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Infantile amnesia: forgotten but not gone

Stella Li, Bridget L. Callaghan and Rick Richardson

Learn. Mem. 2014 21: 135-139

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Review

Infantile amnesia: forgotten but not gone

Stella Li,1 Bridget L. Callaghan, and Rick Richardson
School of Psychology, The University of New South Wales, Sydney, NSW 2052, Australia

Unlike adult memories that can be remembered for many years, memories that are formed early in life are more fragile and
susceptible to being forgotten (a phenomenon known as “infantile” or “childhood” amnesia). Nonetheless, decades of re-
search in both humans and nonhuman animals demonstrate the importance of early life experiences on later physical,
mental, and emotional functioning. This raises the question of how early memories can be so influential if they cannot
be recalled. This review presents one potential solution to this paradox by considering what happens to an early
memory after it has been forgotten. Specifically, we describe evidence showing that these forgotten early-acquired mem-
ories have not permanently decayed from storage. Instead, there appears to be a memory “trace” that persists in the face of
forgetting which continues to affect a variety of behavioral responses later in life. Excitingly, the discovery of this physical
trace will allow us to explore previously untestable issues in new ways, from whether forgetting is due to a failure in retrieval
or storage to how memories can be recovered after extended periods of time. A greater understanding of the characteristics
of this memory trace will provide novel insights into how some memories are left behind in childhood while others are
carried with us, at least in some form, for a lifetime.

Memory, along with most other cognitive abilities, develops been suggested that specific early experiences may be the basis
across the lifespan (Ofen and Shing 2013). While memories ac- of adult psychopathologies (e.g., Jacobs and Nadel 1985; Mineka
quired in adulthood are generally well remembered and persistent and Zinbarg 2006). Hence, although early experiences are rapidly
(e.g., Gale et al. 2004), memories formed earlier in development forgotten, such experiences do appear to have a lasting impact.
are usually quite fragile and rapidly forgotten (a phenomenon Here, we explore some of the ways in which early memories con-
known as “infantile” or “childhood” amnesia [Campbell and tinue to have an influence on later functioning despite being
Campbell 1962; Spear and Parsons 1976; Hayne 2004; Hayne “forgotten.”
and Jack 2011]). The fact that early memories are so fragile has
resulted in a great deal of controversy over the importance of
early experiences on later functioning (e.g., Fraley et al. 2013). Infantile amnesia
Specifically, if early experiences cannot be explicitly recalled,
how can they influence an individual’s functioning later in life? Traditionally, forgetting is defined as the inability to recall and ex-
Although this question remains unanswered, there is an over- press a memory on a behavioral level (e.g., free recall in humans, a
whelming amount of evidence supporting the idea that early ex- learned avoidance response in rodents). Although memory loss
periences are critical for later functioning. For example, there is can be observed in animals of all ages, it is most common in youn-
substantial evidence that the quality of maternal care experienced ger and aged animals, each of which exhibit a rapid rate of forget-
early in life affects the behavioral, neural, and physiological ting compared to adult animals. The faster rate of forgetting in the
responses of the offspring as they mature. In a striking series of young is a well-documented phenomenon. For example, in their
studies, Tottenham and colleagues examined children who expe- now-classic study Campbell and Campbell (1962) trained rats
rienced maternal deprivation in the first two years of life (i.e., had ranging in age from 18 d (infants) to 100 d (adults) on an aversive-
been reared in an orphanage). In one study it was reported that ly motivated avoidance task. When tested immediately after train-
these individuals were more likely to experience depression in ad- ing animals of all ages showed high, and comparable, levels of
olescence (Goff et al. 2013). Further, on a neural level, they also avoidance. As the retention interval increased, however, marked
exhibited altered maturation of the nucleus accumbens, a struc- age differences in performance were observed. Specifically, the in-
ture involved in reward learning. In another study, these individ- fant rats exhibited substantial forgetting after 7 d and complete
uals exhibited amygdala hyperactivity as well as accelerated forgetting after 21 d. In contrast, the adult rats exhibited perfect
maturation of amygdala–prefrontal cortex connectivity (Gee retention even after 42 d, the longest interval tested. Similar re-
et al. 2013); both of these structures are important for emotion sults have been reported with humans in a nonfear based task.
regulation in humans (Hartley and Phelps 2013). As one example, in a series of experiments Rovee-Collier and col-
Numerous animal studies have also demonstrated the impor- leagues have shown that retention in human infants trained on an
tance of early experiences for later functioning. For example, it operant procedure (e.g., the mobile conjugate reinforcement task,
has been reported that infant rats whose mothers engaged in a where the infant learns to kick one leg to produce movement in an
high rate of arched back nursing and licking/grooming exhibit overhanging mobile, or the train task, where the infant learns to
markedly lower hormonal reactions in a stressful situation in press a manipulandum to cause an electric train to move) increas-
adulthood (Liu et al. 1997). In addition, these animals are more es monotonically with age over the first years of life (for review,
exploratory, and perform better at spatial learning and memory
tasks (for review, see Champagne and Curley 2009). It has also # 2014 Li et al. This article is distributed exclusively by Cold Spring Harbor
Laboratory Press for the first 12 months after the full-issue publication date
(see http://learnmem.cshlp.org/site/misc/terms.xhtml). After 12 months, it
1
Corresponding author is available under a Creative Commons License (Attribution-NonCommercial
E-mail [email protected] 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/
Article is online at http://www.learnmem.org/cgi/doi/10.1101/lm.031096.113. 3.0/.

