Infantile Amnesia

Infantile Amnesia
What happens during infantile amnesia?
Adapted from [21]

Infantile amnesia, or childhood amnesia, is a two stage phenomenon, characterized by the near absence of explicit or declarative memory for events that occurred from 2-3 years of age, and spotty memory for events that occurred 3-7 years of age. Forgetting cannot simply be attributed to normal forgetting, as the number of memories that can be recalled as an adult for events that took place during infancy is below what would be expected by extrapolating the adult forgetting curve. Although the neural mechanisms underlying infantile amnesia are still debated, there are many early cognitive and psychological theories, and recent biological theories that attempt to account for the phenomenon. These biological theories generally fall into two categories – one that dictates that brain regions responsible for episodic memory are still immature, and the other that says the ongoing postnatal neurogenesis interferes with the ability to form and consolidate stable memories [1]. Recent research has also shown that the development of infantile amnesia can be alleviated by administering pharmacological agents post-training in rat models (such as epinephrine, norepinephrine, glucose, GABA, and naloxone) [2]. Further research in infantile amnesia shows that it has an important implication in the treatment of anxiety disorders.

1. Early Cognitive and Psychosocial Theories

1.1 Freud's Insights

Freud coined the term “infantile amnesia” after noticing the difficulty in memory retrieval in adult patients. He proposed a “blockade model”, in which he interpreted infantile amnesia as the blockade of repressed memories by the mature ego. Early memories could be repressed due to their association with unwanted feelings. Since peoples’ repressed memories are difficult to recall clearly and accurately, or focused on traumatic events, the practical implication is that they are often susceptible to false suggestion, which can lead to the implantation of false memories. He also proposed a “selective reconstruction” model which dictates that early memories are difficult to recall because they are incongruent and unsupported by adult cognitive processes [3].

1.2 Development of Language

The development of language seems to facilitate better memory recall, as verbal repetition likely aids memory retention [1]. In an assessment of verbal and nonverbal memory recall of 2 to 4 year old children, memory recall is shown to have a positive correlation with age. In addition, children’s performance is correlated with their language ability, such that children with more advanced language skills exhibit superior recall when assessed both verbally and nonverbally, compared to children with less developed language skills. However, children at this age are more reliant on implicit memory, as evidenced by the fact that their declarative memory recall lags behind their implicit memory recall. This indicates that implicit memory is still more important in aiding recall in 2 to 4 year olds than declarative memory, possibly accounting for a later inability to retrieve these memories as adults [4].

1.3 Development of Self-concept

The development of a self-concept proposes that children need to develop a sense of self before personal memories can be retained effectively. Self-recognition is an important requirement for better retention of memory, as it would help one encode and store personal, relevant memories [5][1]

2. Neurological Explanations

2.1 Immature Brain Hypothesis

Key structures for declarative memory formation and consolidation are inadequately mature at the time of birth, despite much of the brain being fully formed. These structures include the cortex and the dentate gyrus of the hippocampus. In addition, several aspects of cortical maturity such as myelination, and synaptic density do not reach adult levels until puberty. Early infant brains are generally slower in processing, and increase with age and increasing myelination [1]. Primate studies, particularly those conducted in infant macaques, demonstrate that increasing novelty preference memory is correlated with protracted hippocampal development [6].

2.1.1 Infant Fear Pathways in Rats

Neural circuits that mediate fear in adult and infant rats
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The differences in the amygdala mediated fear pathway in rats is shown. In the infant system, neurons from
the basolateral amygdala (BLA) send their projections to the central amygdala (CeA), independent of the prelimbic
prefrontal cortex. However, the adult system makes a transition to being prelimbic PFC dependent, and it relies on
projections from the PL-PFC going to the BLA, which in turn project to the CeA to mediate fear memory.
Adapted from [22]

Another difference between adult and and infant brains is demonstrated in the pathways mediating fear in adult and infant rats. Adult rats’ fear pathway involves the prelimbic region of the prefrontal cortex which activates the basolateral amygdala (BLA) which in turn activates neurons in the central amygdala (CeA), while the infant rat system only involves the BLA neurons making connections with the CeA. This transition to becoming prelimbic PFC-dependent may contribute to the difficulty in retrieving fear memories acquired during infancy [7].

2.2 Ongoing Brain Maturation Hypothesis

Ongoing brain maturation explanations suggest that it is the process of protracted postnatal neurogenesis itself that interferes with the ability to form and consolidate stable memories. Early research by Campbell and Spears examined the effects of increasing and decreasing postnatal neurogenesis in infant mice, which form the foundation for a more recent theory, the neurogenic hypothesis.

