Trends in Neuroscience and Education 4 (2015) 108–111

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Trends in Neuroscience and Education

journal homepage: www.elsevier.com/locate/tine

Opinion article

Epigenetics and learning

Birgitta Mc Ewen
Department of Health Sciences, Faculty of Health, Science and Technology, Karlstad University, SE-651 88 Karlstad, Sweden

art ic l e i nf o a b s t r a c t

Article history: Epigenetics, the new field of biology, has given us a scientific explanation model for how the environ-
Received 1 June 2015 ment influences gene expressions. ‘Epi’ means ‘above’ and describes mechanisms that are situated
Received in revised form ‘above’ the base-pair order in the DNA. The benefits of our increased understanding of epigenetics en-
15 October 2015
compass many fields, among them learning. Since the same epigenetic mechanisms seem to be involved
Accepted 9 November 2015
Available online 14 November 2015
in learning, stress and physical exercise, we have a scientific tool to conduct investigations of the cor-
relations between these. In a broader sense, epigenetics brings scientific data to the classical gene-en-
Keywords: vironment-debate. It is important for school staff and school policy-makers to grasp the key concepts of
Epigenetics epigenetics, as it probably soon will be part of the scientific literacy.
Learning
& 2015 Elsevier GmbH. All rights reserved.
Physical exercise
School staff
Stress

1. Introduction arguments would extend and enrich this classical gene-environ-

The new findings of epigenetics influence a great number of
fields, among them learning. It is, therefore, important to under-
stand the key concepts of epigenetics and realize its potential.
Epigenetics deals with the environment's influences on genes and
interactions in gene expressions. For the first time, we now have a
scientific molecular explanation model for how the environment
can interact with genes.
Epigenetic mechanisms seem to be important regulators of
cellular processes throughout the whole life of an organism
[18,34]. It is involved in how an organism develops itself from a
fertilized egg [4]. Epigenetic processes have been shown to occur
during adolescence [8] and adulthood [7]. In this sense, epige-
netics imbues all biology, and has changed our view of the central
processes of life. It has to be stressed that epigenetic mechanisms
should be regarded as an addition and complement to already
known physiological mechanisms.
It has been suggested that epigenetic processes occur during
learning [18,19,7], stress [10,39,6] and physical exercise [1]. The
epigenetic mechanisms seem to be the same [1,39,7]. We are just
in the beginning of understanding the potential epigenetic corre-
lations between learning, stress, and physical exercise. This is an
example of how the environment can influence the expression of
genes, in the sense that e.g. physical exercise could have an effect
on learning. From a broader perspective, epigenetic knowledge
could have consequences for our discussions about What-is-due-
to-genes? and What-is-due-to-the-environment? New epigenetic
E-mail address: birgitta.mcewen@kau.se
ment-debate with scientifically-based facts. The concept of ‘social
inheritance’ is also part of this debate, which ought to be more
nuanced with scientific facts from the epigenetic explanation
model.
As epigenetics probably will influence a lot of areas where
knowledge in biology is crucial, it is important for school staff and
school policy-makers to grasp the key ideas of epigenetics and its
potential benefits for society. This article will give a brief overview
of the current state of affairs in epigenetics and learning. It also
deals with possible links between learning and stress, and learning
and physical exercise, respectively, as the epigenetic processes are
thought to be the same in all these physiological states.
2. What is epigenetics? – definition and mechanisms
The term epigenetics was first coined by Waddington in 1968,
as a way to describe the ordered interactions in the development
of an embryo with genetics (see [38]). The word epigenetics comes
from the Greek epi, ‘over, above, outer,’ and describes mechanisms
above genetics, that is above the order of base-pair nucleotides in
the DNA constituting the genes. Gilbert and Epel [12] defined
epigenetics as ‘those genetic mechanisms that create phenotypic
variation without altering the base-pair nucleotide sequence of the
genes’ (p. 12).
Epigenetic mechanisms constitute many different modifica-
tions on chromatin [16,28]. Chromatin, which is the DNA and its
associated proteins the histones, could be more or less packed. It is
well accepted that when the chromatin configuration is ‘open’ or
‘loose,’ DNA is accessible and could be transcribed with an

