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“Memory has been the cognitive faculty that has been studied more exhaustively by all the professionals of neuroscience. In a century that has been characterized by the increase in life expectancy, much of the effort has been focused on the study of the decline, normal and pathological, of memory in the elderly population.”

However, today I will speak, broadly speaking, of the development of memory at early ages. Being specific, of the development of the memory in the fetus (that is to say, from the 9th week of pregnancy until it is conceived, week 38 approximately) and in the neonate.

Memory in childhood

We will probably all agree that babies are super intelligent and that they are already learning in their mother’s uterus. More than one mom sure could tell us more than one anecdote about it, I’m sure. But, does declarative memory really exist? And, if it exists, why do most of us remember nothing of our childhood before the age of three?

If you have a memory from before 2-3 years it is probably a false memory. This phenomenon is called infantile amnesia. And now we could ask ourselves, if there is infantile amnesia, does it mean that neither the fetus, nor the newborn, nor the child until 3 years of age have a memory? Obviously not. In general, it is assumed that memory is given in different ways and that each of these presentations involves different brain regions and circuits. Learning involves many mechanisms of memory and some of them are not related to the hippocampus (the fundamental structure for the consolidation of new memories).

I will speak about three fundamental learning mechanisms: classical conditioning, operant conditioning and explicit or declarative memory. I will briefly introduce each of these concepts and show what the main human research on the neurodevelopment of these functions, essential for the normal learning of the child, postulate.

Classical conditioning

Classical conditioning is a type of associative learning. It was described in the s. XIX by Ivan Pavlov – the extensively discussed experiment of the bell and salivating dogs.

Basically, in classical conditioning a “neutral stimulus” (without any adaptive value for the organism) is associated with an “unconditioned stimulus”. That is, a stimulus that innately produces a response (similarly, but not equal, to a reflex). Thus the “neutral stimulus” becomes a “conditioned stimulus” since it will give rise to the same response as the “unconditioned stimulus”.

So, do babies associate? A small experiment was performed in which they made a small breath of air, or “buf”, in the eye (unconditioned stimulus), which entailed a flicker response due to air-reflex mode. In subsequent tests the “buf” was performed while the administration of a specific auditory tone (“neutral stimulus”). After some trials the simple production of the tone gave rise to the flicker response – it had become a “conditioned stimulus” -. Therefore, the tone and the “buf” had been associated.

And the fetus, is it capable of associating? It has been seen that babies can respond to stimuli that have been presented to them before their birth. For this, the heart rate of a melody presented during pregnancy through the mother’s abdomen has been measured.

Once the baby was born, the heart response was compared by presenting new melodies (control melodies) of the previously learned melody. It was observed that the cardiac rate changed selectively before the melody presented during pregnancy. Therefore, the fetus is able to associate stimuli.

From a neuroanatomical point of view it is not surprising that babies and the fetus generate associations. In these types of associative learning, in which fear or other emotional responses do not intervene, one of the main cerebral structures in charge is the cerebellum.

Neurogenesis – the birth of new neurons – of the cortex of the cerebellum is completed by 18-20 weeks of gestation. In addition, at birth the Purkinje cells -main cells in the cerebellum- show a morphology similar to those of adults. During the first months after birth there are changes at the biochemical level and neuronal connectivity that lead to the cerebellum being fully operational.

Even so, there will be small variations. In the first months the most conditioned stimuli are gustatory and olfactory, while in later stages the conditions are increased to other stimuli. When emotional aspects intervene in the classical conditioning associative learning involves other structures, whose neurodevelopment is more complex, since more factors must be taken into account. Therefore, I will not talk about it today because it would deflect the main theme of the text.

Operant conditioning

Operative or instrumental conditioning is another type of associative learning. Its discoverer was Edward Thorndike, who investigated the memory of rodents through labyrinths. Basically it is a type of learning that is that if the behaviors are followed by pleasant consequences will be repeated more, and the unpleasant will tend to disappear.

This type of memory is complicated to study in the human fetus, so most current studies have been performed in babies under one year. An experimental method that has been used is the presentation of a toy to a baby, such as a train that will move if the child pulls a lever. Obviously, babies associate the pulling of the lever with the movement of the train, but in this case we will find significant differences depending on the age. In the case of children of 2 months, if once they have associated the movement of the lever with the one of the train we remove the stimulus, then the instrumental learning will last approximately 1-2 days. This basically means that, if after about four days we present the stimulus, the learning will have been forgotten. However, brain development at an early age advances at a frenetic pace and, in contrast, 18-month-old subjects can sustain instrumental learning up to 13 weeks later. So, we can summarize it by saying that the mnesic gradient of operant conditioning improves with age.

What structures does operant conditioning imply? The main neural substrates are those that form the neoestriate -Caudado, Putament and Núcleo Accumbens-. For those who do not know this structure, they are basically nuclei of subcortical gray substance – that is, below the cortex and superior to the brainstem. These nuclei regulate the pyramidal motor circuits, responsible for the voluntary movement. They also intervene in affective, cognitive functions and there is an important relationship with the limbic system. At the time we are born, the striatum is fully formed and its biochemical pattern matures at 12 months.

