. Neuroscientists now have the knowledge and tools to tackle this question, however, and this Forum brings together leading contemporary views on the mechanisms of memory and what the engram means today.

The discovery of activity-induced long-term potentiation LTP and long-term depression LTD of central synapses in the s and 80s further sparked the interest of a whole generation of neurobiologists in studying synaptic plasticity and its relationship to memory. There is now general consensus that persistent modification of the synaptic strength via LTP and LTD of pre-existing connections represents a primary mechanism for the formation of memory engrams.

In addition, LTP and LTD could also lead to the formation of new and elimination of old synapses and thus changes in structural connectivity in the brain.

Indeed, early development of neural circuits, whereby neural activity sculpts synaptic connectivity [ 2 ], depends on processes similar to that associated with LTP and LTD in the adult brain and could be considered as the imprinting of memory engrams generated by early experience.

Andrii Rudenko and Li-Huei Tsai redirect attention to the nuclei of engram cells, discussing the evidence that epigenetic alterations of the neurons activated during memory acquisition may be involved in the long-term retention of memory. They propose that such epigenetic modification represents a priming event during the initial phase of memory formation; memory retrieval would then trigger the expression of the primed genes, leading to protein synthesis and synaptic modification at individual synaptic units.

Depending on the availability of cellular resources, immediate modifications LTP and LTD and long-term turnover formation and elimination of individual synaptic units are bound to influence other units on the same postsynaptic cell. Richard Tsien, Gord Fishell, and Caitlin Mullins focus on the important issue of lateral synaptic interaction and redistribution of synaptic strength associated with LTP and LTD, from the point of view of cellular homeostasis as well as the normalization and signal-to-noise ratio of neuronal activities, and propose a conceptual scheme to address the underlying mechanisms.

The hippocampus is unique in being a key brain region for memory formation and a region in which adult neurogenesis occurs. As proposed by David Marr in his model of hippocampus-dependent memory [ 3 ] and supported by many experimental and clinical studies, episodic memories are transferred after acquisition from the hippocampus to the neocortex for long-term storage. These activity patterns occur during sleep or non-attentive brain states and are replays of neuronal firing sequences triggered by recent experience, for example they can be temporally compressed replayed versions of the sequential neuronal firing seen as the animal traverses through a particular environment.

As discussed by myself and Yang Dan, although spike timing-dependent plasticity could offer a synaptic mechanism for storing sequence information with intervals up to a few hundreds of milliseconds, it remains largely unknown how neural circuits store and recall the temporal sequence of information up to seconds and longer, periods often associated with episodic memory. A compression of the temporal sequence of events such as occurs during sharp wave-ripples in the hippocampus and neocortex offers a potential solution.

The contributing articles of this Forum reflect the tremendous progress made in our understanding of the cellular building blocks of memory. There is a clear consensus on where the memory engram is stored—specific assemblies of synapses activated or formed during memory acquisition—and a substantial body of knowledge on how the engram is generated and maintained in the brain.

As Charles Stevens indicates in his epilogue, and the readers will soon discover, many new territories are now open for exploration. The storage of information refers to the systematic process of collecting and cataloging data so that they can be retrieved on request. One of the most enlightening conceptualizations of the neural representation of stored memory information was developed by Richard Semon, who conceived the Engram Theory, a theory of memory traces [ 4 ].

In addition, reactivation of these cells by relevant recall cues results in retrieval of the specific memory. The theory poses an important question: what is the nature of the persistent changes? In his seminal book published in , Donald Hebb proposed a mechanism based on synaptic plasticity as a substrate of memory [ 1 ]. With an example of two cells connected by an excitatory synapse, if the activation of one cell leads to the activation of the second one, the connection between the two cells is reinforced, a postulate that has been confirmed experimentally [ 5 — 8 ].

The increase in connectivity strength within a diffuse group of cells in a more complex feedforward circuit results in the emergence of an engram cell ensemble. The systematic dissection of the molecular mechanisms involved in synaptic plasticity has revealed that the cascade of events underlying the plastic changes requires two distinct phases [ 9 , 10 ]. The dendritic spines that support the post-synaptic machinery rapidly increase in number [ 12 ].

In a second phase lasting a few hours after the initial encoding period, the increased synaptic weight is maintained by a protein synthesis-dependent process known as cellular consolidation, during which the steady state synthesis of AMPA receptors is shifted to a higher level.

To date, memory storage has mainly been investigated by pharmacological or molecular manipulation and by correlating synaptic changes with the strength of memory recall.

Only recently has it become possible to specifically tag cells activated by learning. The opsin allowed for the artificial light-induced reactivation of the cellular population labeled during learning and resulted in memory retrieval. The same tagging strategy also verified the reactivation of tagged cells upon presentation of retrieval cues. Engram cells displayed changes in synaptic weight typical of LTP such as high current amplitude, insertion of AMPA receptors, high spontaneous excitatory post-synaptic current frequency and amplitude, and increased dendritic spine density.

