Answer: Plasticity is the brain’s capacity to adapt or to change over time by creating new neurons and building new networks.
2.
What does the term heritability mean?
Answer: This is the proportion of variance in symptoms that are explained by the variance in genetic factors (twin studies).
3.
What does the classic theory entail?
Answer: This theory states that a single abnormal gene leads to an abnormal gene product, which leads to neuronal malfunction and mental illness.
4.
What is the stress-diathesis model?
Answer: This model is based on the fact that predisposition of genes + environmental stress can lead to disease. The hypothesis states: mental conditions are caused by multiple small contributions from several genes, all interacting with environmental stressors. A complex set of risk factors can bias a person towards mental illness, but does not cause them. You can inherit the risk but not the disease itself.
5.
What does the term endophenotype mean?
Answer: These are variables that could measure the link between the genotype and the phenotype/inheritance and disease.
Answer: These are closer to the genotype and measure biological phenomena such as electrophysiological responses, neuroimaging, etc. Exaple: depression is linked to an overative amygdala.
8.
What are symptom/system endophenotypes?
Answer: These are closer to the phenotype side and are associated with symptoms in certain conditions. Exaple: insomnia, executive dysfunction, anhedonia.
9.
How does the stress system work?
Answer: There are two pathways, the fast- and the slow-acting pathway. The fast acting pathway works via the hypothalamus that sends a message through the spinal cord, which activates the sympathetic nervous system. This stimulates the medulla of the adrenal gland, which releases (nor)epinephrine into the circulatory system.
Long-term stress actives the slow-acting pathway. This pathway starts with the release of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) by the hypothalamus. This in turn triggers the release of ACTH from the pituitary gland that leads to the production of cortisol by the adrenal cortex (HPA-axis).
10.
How can the HPA stress system be shut down?
Answer: This happens when cortisol itself binds to glucocorticoid receptors (GR) in the brain, which shuts the system down by a negative feedback loop. Cortisol does this by altering gene expression/transcription.
Content preview
MPBD: Etiology of mental traits and disorders
Impulsivity, mood, (anti)social behaviour, The classic theory stated that a single abnormal
stress-sensitivity, resilience and vulnerability gene, leads to an abnormal gene product and that
are behavioural traits. Each of these traits leads to neuronal malfunction and mental illness.
exists along a spectrum. But a single abnormal gene is not sufficient to
cause mental conditions, but what is the pathway
Which factors can contribute to traits/ from gene to mental conditions? What is the
(mental) characteristics and brain disorders? relationship between the genotype and the
• Genetics phenotype? How can genes lead to certain
• Environmental factors such as pregnancy, behaviour? There are new models and
stress, family situation, food intake, war, hypotheses to investigate this pathway:
alcohol or concussions. 1) Complex genetics/diathesis-stress model
2) Differential susceptibly to environment
In the past, it was common to explain these hypothesis
diseases via a nurturing concept, for example, 3) Balancing selection hypothesis
that autism is caused by having a cold, distant
“refrigerator mother” or that homosexuality Stress-diathesis model
is caused by an overly present mother. Later Diathesis means risk. This model is based on the
they discovered that the role of biological fact that predisposition (genes) + environmental
factors is more “nature” than “nurture”. It is stress can lead to disease. The hypothesis is:
therefore important to break down the mental conditions are caused by multiple small
dichotomy between nature-nurture, and view contributions from several genes, all interacting
the brain as in constant interaction with the with environmental stressors. This is also called
environment, society and culture via complex genetics causes a complex set of risk
plasticity. Plasticity is the brain's capacity to factors that can bias a person toward conditions/
adapt or change over time by creating new illnesses but do not cause them, you can inherit
neurons and building new networks. the risk but not the disease itself.
There are new ways of research to unravel the
Most brain disorders are complex, pathways from genotype to phenotype, because
multifactorial disorders where both genetic the pathway is complex the solution is to use
and environmental factors are involved in the intermediaries between the genes and disease/
etiology. There are often interactions and behaviour.
causal loops involved.
Endophenotypes
Twin + adoption studies showed that several These are variables that
behavioural traits and psychiatric diseases could measure the link
are moderate/highly heritable. In between the genotype and
monozygotic twins the genes are 100% the the phenotype/inheritance
same, in dizygotic twins, this is 50%. and disease.