21:135 –139; Published by Cold Spring Harbor Laboratory Press 135 Learning & Memory
ISSN 1549-5485/14; www.learnmem.org
 Downloaded from learnmem.cshlp.org on April 6, 2014 - Published by Cold Spring Harbor Laboratory Press

Enduring early memories despite forgetting

see Rovee-Collier and Cuevas 2009). Thus, the studies described in explicit memory of the pictures there was no developmental
above, along with many others, clearly show that memories ac- difference on a perceptual priming task. That is, when asked to
quired early in life are forgotten much more quickly than those ac- name an out-of-focus picture that progressively came into focus,
quired later in life, at least in terms of conscious recollection or all three age groups performed better (i.e., named the picture
overt behavioral expression of the memory.2 sooner) with familiar pictures from the storybook than with novel
Although we have long been aware of the robust phenome- pictures. Findings like these have led some researchers in the field
non of infantile amnesia, in the past 50 years there have been sur- of human memory development to suggest that early memories
prisingly few advances in our understanding of the physiological leave at least a partial trace that continues to influence later func-
bases of this rapid forgetting. However, several recent papers have tioning despite not being explicitly recalled (e.g., Sroufe et al.
suggested potential molecular and structural mechanisms that 1990).
could be involved in infantile amnesia (e.g., Josselyn and The idea that an unexpressed memory trace might have an
Frankland 2012; Frankland et al. 2013; Callaghan et al. 2014). “implicit” effect on later performance in rodents was recently ex-
These potential mechanisms are largely derived from recent stud- plored by Li and Richardson (2013). In that study, the effect of a
ies on the molecular and structural bases of memory in adults. memory acquired during infancy, but then forgotten, on the neu-
That is, infantile amnesia may be due to the immaturity of one, robiological mechanisms mediating future learning experiences
or more, of these mechanisms in infancy. Determining how the was examined. In adult animals, it is well-established that the
various processes already shown to be important in memory in cellular mechanisms underlying initial learning (“acquisition”)
adulthood change across early development is likely to lead to a involve a series of intracellular signals, one of which is the activa-
much better mechanistic understanding of infantile amnesia. tion of N-methyl-D-aspartate receptors (NMDArs) (Kandel 2001;
However, in this brief review, we focus on a different approach to- Schafe et al. 2001). However, when the same learning experience
ward understanding infantile amnesia. This approach focuses on occurs again (“reacquisition”) NMDArs are no longer required
the possibility that at least some part of these apparently forgotten (e.g., Sanders and Fanselow 2003; Wiltgen et al. 2011). This is re-
early memories persists beyond the point in time where the mem- ferred to as a “switch” from NMDAr-dependent acquisition to
ory is overtly expressed. This “trace” of the memory, although not NMDAr-independent reacquisition. Li and Richardson (2013) ex-
normally expressed in a standard retention test, can still markedly plored whether this switch to NMDAr-independent reacquisition
affect the participant’s behavior in a number of ways. The follow- still occurred if the original learning had been forgotten. Infant
ing sections explore the various ways through which the lasting rats were trained at 17 d of age with noise CS-shock US pairings.
influence of this trace on later functioning can be observed. After 2 wk these infant rats demonstrated complete forgetting by
exhibiting negligible levels of conditioned fear (as assessed
through CS-elicited freezing). Reacquisition following forgetting
Implicit versus explicit memory was NMDAr-independent regardless of whether reacquisition
It has long been noted that the pronounced forgetting observed in occurred 2 or 7 wk after training (forgetting was observed at both