2.2.1 Neurogenic Hypothesis

Neurogenic Hypothesis
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This demonstrates the neurogenic hypothesis: neurogenesis is inversely
correlated with memory formation and retention. As an individual ages, neurogenesis
declines and at the same time, memory retention increases.
Adapted from [23]

The neurogenic hypothesis, proposed by Josselyn and Frankland, dictates that the protracted postnatal neurogenesis in the hippocampus degrades the existing memories by destabilizing hippocampal networks or replacing preexisting synaptic connections. It is an extension of Campbell’s and Spears’ work who examined the effects of increasing neurogenesis in inducing forgetting, and decreasing neurogenesis to promote better memory consolidation, but with less blunt, off-target methods [1]. Some of the evidence that supports the neurogenic hypothesis is outlined, followed by experimental evidence. Supporting Evidence from Animal Models

Mouse model of infantile amnesia
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Mice and rats show protracted postnatal development in the dentate
gyrus, which has connections with the CA3. Adapted from [24]

Guinea pigs only show a 60% increase in brain weight after birth; whereas, rats show an increase of 600%, indicating that much of the guinea pig brain is fully mature at birth, and there is less neurogenesis. There is only 20% addition of granule cells to the dentate gyrus of the hippocampus in guinea pigs, while there is 80% in rats [1]. As a result, when guinea pigs and rats are subjected to an aversively motivated place discrimination task or a passive avoidance paradigm, 5 day old infant guinea pigs show the same memory recall as adult guinea pigs do, while infant rats show infantile amnesia [8]. This can be accounted for by the fact that guinea pig brains are more mature and require less neurogenesis, relative to rats, thus permitting the acquisition and retention of more stable memories.

Adult mice that are CamKIIα deficient show increased neurogenesis in the DG compared to wild type mice. As a result, these adult mice have severely compromised memory retention [9].

Furthermore, presenilin-1 deficient mice show better memory retention than wild type mice when put into an enriched environment. PS-1 attenuates the effects of an enriched environment such that these PS-1 deficient mice had lower levels of neurogenesis, and thus, better memory retention [10].

Exercise also increases levels of neurogenesis, such that increased exercise in adult rodents leads to more rapid clearing of the hippocampal dependent contextual fear memory to hippocampus-independent. Therefore, higher levels of neurogenesis also promote clearing of preexisting information in the hippocampus [10]. Experimental Evidence

Morris Water Maze
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Increased neurogenesis would promote more rapid clearing of
hippocampal-dependent memory, and thus promote forgetting, such that
they would wander around more in a Morris Water Maze paradigm.
Adapted from [25]

By inducing increased neurogenesis in the adult mouse, through methods such as environmental enrichment, exercise, antidepressants, electrical stimulation of the performant pathway, and genetic or pharmacological inhibition of apoptosis, they will exhibit increased forgetting proportional to the degree of stimulation. By decreasing infant neurogenesis through pharmacological and irradiation techniques, the mice are expected to be able to form more stable memories [1]

2.3 Role of CaMKIIα

Infantile amnesia may also be driven by an imbalance between protein kinases and phosphatases. CamKII is a key memory molecule involved in both induction and maintenance of LTP, which is necessary in short term memory. [1] [11]. CAMKII is opposed by Calcineurin which is responsible for the disruption of LTP and memory [11]. At the earliest stages of postnatal development, CAMKII levels are very low and increase over the following 2 weeks, while CaN levels are higher. This imbalance may account for the greater suppression of memory. Other studies have implicated CaN directly in infantile amnesia, as lower levels of CaN in the olfactory bulb correlated with better odor preference memory [12].

2.4 Role of PKMζ

PKMzeta is a molecule implicated in LTP maintenance and LTM, and possibly infantile amnesia, although its role in memory is still debated. Some studies show that when PKMζ expression in the hippocampus or neocortex is inhibited, spatial memories are disrupted [7]. PKMζ is expressed in low levels at birth, so perhaps these low levels are responsible for the unstable memories. Other studies have suggested that PKMζ is implicated in keeping infant synapses in an active state, as it is found predominantly in the perirhinal cortex in infant rats [13].

3. Molecules for Memory Modulation in Rat Models

3.1 Epinephrine

When infant rats are given or norepinephrine, which improve memory retention in adult rats, they exhibit improved performance on a 24 hour after training in a passive avoidance task [2]. In another type of test paradigm, the inhibitory avoidance conditioning paradigm, rats perform worse when tested 24 hours after training, compared to 5 minutes after training, which demonstrates infantile amnesia has occurred. When epinephrine is administered, it attenuates the infantile amnesia experienced by those rats tested 24 hours after training, such that they perform significantly better. Epinephrine is a memory modulator whose mechanism can be explained by the fact that it indirectly causes norepinephrine release from the basolateral amygdala, activates neurons in the locus coeruleus, and causes release of norepinephrine in the hippocampus. These effects of epinephrine ultimately target the hippocampus which is important in modulating memories [14].