Heritability is the proportion of variance in There are two types of
symptoms that are explained by the variance endophenotypes:
in genetic factors. 1) Biological endophenotypes
On the population level, there is a 75% chance 2) Symptom/system endophenotypes
to develop ADHD of which 25% is caused by
the environment and 75% is explained in the Biological endophenotypes
genes. For autism, bipolar disorder, and These are closer to the genotype side and
schizophrenia this is 80%. measure biological phenomena such as
electrophysiological responses to startling,
By the time human genome sequencing was neuroimaging responses to information
possible they found out that there are certain processing, and activation of certain brain
“risk genes”. Though, this is an overly circuits. For example, depression is linked to an
simplistic paradigm since risk genes only overactive amygdala.
increase the risk of developing a certain
disease by a tiny amount.
,Symptom/system endophenotypes There is a social-ecological framework that cannot
These are closer to the phenotype and are be explained by one single factor. There is a
associated with single symptoms in certain dynamic interplay of multiple risks and protective
mental diseases such as insomnia, executive factors that occur along a social ecology continuum
dysfunction, hallucinations, poor fear (WHO, 2014). These factors are individual,
conditioning and anhedonia. relationship and cultural/environmental factors.
Genetic factors in this case fall under individual
Though it is easier to link the endophenotypes factors.
to genes than to the condition/disease, cause
genes are only loosely linked to psychiatric Pre/perinatal risk factors
conditions/disorders and therefore hard to • Maternal stress during pregnancy
identify. • Maternal nutritional deficiency
• Maternal use of tobacco/alcohol/drugs/
The etiology of psychiatric conditions is medications
moving beyond receptors, enzymes and other • Birth complications
molecules as causes. A new paradigm is that • Perinatal nutritional deficiency
psychiatric symptoms are increasingly linked • Maternal separation
to malfunctioning brain circuits. Genes and • Abuse
environmental risk factors conspire to produce • Neglect
inefficient information processing in neuronal • Poor parental care
circuitry. Brain imaging can be used to study
these brain circuits. An example of this is that Other risk factors
in depression the whole neuronal network • Infections
malfunctions instead of only one molecule such • Toxins
as serotonin. All the proteins play a role in the • Brain trauma
network and all of the subparts in the brain • Drug use
need to function properly for communication. • Stressful life events
• Low social economical status
• Poverty
• Community violence
• Lack of mental health care and stigmatization of
mental health problems
• Minority group position
• Cultural factors
• Religious factors
The stress system
How can these environmental factors exert their
But why are subtle molecular abnormalities influence? These factors can alter gene expression
not more penetrant at the behavioural level? via the stress system and epigenetics.
This comes to the fact that there is a healthy
compensatory backup system and risk genes
are not necessarily sufficient to cause mental
conditions/disorders since it is an combination
with environmental risk factors. We need 100+
different risk factors both in genes and
environment to develop a disorder.
The fast-acting pathway works via the sympathetic
nervous system and the slow-acting pathway uses
hormonal systems and involve the hypothalamus-
pituitary-adrenal (HPA) axis. During the fast-
,pathway the hypothalamus sends a neural Epigenetics
message through the spinal cord. The Life experiences can change a person’s mind
sympathetic nervous system is activated and through a chemical coating of the DNA. The genes
stimulates the medulla of the adrenal gland, on the DNA can be blocked so there is no access
which in turn releases epinephrine/ to the expression of these genes. So,
norepinephrine into the circulatory system. environmental programming of gene expression
Epinephrine then activates the cells in the leads to epigenetic changes.
body. When the stress is taking longer, the
slow-acting pathway is activated. This pathway In the nucleus of every cell, the DNA in
starts with the release of corticotropin- chromosomes is tightly wound around proteins,
releasing hormone (CRH) and arginine called histones, to make the long strand of DNA
vasopressin (AVP) by the hypothalamus. This fit into the cell. DNA packaging also controls the
triggers the release of ACTH from the pituitary expression of genes. For a gene to be expressed, a
gland, which leads to the production of chromosome must unravel so that a complex of
glucocorticoids (cortisol) by the adrenal proteins, including transcription factors, can
cortex. The responsiveness of the HPA axis to attach to the appropriate section of the DNA and
stress is determined by the ability of create an RNA molecule. This RNA is then
glucocorticoids to regulate ACTH and CRH translated into a protein. Some chemical changes
release by binding to the glucocorticoid alter gene expression without affecting the
receptor (GR) and shutting the HPA axis down genetic code. Adding methyl groups to cytosine
by negative feedback. Cortisol can activate all inhibits gene expression whereas adding acetyl
the cells in the body since every cell has a groups to histones loosens chromosome
cortisol receptor that works protectively and structure, making the underlying genes easier to
promotes adaptation. So, cortisol functions as transcribe.