adult amnesiacs primarily occurs with certain types of memories intervals). Importantly, the switch from NMDAr-dependent acqui-
(for reviews, see Schacter and Buckner 1998; Moscovitch 2010). sition to NMDAr-independent reacquisition only occurred if the
That is, these individuals typically exhibit difficulties with verbal experience at 17 d of age was an associative learning experience
recall of a past event even though they show altered behavioral re- (i.e., CS –US pairings) and not merely an aversive experience (i.e.,
sponses that could have only resulted from having that experi- unpaired noise-shock presentations). Hence, it appears that early
ence. For example, an adult amnesiac might not recall learning memories can have a long-lasting influence on subsequent learn-
to play a particular song on a piano, but yet is able to perform ing, altering the cellular mechanisms involved in learning later
it. This distinction is referred to as the difference between explicit in life, even though they are no longer overtly expressed at the
and implicit memory. A similar dissociation is observed following behavioral level. Interestingly, the transition to NMDAr-indepen-
forgetting of early memories, where there is a lingering influence dent reacquisition is not observed in adult rats following
of the experience even though it is not explicitly recalled. anisomycin-induced amnesia (Hardt et al. 2009) or following ex-
One example which shows that an enduring memory trace of tinction training in conjunction with administration of fibroblast
an early experience can influence subsequent behavior in humans growth factor-2 (Graham and Richardson 2011) as these manipu-
despite a lack of conscious recollection is provided by the research lations appear to permanently alter or erase the original memory
of Newcombe and her colleagues (for review, see Lloyd and trace. Taken together, the results of these studies suggest that the
Newcombe 2009). In one experiment children were given a recog- switch from NMDAr-dependent acquisition to NMDAr-indepen-
nition test for faces of classmates from preschool. Some children dent reacquisition could be a useful procedure for assessing wheth-
correctly recognized their old classmates while other children er some representation of a memory which is forgotten at a
did not. Regardless of accuracy in recognition, however, children behavioral level is still maintained in the brain.
exhibited a similar skin conductance response to the faces of their
old classmates relative to the faces of unfamiliar children. In an-
other study, 3-yr-olds, 5-yr-olds, and adults were shown pictures Memory reinstatement/reactivation
from a story book. When tested 3 mo later, the 3-yr-olds’ verbal
recognition of the pictures was at chance while the 5-yr-olds The terms “reinstatement” and “reactivation” both refer to a sit-
and adults performed significantly better. Despite this difference uation where an apparently forgotten memory is recovered (i.e.,
is now overtly expressed at test). The difference between the two
terms is that “reinstatement” usually is used in studies where re-
2
Although memories acquired early in life are more rapidly forgotten compared
peated, periodic reminders are given throughout the retention in-
to those acquired later in life, it should be noted that the sensory modality of terval, while “reactivation” usually is used in studies where a
the CS can markedly affect the rate of this forgetting. As a prime example, single reminder is given at the end of the retention interval
there are several studies showing that infant rats retain olfactory-based memo- (Spear and Parsons 1976).
ries well into adulthood (Sevelinges et al. 2008). Nonetheless, when direct age
The obvious implication of the findings described immedi-
comparisons have been made for retention of olfactory-based learning, it is still
the case that the younger animals forget more quickly than older animals ately above is that infantile forgetting is not due to a loss of the
(Markiewicz et al. 1986). early-acquired memory from storage. In other words, this

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Enduring early memories despite forgetting

