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    Engram Neurons: A New Take on Memory Consolidation

    As far back as Plato and Aristotle, people believed that our memories had to be physical somethings that were stored somewhere in the brain. But only in modern times have we learned much about what this something is. First, the something was given a name: memory engram. Then, as knowledge accumulated about what happens in neurons and their synapses as they become active in learning and remembering, it became clear that learning events that could be remembered were causing chemical and physical changes in the junctions (synapses) between neurons that participate in the learning experience. Participating neurons grow new dendritic branches (called spines) and the synapses on those spines enlarge and their neurotransmitter systems become enhanced. These changes constitute the engram. Post-learning reactivation of the synapses holding such an engram can produce recall of the original learning that created the engram.

    In the early days of neuroscience, scientists believed that learning experiences assigned or recruited certain parts of the brain to hold the memory. An experimenter, Karl Lashley, taught certain tasks to lab animals, and then under anesthesia, destroyed different parts of the neocortex in the hopes of finding where the memory was stored. He couldn’t find any particular storage location. What he did find was that the more extensive he made the cortical lesions, the more likely he could erase the memory. In other words, memory of a given experience seemed to be deconstructed and parceled out into different regions.

    Then came quantitative EEG studies by E. Roy John, in which he tracked the location of brain electrical evoked responses in different parts of the cortex during learning experiences. He saw that a given learning experience would produce electrical responses in several parts of the cortex, again suggesting a deconstruction and distribution of memory engrams. This led him to famously proclaim, “Memory is not a thing in a place, but a process in a population.”  Well, we know that this is a bit of over-statement. There is such a thing as a memory engram that is stored in specific places. Nonetheless, there is a distribution process for creating the engram in multiple locations and for orchestrating them into simultaneous and coordinated activity during recall of the memory.

    Modern genetic engineering and neuron staining technology provide powerful new tools to examine neurons that participate in joining the neural circuits involved engrams. There are now ways to image and manipulate engrams at the level of neuronal ensembles.  Several lines of evidence show that engram neurons can be seen histologically and evaluated under various experimental approaches. For example, histological stains revealing neurons that are activated by a learning experience show that they are also active during memory retrieval of that experience. Second, loss-of-function studies show that impairing engram neuron function after an experience impairs subsequent memory retrieval. Third, studies show that memory retrieval can be triggered by optogenic stimulation of engram neurons in the absence of any natural sensory retrieval cues.

    The basic approach used by investigators in the lab of Susumu Tonegawa was to teach mice to avoid walking into a chamber in which they would receive a mild electric shock. Neurons that are activated by this fear conditioning fluoresce in immunohistological stains of brain slices in mice that are sacrificed at various times after learning reveal a memory engram that resides in selected neurons in the amgydala (which processes fear information), in the hippocampus (which converts short-term memory to longer-term memory), and in multiple regions of neocortex (which holds long-term memory in the form of enhanced synaptic capability). Some of these cells still fluoresce when examined many days later, indicating that they have become part of an ensemble of engram neurons that hold a relatively lasting representation of the original learned experience.

    Other mice were genetically engineered so that engram cells would fluoresce and be activated when exposed to light delivered via micro-fiber optic cables surgically implanted in various regions of neocortex. Such light stimulation of engram cells confirmed their engram status, because light stimulation alone triggered the previously learned behavior (freezing in place, rather than entering the shock chamber). A key finding was that engram neurons in the prefrontal cortex were “silent” soon after learning — they could initiate freezing behavior when artificially activated by light delivered via surgically implanted fiber optic filaments, but they did not fire during natural memory recall. In other words, the memory engram was formed right away in all three places (amygdala, hippocampus, and neocortex), but the engram cells in the neocortex had to mature over time to become fully functional.

    Over the next two weeks, the engram neurons in the neocortex gradually matured, as reflected by changes in their anatomy and physiological activity. By the end of that same period, the hippocampal engram cells became silent and were no longer used for natural recall. At this point, the mice could recall the event naturally, without activation of neocortical cells by fiber-optic light. However, traces of the memory remained in the hippocampus, because reactivating those hippocampal neurons with light prompted the animals to freeze.

    The past prevailing view was that learning experiences are temporarily held in circuits in the hippocampus and then later exported out to other parts of brain for final storage. Both in the past and now, all the evidence indicates that the hippocampus is crucial for forming lasting memories of experiences that do not involve motor learning, but the mechanisms had been uncertain. 
    Neuroscientists did know that long-term memories were stored outside of the hippocampus, because people with hippocampal damage can lose the ability to form new long-term memories, but they are still able to recall old memories.

    Now, the new research suggests that memory engrams are not transported from hippocampus to neocortex but are present in both places at the outset of learning. The memory engram in the neocortex just requires maturation for the memory to become more permanent. Moreover, the hippocampus cannot, and need not, hold long-lasting engrams.

    Though this is a new way to think about the mechanisms of how temporary memories consolidate into longer-lasting ones, the conventional idea of consolidation remains confirmed. That is, the memory engram must mature over time in the form of biochemical and anatomical changes in the engram cells. Obviously, such maturation process would be disrupted if those same engram cells are recruited to serve other learning purposes before they have finished their maturation as a specific memory engram. This also helps to explain why subsequent rehearsals help make memories last longer, because each rehearsal re-engages engram neurons into the same kind of activity they performed during learning, thus strengthening the relevant synapses.

    Once memories were formed in the fear-conditioned mice, the engram cells in the amygdala remained unchanged throughout the course of the experiment. Those cells, which are necessary to evoke the emotions linked with specific memories, like fear of entering the shock chamber in this case, communicate with engram cells in both the hippocampus and the prefrontal cortex.

    We don’t know what happens to memory-specific engram cells in the hippocampus. Maybe as they gradually lose their engram status, they become available for processing new kinds of learning experience. Perhaps some traces of engram remain in hippocampus and are accessible for reactivation if highly relevant inputs are received, as could be the case with strong memory cues. Perhaps the important point is that these new techniques for labeling engram cells open the door for new ways to study of memory retrieval, the long-neglected aspect of memory mechanisms.

    Another potentially relevant finding of this kind of research is that memory engrams may become damaged but may still exist in a form that cannot be retrieved by natural means. The fact that such “silent” engrams can be retrieved with direct optogenetic stimulation indicates that failures to recall do not necessarily indicate that the memory is lost. The problem may lie in an inadequacy of the natural memory cues used to triggger memory retrieval.

    The door is also now open for experiments that might advance our understanding of the maturation of engram neurons in the neocortex. What is known so far is that maturation requires initial communication with engram cells in the hippocampus. Disrupting hippocampal connections between hippocampus and frontal cortex prevents the maturation of neocortical engram cells.

    Sources

    Takashi Kitamura, Takashi, et al., (2017). Engrams and circuits crucial for systems consolidation of a memory,” Science, 356(6333), 73-78; DOI: 10.1126/science.aam6808

    Josselyn, Sheena A., and Tonegawa, Susumu (2020). Memory engrams: Recalling the past and imagining the future. Science. 367 (6473), eaaw4325. Doi: 10.1126science.aaw4325. https://science.sciencemag.org/content/367/6473/eaaw4325

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