Scientific Reports in Medicine, 2024; 1(1): 29-37

Scientific Reports in Medicine

ARAŞTIRMA

Molecular Basis of Learning and Memory

Molecular Alterations in Learning and Memory
Perçin PAZARCI1*

Abstract:
1
Dr. Perçin PAZARCI: Çukurova
As commonly known, learning is the process of acquiring a new in- Üniversitesi Tıp Fakültesi, Tıbbi
formation and memory is preservation of acquired information for Biyoloji Anabilim Dalı, Sarıçam,
later use. The difference in learning and memory capacities between Adana, Türkiye
different species and between different individuals of same species e-mail: [email protected]
directed scientists to research the causes of this. According to com- ORCID iD: 0000-0002-3708-0054
monly accepted approach these differences are due to the distinctions
in synaptic alterations. In collaboration with advancing molecular
techniques, the formation mechanisms of synaptic alterations, the rea-
sons of differences between them, the changes that occur in neurons
during learning and the changes that occur in neurons as a result of
memory became popular research subjects nowadays. The researches
that has been done are insufficient, however, many important findings
are obtained until now. The changes that occur in pre-synaptic and
post-synaptic neurons during simple non-associative learning, asso-
ciative learning, short term memory and long term memory have been
researched and different molecular mechanisms have been suggested.
Keywords: Non-Associative Learning, Associative Learning,
Memory, Long Term Potentiation, Synaptic Plasticity
 - 30 - Molecular Basis of Learning and Memory Scientific Reports in Medicine, 2024; 1(1): 29-37

INTRODUCTION Kandel and Schwartz (3) and Carew et al (4) can

be considered the most important and pioneering
In the world of neuroscience, one of the most
ones. Due to its ability to perform specific forms of
complex and fascinating mysteries is the process of
learning (habituation, sensitization, conditioning),
learning and memory. From the first steps taken by
the simplicity of its nervous system, the ease of
a newborn baby to the vivid memory of valuable
deciphering its genetic structure, and the presence
experiences in old age, the brain’s ability to acquire,
of large neurons, Aplysia californica (sea slug)
store and recall information is truly remarkable.
is currently the most commonly chosen model
Over the years, scientists have delved deeply into
organism in research on learning and memory(5).
the neural underpinnings of this phenomenon,
uncovering a complex molecular fabric that brings Learning
together the essence of learning and memory.
Learning styles in living things can be divided
Although there are many different definitions of into many subcategories such as non-associative
learning and memory made by different branches learning, associative learning, imitation, learning
of science such as psychology, sociology, neurology, by watching and listening, and learning through
if we put these definitions together in the simplest experience. Since most of these categories are the
form, learning is the act of acquiring new knowledge areas of interest of psychology and neurology, this
(or ability, behavior, preferences, values, etc.), article will focus on non-associative learning and
and memory is the storage of this information associated learning, which are the basic learning
permanently to be used later when necessary. The styles on which molecular research focuses. The
capacity to learn and remember what has been reason why molecular research focuses on these two
learned is the biggest feature that makes humans subunits is that the results cover one or a few neurons
different from other living creatures. Just as there are and their results give an idea about the functioning
differences in the capacity to learn and remember of the entire system.
among different species, the fact that there are also
Non-Associative Learning
differences between individuals of the same species
has led scientists to search for the reasons that create Non-associative learning can be defined as making
these differences. Especially in recent years, with an inference directly from a situation without
the advances in molecular techniques, previous directly associating it with another event(6). This
neurology and psychology studies have gained a learning form is examined in two subcategories:
different dimension, and the molecular mechanisms habituation and sensitization.
that play a role in the ability to learn and remember Habituation is the state in which the response
have become an important research area. in animals decreases as they are exposed to a
Memory and learning were defined as a repetitive stimulus for a certain period of time(7).
result of synaptic alterations by Hebb (1), who It is a different form of integration. If an animal is
carried out very important studies in the field of exposed to a stimulus and reacts, but later realizes
neuropsychology. Today, although this idea is still that this stimulus is not harmful or beneficial, it
accepted to some extent, it is argued that learning concludes that the stimulus is meaningless and its
and memory are not only a result of these alterations, response gradually decreases with repeated stimuli,
but that many mechanisms within neurons are also or its response may even stop completely. A simple
very important in these two events(2). Research on example of this is the behavior of small birds. When
the second idea has generally intensified after the these birds see a large predator bird placed in a cage,
1980s, and studies have been conducted on many they reflexively start to run away. However, if the
different model organisms. Among these studies, stimulus is repeated in the same way, it realizes that
the predator cannot reach it and stops its reaction.
Scientific Reports in Medicine, 2024; 1(1): 29-37 Pazarcı et - 31 -

