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Summary Molecular Principles of Brain Disorders €5,29
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  3. Vrije Universiteit Amsterdam (VU)
  4.  
  5. Molecular principles of brain disorders (AM_1049)

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Summary Molecular Principles of Brain Disorders
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Comprehensive summary of this course with all the informative images! This summary regards the first 6 lectures. See my other summaries for the other lectures! I got graded this course an 8.5! :)

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  • 4 februari 2023
  • 38
  • 2020/2021
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Voorbeeld van de inhoud

HC 1: etiology of mental traits and disorders 27/10/20
Introduction
-Traits (in a biological way): impulsivity, mood, (anti) social behavior, stress-sensitivity, resilience and vulnerability are
behavioral traits.
• Each of these traits exists along a spectrum -> For example: impulsivity (extremely thoughtful, difficulties decision
taking – extremely impulsive)
-What is normal and abnormal behavior? Is normal what the most people do or what is healthy? Or botch?
-Which traits are a disorder or a variation?
-Other traits: IQ, extraversion, blood pressure etc.
-In this module we talk about mental traits and mental disorders!
-Disorders: diabetes, obesitas, autism (?), depression, schizophrenia -> Were traits become pathological.
-How do traits and disorders rise in general? What are the factors? Two groups:
• Genes/DNA -> nature
• Environmental factors -> nurture
o Can also be biological, like nutrition and pregnancy.
o Example -> trauma -> causes stress (big problem)
-Few years ago, some diseases were explained by nurture events, like a refrigerator mother can give rise to autism to her
child! And being gay was a result of an overly present mother.
• Later -> The role of biological factors became clearer (nature).
-Classic nature-nurture discussion -> a bit outdated.
• Hard reductionism -> “all psychiatric illness is best explained solely in terms of molecular neuroscience”.
-Etiology models for psychiatric disease need to be pluralistic or multilevel!
• Best understood from biological, psychological and sociocultural and economic perspective.
• Break down dichotomy between nature-nurture, but view brain as in constant interaction with environment,
society and culture via plasticity.
• Nature and nurture is a balance! They don’t stand in front of each toher.
-The most brain disorders are not multigenetic, but multifactorial disorders (also environmental factors ofcourse!).
-Often complex interactions and causal loops.
Genes and psychiatry
-Complex puzzle, puzzle parts -> genetics and environmental factors.
-From twin + adoption studies: several behavioural traits and psychiatric diseases moderate / high heritability.
• Heritability -> Proportion of variance in symptoms that is explained by the variance in genetic factors.
o Does not mean that if the heritability is 75%, that you’ll have a 75% change of getting the disorder if one
of your parents has it.
o It looks at a population level, a variation in all the people. What is the cause of the variation of their
symptoms? Is t due to genes or environmental factors?
o Means: for the whole population of the disorder 75% of the variation that you see in symptoms you can
explain through their genes. 25% you can expain by the variation by their environmental factors!
o Major depression -> 40-50%
o ADHD -> 75%
o Autism, bipolar disorder, schizophrenia -> around 80%
-Very difficult to find risk genes! But it is known that there are risk genes! What they did: compare the concordance
(overeenkomst) of a certain trait with monozygotic twins compared with dizygotic twins.
• Monozygotic -> Share 100% of the DNA, if the one has schizophrenia, a relatively very high change the other will
develop it as well.
• Dizygotic -> If monozygotic is 50% dor schizophrenia, this is 6-70% in dizygotic.
o Have about 50% of their DNA in common, but their environmental factors are the same (which also have
an influence on the envelopment of psychiatric disorders of course).
• So, comparing the concordance rate, if it is higher in monozygotic? -> heritability is higher (because more is the
results of genes).
• Missing heritability -> The unknown risk factors.
o What could be the reason that finding this genes is so hard? -> Thinking that one or a few genes are the
risk genes is too simply thought.
▪ Model of single / few risk genes -> overly simplistic paradigm
▪ Classing theory -> Single abnormal gene → abnormal gene product → neuronal malfunction →
mental illness.
• BUT it thus shows, that single abnormal gene is not sufficient to cause mental disorders!

