| Abstract |
Neuroplasticity is the ability of the adult brain to learn new behaviours, to form new
memories and also to change the underlying neural circuit that is responsible for this learning.
This feature may be helpful against cognitive disorders that coincide with systemic nervous
changes, such as aging or the onset of schizophrenia. Thus, the question that arises is whether
innovative activities can lead to changes in basic cognitive function. One such activity is the
training of working memory, which is a very popular theme of study.
Working memory, as the ability to store and process information, is a fundamental cognitive
function. It is systematically considered essential for aspects of daily functioning, such as the
ability to retain attention. One way to improve working memory capacity is through training. A
large amount of research studies and several meta-analyses have tested the benefits of this
training and several of them arguing, whether training can lead to improvements of other
cognitive functions that are related to it. This ability, which constitutes cognitive transfer, is the
aim of this study. In particular, the present study seeks to investigate whether training of working
memory can improve cognitive flexibility in both human and mice. Cognitive flexibility is a
superior executive function, which can be defined as the ability to adapt behaviours in a
changing environment. One prerequisite for improving cognitive flexibility is that the two tasks
(training and transfer) must use a common neuroanatomical and neurophysiological background.
In the present study this is accomplished, since the neuroanatomical background of working
memory focuses on the prefrontal cortex, an upper area of the brain that supports executive
functions. The prefrontal cortex, however, is associated with both the hippocampus, the area that
supports spatial memory, and the orbitofrontal cortex, which supports adaptability to changing
rules.
In particular, the human study examined the effects of working memory training on
cognitive flexibility in a sample of 144 healthy participants, 18-43 years old (74: men & 65: women),
who were divided into three groups. In a)control group: participants had no involvement in the
study for six days following the baseline assessment session, b)partially adapted group: for six
consecutive days following the baseline assessment session, participants were administered the
LNS up to the strings with three digits and c)fully adapted group: for six consecutive days
following the baseline assessment session, participants were administered the LNS up to the last
string. One week after the baseline assessment session, all participants were administered the
Intra / Extra Dimensional Shift test (ID/EDS). During the baseline assessment session,
mouthwash samples of participants were additionally taken. The aim of this step was the
correlation of the performance of the three group of participants with specific genetic
polymorphisms, the COMT (rs4680) and BDNF (rs6265). The results showed a statistically significant effect of working memory training on cognitive
flexibility. More specifically, it turned out that the fully adapted group made less mistakes,
presented with fewer latency and made less efforts to complete the stages of the task compared
to the control group. Regarding gender, it was found that men compared to women participants
took longer to complete the nine stages of the ID / EDS test. However, no other sex differences
were observed in the cognitive flexibility task. Regarding the correlation between the genetic
background and the group, it was found that only in the control group, the participants carrying
the Met / Val allele (heterozygotes) needed a larger number of trials to complete the stages of the
task compared to the homozygous participants ( Val / Val and Met / Met) of control group and also
the heterozygotes participants of partially and fully adapted groups.
Using a similar experimental design, based on the second objective, the animal study
examines the effect of working memory training, using the Delayed Alternation Task (DAT) in the
T-maze, on cognitive flexibility. Specifically, 79 C57BL/6 mice, 2-9 month of age were used (67:
males & 32: females). The animals were divided into three groups, in: a)naive group: mice remained
in their home cage and had no involvement in the task, b)partially adaptive group: mice learned
to alternate arms but, without any delays in the delayed alternation task and c)fully adaptive
group: mice performed the alternation procedure with increasing delays of 10, 20, 30, 40 and 50
seconds, in the same task. The working memory training lasted nine days and two days later, all
the mice underwent a cognitive flexibility assessment task, the Attentional Set - Shifting Task
(AST). Also, in 15 animals of all three groups, the tasks of memory recognition of objects and the
contextual fear learning were performed. At the end of the behavioural tasks, 26 mice were
euthanised and their brains were removed and subject to Golgi-Cox staining technique and Nissl
staining.
The results show that the fully adapted group performed better, as it made fewer errors and
fewer trials to complete the stages of AST compared to the partially adapted group. This
improved image of the fully adapted group was observed in key stages of the task, one of which
require the shifting within dimension (Compound discrimination reversal -CDR). Also, in the
case of female mice, it was found significant differences in the latency in the same task, as it was
found that the fully and partially adapted groups presented with fewer latency in the cases of
right and total trials, in choosing one of the two bowls and the time finding the food reward,
compared to the naive group. Regarding age differences, it was found in Simple Discrimination
and Intradimensional Shift I stage, that the animals aged 6-9 months in the naive group
presented with decreased number of errors compared to the younger ones (2-5 months). Also, the
older animals in the partially adapted group needed a more trials to complete the
Extradimentional Shift stage compared to the younger ones, effect that was not observed in the
other two groups. These differences observed in the three groups in cognitive flexibility were not
observed in the tasks of memory recognition and contextual fear learning. Finally, with the use of Golgi Cox staining, it was found that younger male mice showed a higher density of total and
mature spines compared to the 6-8 months of age mice, in the areas of the prefrontal cortex and
hippocampus. Also, the fully adapted group showed an increased density of mature spines of the
prefrontal cortex (for both sexes) and hippocampus (CA1 region) (only for male mice) in
comparison with naive group. However, no differences were observed in the thickness of the
prefrontal cortex and hippocampus in the three groups, with Nissl staining.
In summary, the findings of this thesis support the importance of translation for
investigating the effects of working memory training on other cognitive functions. This multifaceted
approach contributes to better understanding of the effects of cognitive training and to
the attempt to explore the neural circuit that working memory training acts. The findings have
potential implications in the development of customised early intervention programmes in
populations at-risk, with mild forms of problem.
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Η επίδραση της εξάσκησης της μνήμης εργασίας σε γνωσιακές λειτουργίες και το νευροβιολογικό υπόβαθρο της σε ποντίκια και ανθρώπους