These changes were blocked by the systemic injection of PSI specifically within the consolidation window. Therefore, it is now clear that cells recruited by learning display synaptic changes typical of LTP and are reactivated by retrieval cues, and their reactivation can elicit memory recall. Remarkably, however, protein synthesis-dependent L-LTP seems to be dispensable for memory storage because direct optogenetic activation of the engram cells in PSI-injected mice elicited full memory recall under a variety of conditions.

An integral memory engram may consist of preferential connectivity between engram cell ensembles distributed across multiple brain regions. In the same report [ 16 ] it was shown ex vivo that engram cells from the dentate gyrus established preferential connections with engram cells in the downstream hippocampal CA3 region in a feedforward excitatory engram cell circuit.

Remarkably, this preferential connectivity was maintained in mice rendered amnesic by treatment with PSI within the consolidation window, suggesting that memory storage may survive retrograde amnesia in the form of a neural connectivity pattern. Indeed, optogenetic stimulation of DG engram cells in vivo elicited similar cellular reactivation patterns not only in the CA3 region but also in the amygdala for both control and amnesic groups, thus confirming the persistence of engram cell connectivity.

These observations support the concept of preferential connectivity of engram cell ensembles distributed across multiple brain regions, which is established during learning and persists despite disruption of consolidation and thereby provides a lasting substrate for memory storage. These data also suggest that the synaptic potentiation observed in consolidated engram cells is necessary for memory retrievability and not for storage [ 17 ].

While regulation of synaptic weight provides a scalar quantity to control information retrieval, synaptic connectivity holds the information specificity. This is because synapses that are activated during the encoding stage will dictate the eventual pattern of cellular connectivity of the upstream and downstream engram cell ensembles.

This notion is compatible with the broad view that synapses are the basic units of information storage see Bonhoeffer, this Forum. Neural connections are formed during development and certain circuits hold the innate capability to elicit complex behavioral reactions in response to specific perceptual cues [ 18 ]. However, this does not seem to be the case in the hippocampal formation because inactivation of the downstream CA1 region before CFC results in anterograde amnesia which cannot be bypassed by direct optogenetic stimulation of DG engram cells [ 16 ].

Thus, the memory circuit is not configured under anterograde amnesic conditions and is not, therefore, genetically determined but requires hippocampal activity during memory encoding.

As reported by Ryan et al. So is E-LTP [ 9 , 10 ] and this early phase of plasticity may provide a framework to investigate the formation of new connections. For instance, blocking NMDA receptor function should impair the emergence of learning-induced connectivity patterns.

During the induction of LTP, existing connections can be potentiated [ 19 ] but new connections can also emerge [ 20 ]. A hypothetical way this might happen is through the activation of silent synaptic connections [ 21 ]. These synapses expressing only NMDA receptors and not AMPA receptors can become unsilenced through AMPA receptor insertion, a mechanism that could, in principle, support the formation of learning-induced changes in engram cell connectivity.

Another possibility is that local dendritic protein synthesis contributes to the rapid synapse formation on engram cells, independently of its role in synaptic potentiation see Martin, this Forum. Although learning-induced synaptic potentiation would be suppressed by PSI, the new connectivity pattern could persist through unsilenced synaptic connections of basal unpotentiated strength Fig.

Consistent with this perspective, it has been recently shown that optogenetically induced long-term depression LTD of amygdala cells impaired existing conditioned fear responses but subsequent optogenetically induced LTP of the same cells could restore optogenetic cue-evoked recall of the fear memory [ 22 ].

Synaptic connectivity between engram cells as a mechanism for memory storage. Engram circuit, cells, and synapses are displayed in green , non-engram in gray. During encoding, a network of engram cells is recruited. The preferential connection between engram cells occurs either by potentiation of existing connections blue dotted circles or by unsilencing synapses red dotted circles. A spine density increase supports the synaptic changes.

During consolidation, the steady state synthesis of AMPA receptors is shifted to a higher level and the disruption of consolidation with protein synthesis inhibitors PSI results in retrograde amnesia. However, during PSI-induced amnesia, memory storage persists within an engram-specific set of weak synaptic connections. The ability to tag cells activated by learning has opened up new horizons in the investigation of memory by revealing the role of the engram-specific connectivity in the storage of information.

In his seminal work, Donald Hebb [ 1 ] proposed that the basic mechanism by which memories are stored in the brain is the enhancement of synaptic strength and, in connection with that, morphological changes of the respective synaptic contacts. In other words he proposed that synapses and not cells are the basic building blocks of memory, from a theoretical perspective a reasonable suggestion as there are approximately 10,—, times more synapses in the brain than neurons.