, ▪ What is the pathway from gene to mental illness/phenotype? -> new explanations/new
hypothesis.
-New models explaining this pathway:
• Complex genetics / Diathesis(stress)-risk model (explained in this lecture)
• Differential Susceptibly to Environment Hypothesis (explained in ‘neurobiology of resilience’)
• Balancing Selection Hypothesis (explained in ‘mental illness and creativity’)
-These are complex models and the new wat of doing research is mainly via an endophenotype (-> genotype to
phenotype) approach.
-Complex genetics / Diathesis-risk model -> Predisposition (genetic) + environmental stress = disease (combination)
• A new paradigm, with the hypothesis: mental illness is caused by multiple small contributions from several genes,
all interacting with environmental stressors.
o One of the reasons why it is hard to find the risk genes (because there are a lot)
• You’ll inherit the risk and not the disease! -> Complex set of risk factors that bias person toward illness but do not
cause it.
• Reaching tipping point -> high probability developing disorder (when a lot of genetic and environmental risks
affects you).
o Like drops of water in a bottle and eventually one drop leads to disease, but it is not only this drup, but all
these drops together what cause the flood/disorder.
Endophenotype approach
-Pathway from genotype to phenotype is such a complex pathway, because between them there is so much going on!
-Solution -> endophenotype approach
• Track down important intermediaries between gene (genotype) and
disease/behavior (phenotype).
-Makes determining the pathway easier by the search of the endophenotypes ->
Variables that are somewhere in between the genotype and the phenotype.
• They are measurable, inheritable and closely linked to the disease!
• More precisely measurable than the illness itself. Otherwise it is
extremely difficult to diagnose a certain disease.
• Two types:
o Biological endophenotypes (comes as first in the pathway)
▪ Measurable biological phenomena:
• Electrophysiological response to startle (schrik)
o Example: abnormal response of startle
is associated with schizophrenia.
• Neuroimaging response to information
processing
o Example: activation levels of the
amygdala are above normal in anxiety and depression.
▪ This is more easily to measure then depression itself!
• Activation of certain brain circuit

, o Symptom/(or)system endophenotypes
▪ Single symptoms associated with mental illness:
• Insomnia
• Executive dysfunction
• Hallucinations
• Poor fear conditioning
• Anhedonia -> problem with experiencing pleasure
▪ Mental illness -> Diagnosed if you tick enough boxes (for now).
▪ Better to treat symptoms probably than treating the disease.
• Because the brain can look very different between one person with depression and
another person with depression.
-So, an endophenotype approach:
• Levels of genotype → molecules → circuits → information processing (biological endophenotype) → single
symptom (system endophenotype) → full syndrome of mental disorder
• Closer to gene on pathway > more readily linked to gene
o Endophenotype approach makes it far easier to link risk genes to endophenotypes (biological or
symptom) than to link it to the disease.
• Genes only loosely linked to psychiatric disorders, therefore hard to identify -> easier with this approach, because
you make it more measurable.
-Psychopathology and brain circuits:
• Etiology of psychiatric disorders is moving beyond receptors, enzymes and other molecules as causes for mental
illness. For example: “a psychosis is a consequence of too high levels of dopamine”, we did say that because we
did see that treating this molecule/neurotransmitter/receptor helped, so it must be the cause then, but we now
know that these disorders have a lot of factors that are involved in this disorder.
• New paradigm -> Psychiatric symptoms are increasingly linked to malfunctioning specific brain circuits.
o Because altered working of receptors/NTs/transporters etc results in a altered neurotransmission in the
synaps.
• Genes + environmental risk factors conspire to produce inefficient information processing in neuronal circuitry.
• Brain imaging -> focus on brain circuits.




-One thing is not included in this picture (above), what is this?

, -Why are subtle molecular abnormalities not more ‘penetrant’ at behavioral level? Why does a single altered gene not
directly lead to problems in the behavioral?
• Because: we have so much complementary/redundant backup systems! -> If there is something wrong is system
1, you’ll always will have system 2 who also can do the job (this is how our body works).
• So, risk genes are not necessarily sufficient to cause mental illness.
• SO, with this concluded, it is the combination with environmental risk factors (stress, life events, biological
stressors such as viruses, toxins etc).
• So, multiple systems are influenced (in a bad way).




Social-ecological framework & Environmental risk factors
-You have both risk decreasing and increasing factors!
-‘Social-ecological framework’ -> No single factor can explain, by the WHO (2014).
• Dynamic interplay of multiple risk and protective factors.
• Risk and protective factors: occurring along different levels -> ‘social ecology continuum’ (WHO, 2014):
o Individual (also genetic factors are individual factors)
o Relationship
o Cultural/environmental factors
-Individual risk factors:
• Genes (not environmental)
• Pre/peri natal (voor de geboorte of tijdens) risk factors:
o Maternal stress during pregnancy
o Maternal nutritional deficiency
o Maternal use of tobacco / alcohol / drugs / medication
o Birth complications:
▪ Perinatal nutritional deficiency (too low oxygen for example)
▪ Maternal separation -> Risk factor at level of the relationship
-Relationship risk factors:
• Abuse: sexual, physical or emotional
• Neglect (verwaarlozing)
• Poor parental care
• These factors have a very big influence -> suspects of the environmental risk factors.
-Environmental/biological environmental risk factors:

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