Therefore, one could infer the possibility that primitive instrumental conditioning existed in the fetus; although the circumstances and context make it difficult to think of effective experimental designs to evaluate this function.

Declarative memory

And now comes the fundamental issue. Do the neonates have a declarative memory? First, we should define the concept of declarative memory and differentiate it from its sister: implicit or procedural memory.

The declarative memory is that which is popularly known as memory, that is, the fixation in our memories of facts and information that are acquired with learning and experience, and to which we access in a conscious manner. On the other hand, the implicit memory is one that fixes motor patterns and procedures that is revealed by its execution and not so much by its conscious memory – and if you do not believe me try to explain all the muscles that you use to go by bike and movements specific you do.

We will find two fundamental problems in the study of declarative memory in newborns: first, the baby does not speak and, therefore, we can not use verbal tests for their evaluation. Secondly, and as a consequence of the previous point, it will be difficult to discriminate the tasks in which the baby makes use of his implicit or explicit memory.

The conclusions about the ontogeny of memory that I will talk about in a few moments will be from the paradigm of “the preference to novelty”. This experimental method is simple and consists of two experimental phases: first, a “familiarization phase” in which the child is shown during a fixed period of time a series of stimuli -generally images of different types- and a second “test phase” in which two stimuli are presented: a new one and one that had previously seen in the familiarization phase.

Generally, the visual preference for novelty is observed by the baby, through different measuring instruments. Therefore, the idea is that if the neonate looks more time to the new stimulus it means that he recognizes the other. Would it be, therefore, the recognition of new images a suitable paradigm for the construct of declarative memory?

It has been seen that patients with damage to the medial temporal lobe (LTM) do not show preference for novelty if the period between the familiarization phase and the test is greater than 2 minutes. In studies of lesions in primates it has also been seen that LTM and, especially, the hippocampus are necessary structures for recognition and, therefore, for preference to novelty. Even so, other authors have reported that behavioral measures of preference for novelty are more sensitive to hippocampal damage than other recognition tasks. These results would question the construct validity of the paradigm of preference to novelty. However, in general it is considered as a type of pre-explicit memory and a good study paradigm, although not the only one.

Characteristics of declarative memory

So, I will talk about three basic characteristics of declarative memory from this experimental model:
Coding

By coding – not consolidation – we refer to the ability of the baby to integrate the information and fix it. In general, studies show that children of 6 months already show a preference for novelty and, therefore, we conclude that they recognize. Even so, we found significant differences in coding times with respect to 12-month-old children, for example, needing these last few exposure times in the familiarization phase to encode and fix the stimuli. Being specific, a 6-month-old child needs three times more time to show a recognition capacity similar to that of a 12-month-old child. However, the differences in relation to age are attenuated after 12 months of age and it has been seen that children aged 1 to 4 years show equivalent behavior with similar familiarization periods. In general, these results suggest that while the beginnings of declarative memory appear in the first year of life, we will find an effect of age on the coding capacity that will occur especially in the first year of life. These changes can be related to different neurodevelopment processes that I will talk about later.

Retention

By retention we refer to the time or “delay” in which the neonate can keep an information, to later recognize it. Applying it to our paradigm would be the time we pass between the familiarization phase and the test phase. With coding times equivalent, babies with more months can show higher percentages of retention. In an experiment in which the performance of this function was compared in children of 6 and 9 months, it was observed that only children of 9 months could maintain the information if a delay was applied between the two phases of the experiment. Instead. The children of 6 months only showed preference to the novelty if the test phase was carried out immediately after the familiarization phase. Broadly speaking, it has been seen that the effects of age on retention occur until early childhood.

Recovery or evocation

By evocation we refer to the ability to rescue a memory from long-term memory and make it operational for an end. It is the main capacity that we use when we bring our experiences or memories to the present. It is also the most difficult ability to assess in babies because of the lack of language. In a study that used the paradigm we talked about, the authors solved the problem of language in a very original way. They made different groups of neonates: 6, 12, 18 and 24 months. In the familiarization phase, they presented objects in a background with a specific color. When the 4 groups were immediately applied to the test phase, all showed similar preferences to the novelty as long as the background color in the test phase was the same as in the familiarization phase. When it was not like that, and in the test a fund of another color was applied, only the babies of 18 and 24 months showed preference to the novelty. This shows that the babies’ memory is extremely specific. Small changes in the central stimulus or in the context can lead to the ability to recover.

The neurodevelopment of the hippocampus

To understand the neurodevelopment of the hippocampus and relate it to the behavioral events we have discussed, we must understand a series of processes related to neuronal maturation that are common in all areas of the brain.