3.2 GABA

FG7142 injection after an intermediate or long retention interval
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Experiment 2A shows that FG7142 administration after an intermediate retention interval
(at doses of 0, 1, 5 or 10 mg/kg) has no effect in alleviating the Kamin effect. Experiment 2B
shows that FG7142 at doses of 10 mg/kg, alleviates infantile amnesia (which is observed at
48 hours, ie. a longer interval), as indicated by the higher % freezing, relative to 0 mg/kg
FG7142 administration.
Adapted from [26]

Pharmacological inhibition prior to testing can also mitigate infantile amnesia, as evidenced by injections of GABAA receptor inverse agonist FG-7142 which alleviates the effects of infantile amnesia after a fear conditioning paradigm [2]. The types of forgetting induced were observed after a long retention interval (infantile amnesia) and an intermediate one (Kamin effect). 18-day old infant rats were subject to a contextual fear conditioning paradigm, where better fear learning is measured with increased freezing. Forgetting after 48 hours (a long retention interval) was alleviated by administration of FG7142, but it did not affect forgetting after 1 hour. GABAA is a key inhibitory neurotransmitter, with receptors commonly found in the amygdala, which plays a key role in fear memory. For infantile amnesia to be attenuated, inhibition of GABA was achieved by the pretest injection of a GABA agonist (FG7142) [15].

Other studies have also shown that administration of GABA agonists in 16 day old mice also demonstrated attenuated infantile amnesia [16]. Rats are subject to a fear conditioning paradigm where white noise is associated with a shock. Reactivation of memory (by giving a reminder shock) prior to the test showed high levels of freezing, but if a reminder shock was followed by midazolam, a GABA agonist, the memory was not reactivated. In other words, administration of GABA agonists immediately after a reminder shock resulted in low levels of freezing. When midazolam was administered 2 hours after a reminder shock, it did not reduce the memory reactivation (high levels of freezing are still observed) [16].

In another experiment, FG7142 also showed recovery of a fear memory, but also alleviated memory for a passive avoidance paradigm, and memory for a latently inhibited conditioned stimulus [17].
Thus, GABAergic transmission is involved in suppressing retrieval of infantile memories.

3.3 Naloxone

Endogenous opioid peptides and receptors are also important, as they help modulate learning, memory and motivation in mammals. When an opioid receptor agonist is administered posttraining, infantile amnesia is enhanced, while antagonists of the endogenous opioid system mitigate the effects of infantile amnesia. When infant rats are subjected to a contextual fear conditioning paradigm, where they are taught to associate an auditory conditioned stimulus with a footshock unconditioned stimulus, they exhibit excellent recall 1 day after the training, but less after 10 days of training. This can be attributed to infantile amnesia [2]. However, when 18 day old rats are injected naloxone, an opioid receptor antagonist 1 minute prior to the contextual fear conditioning, this alleviated infantile amnesia. These effects are not seen when injected 24 hr after training, but are seen when injected prior to test 7 days (a longer retention interval) after training. The mechanism of naloxone is due to its actions on central opioid receptors, and not due to naloxone eliciting fear or freezing, as injection of naloxone did not produce fear in untrained rats. Thus, these central opioid receptors are implicated in the retrieval of fear memories [2].

3.4 Glucose

Glucose can also attenuate infantile amnesia. 17 day old rats are subject to a passive avoidance conditioning paradigm, followed by either a saline or glucose injection 24 hours after. Rats administered glucose show better memory, while those given saline demonstrate poor retention, indicative of infantile amnesia. Thus, glucose significantly attenuates infantile amnesia. The neural bases underlying this mechanism can be ascribed to the fact that glucose interacts directly and indirectly with multiple neurotransmitter systems to alleviate forgetting [18]. Other studies have shown that immediate injection of glucose after a passive avoidance conditioning paradigm also resulted in better performance in infant rats, relative to a saline injection [19].

4. Implications

4.1 Possible Treatment for Anxiety Disorders

Persistent fear responses are a hallmark of anxiety disorders. If infantile forgetting could be stimulated in adults, it could be used as a treatment to alleviate these fear responses [7]. Recent research has looked at the possibility of inducing infant-like elimination of memory in adults, by degrading perineuronal nets (PNNs) using chondroitinase ABC, in the amygdala. Towards the end stages of high levels of early postnatal neurogenesis , PNNs are observed around amygdala neurons, which cause extinction learning. Thus, this infant-like extinction may be used to induce loss of erasure-resistant fear memories in patients with anxiety disorders [20]

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