forgetting must be due to a retrieval failure. Additional evidence gest that pMAPK levels in the amygdala track past learning history
for this claim is provided by a study by Campbell and Jaynes and may be a long-term marker of fear memory storage. That
(1966) who reported that infantile amnesia in rats could be allevi- study provided the first neural evidence for a memory trace which
ated by “reminders” given periodically throughout the retention persists in the face of infantile forgetting.
interval. Since that study there has been a plethora of additional The discovery of a neural marker of past learning experience
studies supporting this finding in a variety of tasks and in both hu- that persists despite forgetting on the behavioral level may prove
mans and nonhuman subjects. For instance, Spear and Parsons useful in a number of ways. For example, although the studies de-
(1976) conditioned 16-d-old rats (infants) to fear a light CS by scribed above on memory reinstatement/reactivation clearly
pairing it with a footshock US. Animals were tested 28 d after demonstrate that many instances of infantile forgetting are due
training and, as expected, substantial forgetting occurred (i.e., in- to a retrieval failure, this does not mean they always are. That is,
fantile amnesia was observed). However, 24 h prior to test some forgetting of early memories may go through two phases. In the
animals were given a single shock presentation. Animals that re- first phase, the memory is no longer explicitly expressed, but
ceived the pretest shock “reminder” exhibited high levels of fear can be recovered if an appropriate reminder treatment is given pri-
of the light CS at test. To ensure that the reminder shock did or to test. However, if the memory remains in this dormant state
not cause any learning by itself, a separate group of animals (i.e., available but not accessible) long enough, then it may decay
were not trained but were given the shock prior to test. The light sufficiently such that there is no longer a representation of it in
CS did not elicit fear in these animals, demonstrating that the the brain (see Callaghan et al. 2014, for a consideration of various
treatment alleviated forgetting by reactivating the original mem- neural and molecular processes that could be involved in infantile
ory rather than producing sufficient new learning to lead to the amnesia). In other words, infantile forgetting, and forgetting
behavioral response of interest. Although most early studies of more generally, could sometimes be due to a retrieval failure
this phenomenon used footshock as the reminder cue, later stud- and other times to a storage failure; the presence or absence of
ies showed that infantile amnesia could be attenuated through the physical trace could potentially distinguish between the two
other pretest treatments, such as hormonal or pharmacological cases.
agents (e.g., epinephrine [Haroutunian and Riccio 1977] and The observation of a successful reinstatement/reactivation
FG-7142 [Kim et al. 2006]). All of these studies, as well as those de- effect clearly shows that any observed forgetting was due to a re-
scribed earlier in the section on explicit/implicit memory, show trieval failure. However, the failure to detect such an effect does
that some representation of the original memory formed in infan- not necessarily mean that the memory trace has decayed from
cy must still be present later in development despite the fact that storage; rather, such a result could be due to an ineffective remind-
the memory is not easily retrieved or overtly expressed. er cue. This issue has long been noted, but without having any in-
Similar findings have been reported in human infants. For dependent evidence of the memory trace, other than successful
example, Davis and Rovee-Collier (1983) trained 8-wk-old infants reactivation, it has not been possible to test these various possibil-
on an operant conditioning task where the infant learned to kick ities. The demonstration of a detectable neural signal resulting
their foot in order to move a mobile suspended above them. Two from a specific learning experience could be very useful in this sit-
weeks after training, all infants showed complete forgetting of this uation. That is, if animals fail to recover a memory following a re-
task. However, infants showed little to no forgetting if they had re- minder treatment, but they exhibit evidence of the physical trace
ceived a reminder treatment (exposure to the moving mobile) 24 (e.g., altered pMAPK activity in the amygdala), then a stronger
h prior to the long-term retention test. Thus, just like in the rodent conclusion can be made that the particular reminder treatment
studies, even when forgetting occurs on a behavioral level, mem- used was ineffective in that situation.
ories acquired by infant humans are not permanently lost or It will be interesting to determine whether other neural
erased. markers of memory can also be used to explore the issue of wheth-
er infantile forgetting is due to a storage or retrieval failure. As one
example, Han and colleagues took advantage of the finding that
Empirical evidence for a physical memory trace after changes in cyclic-AMP response element binding protein (CREB)
expression plays a role in the formation of a memory trace.
infantile forgetting
Specifically, they reported that experimentally increasing CREB
The studies described in the two preceding sections suggest that expression in subpopulations of neurons in the lateral amygdala
there must be some neural representation of the early-acquired following auditory fear conditioning resulted in the recruitment
memory even when it is not behaviorally expressed. Evidence of those neurons into the memory trace (Han et al. 2007). In a sub-
for such a physical trace was recently provided in a study by sequent study they showed that deletion of these CREB-overex-
Kim et al. (2012). In that study, 16- and 23-d-old rats were given pressing neurons reduced memory expression (Han et al. 2009).
noise CS-shock US pairings. When tested immediately after train- It is currently unknown whether the same results would be ob-
ing, rats at both ages showed similar levels of conditioned fear (as served in the infant animal. In other words, is CREB expression
assessed through CS-elicited freezing). When tested 2 d later, how- also important for the formation of a memory trace in the infant
ever, only the 23-d-old rats continued to exhibit fear to the CS, animal? If so, then heightened CREB expression in the amygdala,
while the 16-d-old rats showed low levels of CS-elicited freezing, especially at long intervals following initial learning, may be used
indicating forgetting. Following test, the amount of phosphory- to predict the success of memory reinstatement/reactivation.
lated mitogen-activated protein kinase (pMAPK) in the amygdala The discovery of these various neural markers can help us to
was analyzed using immunohistochemistry. Despite failing to distinguish between retrieval- and storage-based failures in mem-
behaviorally express the memory, the 16-d-old rats tested at the ory. However, one issue that requires further investigation is why
2-d interval had heightened pMAPK activity in the amygdala, the animal exhibits forgetting even when there is a neural signa-
comparable to that observed in the 23-d-old rats who had exhib- ture of the memory persisting in the brain. As previously men-
ited high levels of freezing at test. Importantly, both of these tioned, it is likely that forgetting occurs in stages. Thus, it is
groups differed in levels of amygdala pMAPK activity relative to possible that the strength of the memory trace also degrades in
same-age animals given explicitly unpaired presentations of the stages. For instance, it may be that the behavioral expression or ex-
CS and US at training and then tested 2 d later; the rats in this un- plicit recall of a memory requires the whole (or nearly whole)
paired condition did not express fear of the CS. These results sug- memory trace to be present in the brain. When an animal forgets