a transcription factor and can alter gene
expression. Cortisol affects the heart rate, and Epigenetic programming by maternal behaviour
blood pressure, and can also suppress the In 2004 there was a breakthrough in
immune system. Because of this, the system neuroscience and psychology. Known was that
can be toxic to the brain/body. A healthy stress variations in maternal care affect the HPA-axis
system (HPA axis) has plenty of receptors response to stress in the offspring. Parenting
present in the brain so the system can be shut practices can profoundly shape a child’s
down. But if there is too much stress the level development and mental health and there is
of receptors is very low (low gene expression) evidence of this phenomenon via epigenetics.
and the system cannot be shut down. This
leads to an overactive system and if this goes
on for too long there is a higher risk for
depression or anxiety.
Early life stress can cause a lifelong overactive
HPA axis due to fewer glucocorticoid receptors
and less negative feedback to shut the system
down.
Researchers tested the hypothesis that when
there is a good quality of parental care there is
high levels of grooming and licking and the
offsprings of the mother have a normally
functioning stress system with low default
, cortisol, with a peak, when the animals are But we do not know the cause, is the methylation
stressed that goes back to the baseline level different due to the licking and grooming of
afterwards. The other part of the hypothesis is the mothers or is there another reason? A
that when there is the low-quality of maternal reason for this could be that methylation is there
care and low levels of licking and grooming, the because of the different LG behaviour of the
stress system of the offspring will be mother. Secondly, it could also be that it is
hyperactive and will cause high levels of inherited from the parents. Lastly, it could also
cortisol and when stressed the peak will be be just a genetic effect, so the mothers act
higher and will not go back to the normal differently because their DNA is differently
baseline. methylated. To test if this is true the pups of low
LG mothers are put together with high LG
The question is: is the promoter of the brain mothers and the other way around, this is called
cortisol receptor gene more heavily methylated cross-fostering. Graph D shows the results of
in offspring from low licking and grooming this, you can see that there is only a difference in
(LG) compared to offspring from high licking methylation on site 16 (5’ CpG dinucleotide). So,
and grooming? in the low LG pups that were fostered by high LG
mothers methylation was the same as in the
offspring of high LG mothers. But on-site 17 (3’
CpG dinucleotide) they have equal levels of
methylation. They also combined LL and HH as a
control of the effect of being taken away from the
mother, which could also have a (stress) effect on
the pups. If the genetics of the mother does not
affect the offspring it is expected to see no
change in methylation levels after they are
cross-fostered, but this is not the case. So,
methylation follows the behaviour of the foster
mother. The cross-fostering experiment gives
evidence that the causal effect of the genes of the
mothers is ruled out.
In graph E they only look at the biological
mother again. E20 is the embryo phase day 20
and P1 is the first day of birth of the offspring
from the biological mother. P90 is 90 days after
birth when the rats are adults. You can see that
at P1 there is de novo methylation at birth for all
rats. So, the methylation comes from a natural
Birth
mother foster mother de novo event of methylation at birth. After
birth, you can see that the groups of high LG
This figure shows a sequence map of the exon mothers have a decrease in methylation, which
1,7 GR promoter. Maternal care alters the stays for the rest of their lives. If there is low LG,
methylation of a cytosine of this GR promoter. the methylation stays present and does not go
In this promoter, there are 17 spots where this away. So low LG in the first 10 days of the rat's
can take place. Site 16 (5’ CpG dinucleotide) life causes the methylation to stay there for the
and 17 (3’ CpG dinucleotide) are crucial for the rest of its life. Thus, the behaviour of the mother
binding transcription factors to the DNA. influences the methylation patterns at crucial
spots for gene expression for crucial cortisol
First, they want to know whether there is a brain receptors. The hypothesis is that because
difference between the pups from low LG and of the methylation in specifically area 16 (in 17 is
high LG mothers on the methylation level. no difference in methylation), transcription
Diagram C shows that there is more factors cannot bind. But is it the methylation
methylation in the pups from low LG mothers, levels that causes the stress levels to be
which means that the DNA is more compact hyperactive? With the next experiment, they
and cannot be transcribed, there is lower gene wanted to check if low LG give high levels of
expression. So, the hypothesis is confirmed. methylation, which makes it harder for
transcription factors to bind, and because of that
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