However, the results of these intervention
studies provide direction as to which processes
we should focus our efforts to understand how
the brain actually forms and retrieves mem-
ory. Furthermore, the high specificity of the
state-of-the-art intervention methods, spanning
from the molecular level up to the behavioral
level, have already revealed mechanisms that
would have been difficult to study using other
techniques. For instance, these artificial inter-
vention studies allowed the field to identify
the silent state of an engram and the mech-
anism underlying memory allocation.
More than 100 years ago, Semon put forth a
law of engraphy. Combining these theoretical
ideas with the new tools that allow researchers
to image and manipulate engrams at the level
of cell ensembles facilitated many important
insights into memory function. For instance,
evidence indicates that both increased intrin-
sic excitability and synaptic plasticity work
hand in hand to form engrams and that these
processes may also be important in memory
linking, memory retrieval, and memory con-
solidation. Interestingly, disrupting synaptic
plasticity in engram cells either by disease
processes (as in mice used to study AD) or
amnestic drugs (such asprotein synthesis in-
hibitors) or during some natural behaviors
(housing condition in social discrimination
memory, memory systems consolidation, and
perhaps fear extinction training) silences en-
grams such that they can no longer be ac-
cessed by normal sensory cues. However, these
studies show that silentengrams still exist in
the brain and that the information they rep-
resent may not be forever lost. The pioneering
psychologist and behaviorist Edward Tolman
( 231 )advancedtheconceptoflatentlearning
and latent memory: learning that occurs with-
out reinforcement, the memory of which is not
revealed or expressed until the need or mo-
tivation for the acquired knowledge arises
( 232 , 233 ). It would be interesting to deter-
mine whether at least some latent memories
are based on silent engrams and, if so, use the
conversion of silent engram to active engram as
a means of identifying and characterizing the
brain circuits mediating the relevant motivation.
A continuum of engram accessibility states
mayexist.Engramsmaybeentirelyunavail-
able and not retrievable, even through artifi-
cial means (the memory would be forgotten).
Or,engramsmaybesilencedsuchthatmem-
ories may be retrieved by artificially reactivat-
ing engram cells. The processes that silence or
erase an engram, as well as strategies for un-
silencing engrams, are a subject for further
investigation. That it was possible to arti-
ficially reactivate silent engrams in mice de-signed to study the memory deficits of AD
hint at the extraordinary translational po-
tential of this line of research.
Some additional general themes emerge
from the results of engram studies. The first
theme is that findings from engram studies
are reminiscent of reconsolidation studies.
Upon retrieval, a memory may enter a labile
and modifiable state that lasts for several
hours. The process of restabilizing this mem-
oryisreferredtoasreconsolidation.Although
reconsolidation has a longer history ( 234 ), the
modern reawakening of this phenomenon
stems from a finding by Nader, LeDoux, and
Schafe ( 235 ). At the time that this ground-
breaking study was conducted, the general
thinking was that memories become stabi-
lized in a process of cellular consolidation that
occurs once, shortly after a learning experi-
ence. However, Nader, LeDoux, and Schafe
challenged this view by showing that memory
retrieval opens a several-hour“reconsolidation
window”during which different interventions
may weaken or strengthen the original mem-
ory. For instance, disrupting protein synthesis
during the reconsolidation window of a condi-
tioned fear memory produced apparent am-
nesia for this memory. This result was replicated
and generalized to several types of memory
( 156 , 236 , 237 ). There are many similarities
between this reconsolidation blockade and
engram silencing. For instance, reconsolidation
blockade is only observed when a memory is
being actively retrieved, because administer-
ing anisomycin (or another similar interven-
tion) in the absence of memory reactivation
does not impair its subsequent retrieval. Viewed
from an“engram conceptual framework,”re-
trieval of a specific memory would activate the
underlying engram, and disrupting protein syn-
thesis shortly after this activation might silence
this engram. The function of reconsolidation
maybetoupdateamemory( 1 , 211 , 238 – 240 ).
That the reconsolidation window is not unlike
the coallocation window suggests that these
two processes might be similar ways of ex-
plaining the same (or similar) phenomenon
at different levels of analysis.
A second emerging theme is that of com-
petition. Allocation to an engram involves
competition between eligible neurons within
a given brain region at the time of memory
encoding. Competition represents a funda-
mental property of many biological systems
and has been previously shown to be im-
portant in other mnemonic phenomena. For
instance, memory traces may compete for con-
trol of behavior at the time of retrieval ( 241 ).
In addition, human studies reveal that mem-
ories may compete if they are linked to a
common retrieval cue. Retrieval of a target
memory may lead to retrieval-induced for-
getting of currently irrelevant competing mem-
ories ( 242 ).Josselynet al.,Science 367 , eaaw4325 (2020) 3 January 2020 10 of 14
Fig. 5. Neuronal allocation and memory linking.Neurons with increased excitability at the time of event
1 (blue) are allocated to the engram supporting this memory (blue filled circles outlined in orange).
These allocated engram neurons remain more excitable than their neighbors for several hours after event 1. If
a similar event 2 (green) occurs during this time, neurons allocated to the engram supporting event 1 are
more excitable and, therefore, also allocated to the engram supporting event 2 (blue and green filled circles
outlined in orange). In this way, neurons are coallocated to events 1 and 2. By virtue of coallocation, these
two memories become linked. After some time, neurons allocated to the engram supporting event 1 become
less excitable than their neighbors (“refractory”),andifevent2occursinthistimewindow,anewpopulation
of more excitable neurons wins the competition for allocation to the engram supporting event 2. This
disallocation allows the two memories to be remembered separately. Circles with red dashed outlines represent
less excitable neurons.
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