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Enduring early memories despite forgetting

but the memory can still be reactivated and retrieved, then a par- trace of the experience persists even when memories are no longer
tial memory trace may be observed. The final stage, when an ani- recalled or expressed. This finding highlights the importance of
mal forgets and the memory cannot be reactivated, may reflect the considering what the term “forgetting” actually means—is it
complete decay of the memory trace. Future studies could test this merely the absence of behavioral expression or is it when even
possibility by examining the levels of pMAPK expression in the “implicit” effects on later performance are no longer observable?
amygdala at different time points following learning. We would We suggest that forgetting, at least nonreversible and permanent
expect that the level of pMAPK expression decreases over time un- forgetting, occurs when both of these characteristics are observed.
til the point where no pMAPK activity is observed, thus reflecting In this review, we hypothesized that the “implicit” effects of
the complete and permanent loss of memory. early memories on later performance are due to the persistence of
the neural signature representing that memory. What we current-
ly do not know is how long these physical traces last. Kim et al.
When infantile forgetting does not occur (2012) only examined pMAPK levels 2 d after training, and it is
possible that heightened pMAPK activity in the amygdala is ob-
Although infantile amnesia is one of the strongest, and most fre-
served weeks, months, or even years later. This would be exciting
quently observed, characteristics of infant memory, there appear
on a clinical level because we could reactivate and potentially ex-
to be some circumstances where infants exhibit much longer-
tinguish aversive or traumatic early memories rather than allow-
lasting retention of early experiences. A largely ignored area of re-
ing the memories to persist in their implicit form, with their
search has been the interaction between early adversity and the
attendant consequences which are not attributed to a specific ex-
development of memory. This is an important gap in the literature
perience as that memory is not explicitly recalled. Future research
considering that early adversity has been shown to be associated
also needs to determine how reactivation/reminder treatments
with alterations in the developmental trajectory of neural regions
interact with the memory trace. It may be that periodic reminders
important for memory (e.g., Gee et al. 2013). Whether infantile
ward off the decay of the memory by working to stabilize the
amnesia remained a characteristic of memory development fol-
memory trace. This is of interest clinically because it may explain
lowing early life adverse rearing (i.e., maternal separation) was re-
how some early memories are more resilient to disruption than
cently investigated by Callaghan and Richardson (2012). In that
others. Additional research into these persisting neural markers
study infant rats were given pairings of a noise CS and a shock
of memory will hopefully provide us with greater insight into
US, and tested for their fear of the noise CS either 1 or 10 d later.
how some memories may, indeed, last a lifetime. Overall, this re-
Both standard-reared (SR) and maternally separated (MS) rats
view shows that while the study of infantile amnesia in the last 50
learned the association, as both expressed fear at the 1-d interval.
yr has focused predominantly at the behavioral level, our explora-
However, while the SR rats rapidly forgot the association, express-
tion of the phenomenon on a mechanistic level is only just
ing negligible levels of CS-elicited freezing just 10 d later, MS in-
beginning.
fant rats maintained a high level of fear at the 10-d interval. The
MS rats trained as infants continued to express conditioned fear
up to 30 d after the conditioning episode (i.e., well into the young
adult period of development), suggesting that MS drastically en-
Acknowledgments
hances retention of infant memories. Enhanced memory reten- Preparation of this manuscript was supported by grants from the
Australian Research Council (DP120104925) and the National
tion was also observed if animals were reared by mothers who
Health and Medical Research Council (APP1031688) to R.R.
had their drinking water supplemented with the stress hormone
corticosterone across the same period of time (i.e., postnatal
days 2 – 14). Thus, early exposure to stress appears to alter the
developmental trajectory of memory, accelerating the emergence
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