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Review
. 2019 Oct;22(10):1576-1585.
doi: 10.1038/s41593-019-0493-1. Epub 2019 Sep 24.

The Neurobiological Foundation of Memory Retrieval

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Free PMC article
Review

The Neurobiological Foundation of Memory Retrieval

Paul W Frankland et al. Nat Neurosci. .
Free PMC article

Abstract

Memory retrieval involves the interaction between external sensory or internally generated cues and stored memory traces (or engrams) in a process termed 'ecphory'. While ecphory has been examined in human cognitive neuroscience research, its neurobiological foundation is less understood. To the extent that ecphory involves 'reawakening' of engrams, leveraging recently developed technologies that can identify and manipulate engrams in rodents provides a fertile avenue for examining retrieval at the level of neuronal ensembles. Here we evaluate emerging neuroscientific research of this type, using cognitive theory as a guiding principle to organize and interpret initial findings. Our Review highlights the critical interaction between engrams and retrieval cues (environmental or artificial) for memory accessibility and retrieval success. These findings also highlight the intimate relationship between the mechanisms important in forming engrams and those important in their recovery, as captured in the cognitive notion of 'encoding specificity'. Finally, we identify several questions that currently remain unanswered.

Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Fig. 1 |
Fig. 1 |. Tulving and Pearlstone’s experiment on retrieval failure.
Subjects were presented with a series of words. These words were drawn from multiple categories (for example, types of birds, flowers, etc.). In the test phase, subjects were asked to recall as many words as they could from the list (free recall) or from the specific categories (cued recall). The cued recall group performed considerably better than the free recall group across categories, indicating that retrieval cues present at the time of recall determine engram accessibility and subsequent success at remembering.
Fig. 2 |
Fig. 2 |. Preventing and inducing ecphory by direct manipulation of fear memory engrams.
a, In this experiment, neuronal ensembles in the CA1 region of the hippocampus were tagged with the inhibitory opsin, ArchT, during contextual fear conditioning (left). When placed back into the training context (i.e., the retrieval cue), mice froze (middle). However, optogenetic inhibition of the tagged ensemble during this test reduced freezing levels (right), indicating that engram silencing can prevent ecphory even in the presence of natural retrieval cues. b, In this experiment, neuronal ensembles in the DG region of the hippocampus were tagged with the excitatory opsin, ChR2, during contextual fear conditioning (left). When placed into a distinct context, mice did not freeze (middle). However, optogenetic activation of the tagged ensemble during this test induced freezing (right), indicating that engram activation, in the absence of natural retrieval cues, can induce ecphory.
Fig. 3 |
Fig. 3 |. Ecphory for an artificially generated engram.
a, In these experiments, mice formed either a real (top) or an artificial (bottom) odor aversion memory. For the real odor memory, an odor (acetophenone; green) was paired with shock during training. When mice were subsequently presented with the conditioned odor (acetophenone) or a distinct odor (carvone; orange), mice exhibited conditioned aversion to acetophenone. For the artificial odor memory, photostimulation of a specific olfactory glomerulus (M72) was paired with photostimulation of lateral habenula inputs into the VTA. When mice were subsequently tested, they avoided the M72 odorant acetophenone (green), preferring to spend time on the carvone (non-M72 odorant; orange) side of the apparatus. b, In these experiments, mice formed either a real (top) or an artificial (bottom) odor attraction memory. For the real odor memory, an odor (acetophenone; green) was paired with food during training. When mice were subsequently presented with the conditioned odor (acetophenone) or a distinct odor (carvone; orange), mice exhibited conditioned attraction to acetophenone. For the artificial odor memory, photostimulation of the M72 olfactory glomerulus was paired with photostimulation of laterodorsal tegmental nucleus inputs into the VTA. When mice were subsequently tested, they approached (rather than avoided) the M72 odorant acetophenone (green), even though they had never had never encountered this odor previously.
Fig. 4 |
Fig. 4 |. Silencing of the engram. Engrams exist in different states of accessibility.
Engrams exist in a dormant state (where natural retrieval cues induce engram activation and successful retrieval), a silent state (where only direct optogenetic engram activation induces successful retrieval) and an unavailable state (where all information has been lost, and the memory is inaccessible regardless of the nature of access attempts). Transitions from dormant → silent→ unavailable likely reflect forgetting mechanisms (for example, weakening and loss of synaptic connectivity among engram cells or the addition of new connectivity as a consequence of neurogenesis). LTD, long-term depression.
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