First of all, we have the bias of thinking that “neurogenesis”, or the birth of new neurons, is all in which the brain development is summarized. That is a blunder. Maturation also implies “cell migration”, by which the neurons reach their proper final position. When they have reached their position, the neurons send their axons to the target regions they innervate and, subsequently, these axons will be myelinated. When the cell is already operational, the processes of “dendritic arborization” of the cell body and the axon will begin. In this way, we will obtain a large number of synapses – “Sinaptogenesis” – which will be largely eliminated during childhood based on our experiences. In this way, the brain makes sure to leave only those synapses that participate in operational circuits. In more adult stages, “Apoptosis” will also play a very important role, which will eliminate those neurons that, similarly to synapses, do not have a relevant role in neuronal circuits. Therefore, maturing in our brain is not about adding, but rather about subtracting. The brain is a spectacular organ and always seeks efficiency. Maturing is similar to the task performed by Michelangelo to carve his David from a marble block.

The only difference is that we are sculpted by our experiences, parents, loved ones, etc., to give rise to our phenotype.

If we observe the hippocampal neuroanatomy we will be surprised to know that most of the structures that are related to it (entorhinal cortex, subiculum, Ammonis horn …) can already be differentiated at week 10 of gestation, and at week 14-15 they are already differentiated cellularly. Cell migration is also very fast and in the first trimester it already resembles that of an adult. So, why, if the hippocampus is already formed and operational three months after the child is born, do we see so much difference in our experiments between children of 6 and 12 months, for example? Well for the same reason that I have already stressed in other entries: the hippocampus is not everything and neurogenesis is not either. The dentate gyrus – a neighboring structure of the hippocampus – requires a much longer period of development than the hippocampus and the authors claim that its granular cell layers mature at 11 months of age and would adopt a morphology similar to adulthood at one year of age. On the other hand, in the hippocampus we find different groups of GABAergic cells -small inhibitory interneurons- that have been seen to play an essential role in the combined processes of memory and attention.

GABAergic cells are those that take longer to mature in our nervous system and it has even been seen that GABA plays opposite roles depending on the age we observe. These cells mature between 2 and 8 years of age. Thus, much of the mnesic gradient observed in the capacity of coding, retention and recovery will be due to the maturation of the connections between the hippocampus and the dentate gyrus and, in addition, to the formation of the inhibitory circuits.

This is not ending here…

As we have seen, declarative memory depends on the medial temporal lobe (LTM) and the maturation of the dentate gyrus explains a large part of the differences observed in babies from 1 month to two years. But is that all? There is a question that we have not answered yet. Why is infantile amnesia? Or why do we not remember anything before the age of 3? Once again the question is answered if we leave a little time in peace to the hippocampus.

The maturation of the connections between the LTM and the regions of the prefrontal cortex have been related to a large number of mnesic strategies in the adult child.

Declarative memory is in continuous development during childhood and improves thanks to strategies in the capacity of coding, retention and recovery. Neuroimaging studies have shown that while the recall capacity of a story is related to LTM in children from 7 to 8 years old; in children 10 to 18 years old, it is related to both the LTM and the prefrontal cortex. Therefore, one of the main hypotheses that explain infantile amnesia are the scarce functional connections between the prefrontal cortex and the hippocampus and the LTM. Even so there is no definitive conclusion to this question and other molecular hypotheses about it are also interesting. But they are points that we will deal with on another occasion.

Conclusions

When we are born, the brain represents 10% of our body weight – when we are adults it is 2% – and spends 20% of the body’s oxygen and 25% of the glucose -this more or less the same as an adult-. In exchange for this, we are dependent beings who need the care of parents. No baby can survive on its own. We are an easy target in any natural environment. The reason for this “neuro-decompensation” is that the fetus and the baby have a considerable amount of learning mechanisms -some of them have not been mentioned here, such as the ability to “priming” -. There is something that all grandmothers say and it is true: babies and children are sponges. But they are because our evolution has demanded it. And this not only in humans, but in other mammals.

Therefore, declarative or explicit memory exists in babies, but in an immature way. To mature satisfactorily requires the experience and education of the social environment in which we are involved as gregarious mammals. But why study all this?

In a society that has focused its clinical attention on cancer and Alzheimer’s disease, more minor diseases such as infantile paralysis, autism, various learning disorders, ADHD -which exists, if there is one- are forgotten. epilepsies in children and a long etcetera (I am very sorry if I leave a lot more still unnamed minorities); that affect our children. They have delays in their school development. They also produce a delay and social rejection. And we are not talking about people who have completed their life cycle. We are talking about children whose insertion in society may be at stake.

Understanding normal neurodevelopment is essential to understand pathological development. And understanding the biological substratum of a pathology is essential to look for pharmacological targets, effective non-pharmacological therapies and to look for ways of early and preventive diagnosis. And for this we should not only investigate the memory, but all the cognitive faculties that are affected in the aforementioned pathologies: language, normal psychomotor development, attention, executive functions, and so on. Understanding this is indispensable.

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