By now it is well established that morphological changes at the synaptic level occur in conjunction with stimuli that are thought to mimic learning events. In vitro experiments [ 12 , 23 ] have shown that long-term potentiation results in the addition of dendritic spines, tiny protrusions which harbor synaptic contacts. Tens of thousands of these spines decorate the dendrites of most excitatory cells in the hippocampus and the neocortex.

And indeed, further studies showed that spines not only come and go but also change their shape during putative learning events [ 19 ], a suggestion that had been put forward in a purely theoretical paper by Francis Crick [ 24 ].

So, it is well established that spines emerge, disappear, and change with cellular events thought to underlie learning processes. But is this merely a correlation or are there ways towards showing that these events really lie at the basis of learning and memory storage in the brain?

Recent experiments have made substantial progress in this respect. The first study that made a clear case that spines are important for the long-term storage of information was done in the visual cortex of mice [ 25 ]. In the visual cortex it is well known that synaptic connections are established or modified with changes in visual experience, like the temporary closure of one eye.

It has been shown that the same effect occurs in the visual system [ 27 ]. Mice were monocularly deprived for a couple of days early in life so that the visual system adapted to this change of the visual environment. Subsequently, animals were subjected to normal vision again so that their visual cortex reverted to normal function.

If monocular deprivation was then performed a second time, much later in life, when normally this procedure has only a very limited effect if any , substantial adaptation still takes place because of the early experience that the animal has had. Importantly, this savings effect could be related to new spines that emerged during the first plasticity episode and persisted [ 25 ].

The fact that there was no growth of additional spines during the second plasticity period, while the functional adaptation occurred much faster and more reliably, suggests that the persistent spines facilitate the second adaptation [ 25 ].

Two subsequent studies [ 28 , 29 ] further bolstered the case by showing that also in the motor cortex the generation of new spines forms the basis of learning motor tasks of different sorts.

Furthermore, this study demonstrated that learning different tasks involves different sets of spines, providing a strong argument for spines and not cells being the relevant entity for information storage in the brain.

These three papers were among the first to make a strong case for a causal relationship between new or changing spines and learning or information storage in the brain. Subsequently, a number of studies further strengthened this hypothesis.

Some of them used fear conditioning to show that also in this paradigm learning is paralleled by structural changes: fear extinction and fear conditioning are marked by the generation or removal of spines in the frontal association cortex [ 30 ] and the auditory cortex [ 31 ].

One particularly interesting finding in this context is that extinction induces appearance of spines that were eliminated upon the original fear conditioning to the same stimulus but not to a distinct conditioned stimulus, suggesting that the spines are again specifically associated with extinction of one specific association [ 30 ]. Interestingly, also in a completely different animal model—song learning in zebra finches—it was shown that new spines are generated in the forebrain nucleus HVC when an animal learns a new song from a tutor [ 32 ].

Finally, what about the experiment that has long been on the agenda [ 33 ], namely to specifically ablate spines that have been generated during learning? If the above interpretations are true, spine ablation should lead to forgetting of the information that was learned when the new spines were generated.

First important strides in that direction have been made in a recent experiment by the group of Haruo Kasai [ 34 ], who specifically labeled spines that were generated at a particular time window immediately after learning.

When these spines were later ablated or at least reduced in size, the animal indeed forgot the previously learned information. The learning paradigm is so far relatively simple rotarod learning but it provides a very nice indication that the generation of new spines or their enlargement is truly causal at least in some forms of learning.

Taken together, there is now considerable evidence from different species as well as from different learning paradigms that spines, and thus synapses, change when an animal learns. Furthermore, there are convincing indications that the maintenance of previously established structural connections on the level of dendritic spines explains the memory phenomenon of savings.

Finally, if spines are ablated, an animal forgets what it has learned through the addition of new or stronger spine synapses.

This is of course not to say that engrams are not visible on the level of single cells see preceding contribution to this Forum by Pignatelli, Ryan, and Tonegawa ; after all, the activity of cells is determined by the complement of their synapses.

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What is memory? The present state of the engram

Una vez desarrollado cada vez que se le quiere realizar nuevamente, recorre el patrn motor memorizado y es repetido en forma automtica, el mismo patrn. Para Guyton representa una zona donde una persona experimenta los efectos de movimiento motores y registra los recuerdos de los diferentes tipos de movimientos. Estos tipos de movimientos son realmente los patrones o modelos de movimientos. Cuando se quiere realizar un acto determinado, se recurre a estos engramas, despus se pone en marcha el sistema motor del cerebelo para reproducir aquella sensacin que ha quedado grabado en el engrama. Esta web usa cookies para mejorar tu experiencia. Out of these cookies, the cookies that are categorized as necessary are stored on your browser as they are essential for the working of basic functionalities of the website. We also use third-party cookies that help us analyze and understand how you use this website.




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