http://dx.doi.org/10.1016/j.tine.2015.11.002
2211-9493/& 2015 Elsevier GmbH. All rights reserved.
 B. Mc Ewen / Trends in Neuroscience and Education 4 (2015) 108–111
increased expression of genes as a consequence [12]. On the
contrary, a ‘closed’ or ‘tight’ chromatin configuration makes the
DNA inaccessible with the consequence of no genes being ex-
pressed. The most studied modifications are DNA methylation,
histone modifications, and epigenetic control mediated by small
regulatory RNAs, especially microRNAs, miRNAs [32].
3. Brief review of the current state of affairs
3.1. Epigenetics and learning
Epigenetic mechanisms are suggested to have a role in learning
and memory formation and storage [18,19,24–26,7]. Two regions
in the brain are of special interest: the hippocampus, which is
critical for memory consolidation but not essential for long-term
memory storage [7], and the cortex, the site for long-term memory
storage [25,31]. Day and Sweatt [7] speculated that there are two
different epigenetic mechanisms, one that participates in the
consolidation in the hippocampus, and another that participates in
the memory storage in the cortex. The authors also speculated that
there ought to be a fundamental difference between these two
mechanisms. Hippocampus needs to be plastic and be reset after
each consolidation, while the cortex would promote stability to
promote long-term maintenance of memory. To exemplify this, a
study by Day and Sweatt [7] showed that fear conditions produced
transient changes in the DNA methylation in the hippocampus, but
prolonged changes in the DNA methylation in the cortex.
Establishment of new active synaptic connections in the brain
is crucial during learning and memory formation [5]. These au-
thors stated that epigenetics has been shown to be one of these
mechanisms, which generates and maintains changes in the sy-
naptic plasticity and memory formation. According to Lipsky [19],
each of the three epigenetic mechanisms, DNA methylation, his-
tone modifications and miRNA activities, are critical to learning
and memory formation, and their activities show a high degree of
tissue specificity. Cortés-Mendoza et al. [5] speculated that epi-
genetic modifications could differ between various types of neu-
rons, and in different parts of the brain. These authors stressed
that further research is needed to better understand the me-
chanisms by which cognitive epigenetic modifications are gener-
ated, maintained, and removed.
3.2. Epigenetics and stress
Epigenetic mechanisms are also discussed to be part of the
stress-related symptoms. It is important to underline that this
research area is in its infancy. Only a few studies have investigated
human adolescent stress in the context of epigenetic mechanisms,
of which two are reported here: Essex et al. [8] and van IJzendoorn
et al. [36]. These studies discuss possible long-lasting effects of
stress on the epigenetic pattern in human adolescents. More stu-
dies have been performed in animal models, and some of these
will briefly be described below. Although not directly applicable to
a school situation, the mentioned articles suggest connections
between epigenetic mechanisms and stress.
Essex et al. [8] showed correlations between parent reports of
high levels of stress during their children's infancy and preschool
periods and differences in DNA methylation, when the children
were fifteen-year-old. The sample was comprised of 109 adoles-
cents, taken out from a group of 570, and compared to the rest of
the group. DNA was derived from buccal epithelial cells. The study
of van IJzendoorn et al. [36] reported epigenetic pattern changes in
a study with 143 adopted individuals with an average age of 39
years. The individuals were interviewed about their childhood
attachment experiences, current relationships with their adoptive
109
parents, and experiences of loss and trauma. DNA was obtained
from the lymphoblast cells. It was shown that unresolved loss or
other trauma was correlated with a changed DNA methylation
pattern. Unresolved loss or trauma is strongly associated with
posttraumatic stress symptoms [2].
Connections between epigenetics and stress-related symptoms
have been studied in animal models [10,11,21,23,39,6]. The study
by Weaver et al. [39] shows that adverse circumstances early in life
could influence the rest of an organism's life. In their rat model,
the connection between the epigenetic mechanisms and life-long
stress symptoms was described. Maternal behavior toward her
offspring the first week after birth decided the level of methylation
at a special gene site. The more intensively the female rats
groomed and licked their pups, the more glucocorticoid receptors
were later found in the offsprings' brains, and this pattern was
mediated through epigenetic mechanisms. More glucocorticoid
receptors are associated with a higher ability to deal with stress
[12]. Thus, maternal behavior, just after birth, influenced the
whole lives of the offspring.
Similarly, the adult brain reveals epigenetic marks upon stress.
In a model with adult rats, acute stress induced rapid changes in
the histone methylation after less than two hours [21]. The
changes persisted for at least 24 h. This suggests that changes in
the chromatin formation are much more dynamic than previously
believed, and might be one factor in the brain's response to stress.
McEwen et al. [21] stated, “The adult, as well as developing brain,
possess a remarkable ability to show reversible structural and
functional plasticity in response to stressful and other experi-
ences” (p. 3). Correlations between epigenetics and stress are also