Sensitization is the sudden increase in the Following this stage, the question “What triggers
response to a repeated stimulus above the normal these different responses?” arose, leading to an
level or an increase in the response to the same investigation of the changes occurring in neurons
stimulus after habituation, typically by changing after habituation and sensitization. During the
the stimulus(7). Using the example given above, if first and next few touches to the siphon, neurons
the predator bird is released from its cage, the prey generate action potentials in a normal manner.
bird’s response will be greater than usual because the However, as the number of stimulation increases,
stimulus has suddenly changed, catching the prey calcium channels at the axon ends of pre-synaptic
bird unprepared. Another example of sensitization neurons (sensor neurons) are partially inactivated
could be a person rubbing his arm. The first reaction and the amount of neurotransmitter substance
this person will give will be the same as the reaction secreted to post-synaptic neurons (motor neurons)
he would give to the slight warmth he would feel. decreases. As the number of stimuli increases, more
However, if the stimulus (rubbing) continues to be calcium channels become inactivated, resulting in
repeated, the warmth may start to be perceived as a decrease in the response. Even when there is a
pain, leading to a change in the response. break of several hours in touching the siphon, very
These two simple forms of learning have been little response is elicited from the organism upon
observed in all living things with a nervous system subsequent stimulation(3). This has been considered
and have molecularly the same dynamics(8). Kandel as the simplest learning dynamic.
and Schwartz (3) first explained the molecular In the next phase of the study, an electric shock
mechanism and formation of these learning styles was given to the head area of the organism. It was
with their research. In their study, the behavior of found that this shock stimulated the third group of
Aplysia californica was examined. This organism neurons seen in Figure 1 and triggered the release
has a structure called a siphon, and it possesses of serotonin from these neurons(3). As shown in
sensor neurons connected to this region (Figure Figure 2(10), it was found that the released serotonin
1)(9). These sensor neurons are linked to motor subsequently triggered cAMP synthesis in sensor
neurons that control the gill muscles. When the neurons, and cAMP activated protein kinases. The
siphon is touched or stimulated, the interaction of activated protein kinases then inhibited serotonin-
these neurons results in the organism retracting its sensitive potassium channels, reducing their activity.
gill through a coordinated response (gill withdrawal As a result, due to the potassium channels responsible
reflex). In the conducted study, the contraction for repolarization in neurons, the decreased activity
potential of the gill muscles was measured in leads to prolonged action potential duration.
response to the initial stimulation of the siphon and Consequently, it was concluded that the calcium
with an increasing number of stimuli. It was observed channels at the axon terminals remained open for
that this potential gradually decreased with each a longer duration, resulting in an increased release
subsequent stimulation (habituation)(3). Following of neurotransmitter from sensor neurons(3). As
the habituation phase, the organism’s head region one might predict, the increased neurotransmitter
was subjected to an electric shock, and then, when amount will lead to more stimulation in the post-
the siphon was touched, the contraction potential synaptic region and confirm the observed situation.
of the gill muscles was measured. Interestingly, it In many subsequent studies with different organisms,
was observed that this potential was significantly similar results have been found, and it is generally
higher than the normal potential (sensitization)(3). accepted that basic forms non-associative learning
are consistent across various species(11).
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Figure 1. Representation of the nervous system of Aplysia California

Figure 2. Short-term sensitization. (1) Binding of serotonin to G-Protein coupled receptor. (2) Stimulation of cAMP formation.
(3) Binding of cAMP to the regulatory subunit of Protein Kinase A (PKA). (4) Catalytic subunits of PKA phosphorylate
potassium channels. (5) Closing of potassium channels, prolongation of action potential duration, more calcium inflow. (6) More
neurotransmitter release as a result of excess calcium(10).
Scientific Reports in Medicine, 2024; 1(1): 29-37 Pazarcı et - 33 -

In studies conducted in subsequent years, it have intensified interest in this subject. Kandel (15)
has been frequently claimed that habituation and demonstrated that Aplysia californica can learn
sensitization are not only short-term but also lead through classical conditioning and explained changes
to long-term learning(12). Various research has at the molecular level. In the conducted study, the
been conducted on this subject. Dash et al (13) snails were first subjected to an electric shock to the
proposed, contrary to the mechanism described head region, followed by touching their siphon. As
above that remains active for a short period, that previously indicated, an increased response in the
for this simple form of learning to be long-lasting gill withdrawal reflex was observed compared to
and transform into a kind of memory, some form of normal. A second group of Aplysia was not subjected
protein synthesis is necessary. In their research on to electric shock and served as the control group. It
this subject, they hypothesized that cAMP not only was found that, after a certain period the snails in the
activates protein kinases but also binds to Cyclic first group exhibited a heightened response when
AMP Response Element-Binding proteins (CREB). their siphon was touched even without receiving
As it is known, CREBs perform functions that electric shock, compared to the control group.
regulate transcription in the cell. The results of their Furthermore, this heightened response could extend
research indicated that the activation of CREBs leads for up to 3-4 weeks depending on the frequency
to changes in the number of potassium channels of electric shock application. Subsequently, the
sensitive to various neurotransmitters and voltage- neurons leading to the sensor neuron from the head
gated calcium channels. They have suggested that region of the snails that received electric shocks were
this plays a role in the permanence of learning(13). destroyed, after which their siphon was touched.
In subsequent similar studies, it was observed that Surprisingly, it was measured that the organisms
organisms given CREB inhibitors during habituation exhibited the same intensity of reflex(15). This led
or sensitization were unable to convert this short- to the conclusion that the changes were not due to
term learning into long-term learning(14). This alterations in the neurons originating from the head
observation supported the idea that CREB plays region involved in conditioning, but rather resulted
a crucial role in the conversion of short-term into from changes in the neurons originating from the
long-term learning. siphon. These changes were then investigated. It
was found that repeated electric shocks increased
Associative Learning
serotonin release from neurons originating from the
Associative learning can be categorized into classical head region, leading to longer opening of calcium
conditioning and operant conditioning. Classical channels. However, with the continuous repetition
conditioning is defined as the triggering of one of electric shocks, it was observed that the calcium
stimulus by another independent stimulus when levels in neurons increased significantly. Due to the
they are perceived consecutively for a long time. It excess calcium levels, some of the calcium binds to
was first discovered by Ivan Pavlov as a result of his calmodulin. The resulting complex was observed
research on dogs. to activate a type of adenylate cyclase called
Operant conditioning is the regulation of calcium-calmodulin-dependent adenylate cyclase,
subsequent behaviors according to the consequences which is found exclusively in neurons. It has been
of a behavior. This concept was initially introduced suggested that instead of the short-lived activation
by Edward L. Thorndike. The increased permanence via G-protein seen in classical sensitization,
of these two types of learning and the greater the stable structure of the calcium-calmodulin
resemblance of the mechanisms influencing long- complex triggers the synthesis of cAMP in the cell
term memory compared to non-associative learning for a prolonged period, thereby ensuring that the
 - 34 - Molecular Basis of Learning and Memory Scientific Reports in Medicine, 2024; 1(1): 29-37