described by Hunter [15], who discussed interactions between
stress and corticosteroids and epigenetic mechanisms in the brain.
Other studies show that stress early in life induces epigenetic
changes and could be a risk for life-long depression [27]. Fur-
thermore, environmental stressors during childhood and adoles-
cence are discussed to result in neuropsychiatric disorders in
adulthood [29].
3.3. Epigenetics, learning, and stress
The epigenetic mechanisms described in stressful situations
and during learning and memory storage seem to be the same
[39,7]. Yet, there are only a few studies that touch upon the effects
of stress on learning in light of epigenetic mechanisms. Mifsud
et al. [22] discussed the role of synergetic interactions between
different pathways in response to stress and learning and memory
formation. The authors speculated, “Epigenetic mechanisms and
their role in memory formation may therefore be the molecular
basis for the crossover between stress studies and learning para-
digms” (p. 1312). Furthermore, McClelland et al. [20] discussed
that chronic early-life stress could result in deficits in the structure
and function of neurons in the hippocampus, implicating influ-
ences on learning and memory formation throughout life. Thus,
there are speculations about correlations between learning and
memory storage on the one hand, and stress on the other, through
epigenetic mechanisms.
3.4. Learning and physical exercise
Evidence is accumulating that physical activity promotes aca-
demic achievement [3,30,33,35,9]. An intervention program with
an almost double amount of school-based physical activity, in-
cluding circa 200 children in grade 5 in a Swedish, medium-sized,
city was performed by Käll et al. [17]. As a result, the children
increased their odds for achieving the national learning goals in
Swedish, English, and mathematics two-fold, compared to chil-
dren not participating in the program. Evidence shows that
110 B. Mc Ewen / Trends in Neuroscience and Education 4 (2015) 108–111
exercise has profound benefits on the brain and improves learning
and memory [37]. Gomes da Silva et al. [13] showed that early-life
exercise improved spatial learning and memory, and induced po-
sitive changes for both the structural and functional formation of
the hippocampus. Thus, there seems to be a correlation between
physical exercise and learning.
3.5. Epigenetics, learning, and physical exercise
One of the few studies encompassing an epigenetic approach to
physical activity and learning is from Abel and Rissman [1]. The
authors reported that physical exercise was associated with posi-
tive neural functioning, and that this was correlated with a
changed epigenetic pattern in the brain. The authors used a model
with adolescent male mice, where expression levels of genes as-
sociated with epigenetic modifying enzymes were assayed in two
regions of the brain. Gomez-Pinilla et al. [14] showed that volun-
tary exercise changed the rats' DNA methylation pattern in the
hippocampus for the molecule brain-derived neurotrophic factor
(BDNF), which is important for the rat's hippocampal learning. The
authors pointed to the importance of exercise to control gene
transcription, in the context of brain function and plasticity. Thus,
there are indications that epigenetic mechanisms could be corre-
lated to the connection between physical exercise and positive
neural functioning.
3.6. Connections between learning, stress, and physical exercise from
an epigenetic perspective
More and more studies point to the importance of epigenetic
processes in learning and memory formation. Studies have shown
that epigenetic processes occur in those parts of the brain where
learning and memory formation is situated [19,26,7]. Epigenetic
processes are also described in the research about stress and
physical exercise, respectively. It has become apparent that the
same epigenetic mechanisms are found in the processes of stress,
physical exercise, learning, and memory formation. Thus, we have
added a new tool to understand the correlations and connections
between learning, memory formation, stress, and physical exercise
on a molecular level. Knowledge about epigenetic processes is a
new bridge between these.
4. Conclusion
Thanks to the progress within the understanding of the epi-
genetic processes, we now for the first time have a scientific mo-
lecular explanation model for how the environment influences
gene expressions. This will probably have a great impact in nu-
merous fields, among them learning. The learning process in itself
seems to be regulated by the epigenetic processes. Furthermore,
conditions that could influence learning, such as stress and phy-
sical exercise, also seem to be regulated by epigenetics. Upon
combining these findings, we are at the starting-point of under-
standing how conditions like stress and physical exercise might
influence learning through epigenetic mechanisms. From an even
broader perspective, this could have implications for our under-
standing of the classical gene-environment-debate; moreover, we
are now at the beginning of giving a scientific explanation to the
concept ‘social inheritance’. It is important to use scientific, well-
founded, arguments in the debate; the new knowledge of epige-
netics brings such valuable data. Knowledge about epigenetics is
predicted to soon be part of the scientific literacy. It is, therefore,
important that the key principles of epigenetic processes and its
consequences for individuals and society are understood by school
staff and school policy-makers and that they are taught to the
students in schools.
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