conditioning is not forgotten for a certain period of (17) found that N-methyl D-aspartate receptors
time(15). This study, while not explaining situations (NMDAR) and amino-3-hydroxy-5-methyl-4-
where conditioning lasts for an extended period, has isoxazolepropionic acid receptors (AMPAR) in
shed light on medium-term memory in organisms. the postsynaptic neuron are activated by a type of
protein kinase called continuous kinases. NMDAR
Memory
and AMPAR are ionotropic glutamate receptors,
Memory is generally studied under two main and when glutamate binds to these receptors, they
categories: short-term and long-term memory. Short- allow the entry of cations such as calcium, sodium,
term memory involves the immediate processing and and potassium into the cell(10). According to their
evaluation of stimuli from sensory organs, followed findings, an enzyme called ubiquitin hydrolase
by its rapid decay. The molecular dynamics of short- is produced in the postsynaptic neuron that is
term memory are generally accepted to be similar continuously stimulated together, and the amount
to those of simple non-associative learning, as of ubiquitin in the postsynaptic region is reduced
described earlier. Since necessary information about in this way. Ubiquitin is known to mark proteins
this topic has been provided above, this section will for degradation, and as a result of its decreased
focus on long-term memory. amount, the duration of activity of proteins in the
According to neuroscience, synaptic alterations postsynaptic region is prolonged. Consequently,
form the basis of all memory, as mentioned earlier. continuous kinases emerge, and the activities and
These alterations include Long-Term Potentiation permeabilities of NMDAR and AMPAR change.
(LTP), Long-Term Depression (LTD), and When this situation persists, SP and LTP occur(17).
Synaptic Plasticity (SP)(16). Briefly, LTP refers According to the second proposed model,
to the long-lasting and persistent enhancement the strength of the synapse between two neurons
of communication between two neurons that are is dependent on the number of ion channels it
continuously stimulated together. LTD, on the possesses(18). In a dynamic state, NMDAR and
other hand, is the opposite, involving a long-lasting AMPAR are continuously balanced through
decrease in the connection between two neurons. exocytosis and endocytosis. However, changes in
SP encompasses the ability of synapses between two synaptic activity between two neurons can shift
neurons to change their interaction depending on the this balance towards the addition or removal of
current situation(16). While studies in neuroscience new NMDAR and AMPAR, resulting in either
have revealed many findings about which brain LTP or LTD(19). Additionally, in LTP, it has been
regions are active during specific activities, they determined in various studies that these types of
have not fully explained the reasons behind LTP, receptors outside the synaptic region are encouraged
LTD, and SP occurring in different brain regions. to undergo endocytosis by dynamin and clathrin
To elucidate these reasons, numerous studies are and are subsequently transported to the synaptic
ongoing, utilizing advancing molecular techniques. region(20).
The aim of these studies is to uncover the molecular Hawkins et al (21) investigated the changes
mechanisms underlying long-term learning and occurring in the presynaptic neuron during LTP and
memory. SP through their research. They suggested a model
Two different perspectives have been proposed where a series of activations and protein syntheses
for molecular bases of these changes. The first one work together and influence long-term memory. The
suggests that synaptic function changes as a result proposed model resulting from this study is depicted
of modifications in synaptic proteins. Shi et al in Figure 3(22).
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Figure 3. Changes in the pre-synaptic neuron in LTP and SP. (1) Short-term strengthening of synaptic connection as a result of
neurotransmitters. (2) Balance of kinase and phosphatase activities at the synapse. (3) Retrograde transport from synapse to nucleus.
(4) Activation of transcription factors. (5) Activity-dependent induction of gene expression. (6) Chromatin alteration and epigenetic
changes. (7) Capture of newly synthesized products by synapses. (8) Stimulation of local protein synthesis in active synapses (9)
Development of the synapse and formation of new synaptic regions. (10) Activation of pre-existing silent synaptic regions. (11)
Stimulation of other nearby neurons by self-triggering molecular mechanisms(22).

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Funding: No funding is used for the study

Conflict of Interest: Authors declare no conflicts of interest

Ethical Declaration: Since this study is a review article, ethics committee approval is not required, and the
Helsinki Declaration rules were followed to conduct this study.