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Summary Lectures Molecular Principles of Brain Disorders
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Molecular Principles of Brain Disorders lectures from Hylke Vervaeke.
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Lecture 1 – Etiology of brain disordersInteractions gene-environment:
Many environmental concepts can influence the expression of genes. So gene expression is a short
term adaptation to environmental circumstances. This can be both good and pathological. This can
be done through two pathways:
1. The stress system
2. Epigenetic modifications
Genes:
How do we know what the contribution of genes are in the etiology of certain disorders? Therefore
we need to use twin and/or adoption studies.
Heritability:
Heritability → proportion of variance in symptoms that is explained by the variance in genetic
factors.
The heritability of depression is 40-50%, the heritability to ASPD also is 40-50% and the heritability of
autism, bipolar disorders and schizophrenia is around 80%. So the variance in symptoms of
schizophrenia patients is 80% explained by the variance in genetic factors. So if the variety of
symptoms is more explained by the variety in genes, the heritability will be high. If the variety of
symptoms is more explained by the variety in environmental factors, the heritability will be low.
Heritability misconceptions:
1. If I have Schizophrenia, then 80% of my symptoms is due to genetic causes and 20% due to
environmental causes.
2. If one of my parents has Schizophrenia, then I have 80% chance to also get Schizophrenia.
Classic theory (not valid):
In the post human genome project era, people taught that a
single abnormal gene leads to an abnormal gene product,
which leads to neuronal malfunction which leads to mental
illness. However, this model does not take into account the
heritability. A single abnormal gene is not sufficient to cause
mental disorders.
,New paradigm: Stress-diathesis model:
Hypothesis: mental illness is caused by multiple small contributions from several genes, all
interacting with environmental stressors. This system is far more complex, so they call this new
paradigm: ‘complex genetics’. So the complex genetics is a set of risk factors that bias person toward
illness but do not cause it. This concept also applies to hypertension, obesities, diabetes etc. So a
person inherits a risk to a disorder and not the disorder itself.
Why are subtle molecular abnormalities not always more ‘penetrant’ at behavioural level? Because
we have a healthy compensatory backup system. So having risk genes is not necessary sufficient to
cause mental illness.
So this new model is called the Stress-diathesis model: A combination with environmental risk factors
(stress, life events, biological stressors such as viruses, toxins) with risk genes can cause mental
illness.
New paradigm: Brain circuits:
Psychiatric symptoms are increasingly linked to malfunctioning specific brain circuits. Genes +
environmental risk factors conspire to produce inefficient information processing in neuronal
circuitry. Brain imaging is used for brain circuits research.
Endophenotype approach:
Endophenotype → fragmentize a disorder and find risk
genes that are linked to a fragment
Important intermediaries between gene and disease.
→ Biological phenotype that is linked to a disorder, is
heritable and is easy to measure.
,These system endophenotypes can be
symptoms. For instance an increased
amygdala at depressions. You can look for
genes that cause this increased amygdala.
So the increased amygdala (symptom) can
be a fragment of the biological
endophenotype.
Molecular abnormalities (risk gene 1 or 2)
→ altered enzyme function →
overactivation of circuit A (biological
endophenotype) → this leads to a single
symptom (executive dysfunction) →
another risk gene (3) leads to
hypofunction of circuit B → symptom
endophenotype delusions → these
symptoms together form the phenotype
Schizophrenia. However, this
hypothetical path doesn’t take into
account the effect of environmental
factors.
In this model, the environmental
stressors are also taken into account. So
risk genes in combination with major
stressors can lead to dysfunction in brain
circuits. This leads to specific symptom
endophenotypes (symptoms) and these
symptoms together form the disease.
, Environmental factors:
Stress
Stress system:
1. Fast-acting pathway → (nor)adrenaline (fast-acting and not-long-lasting)
2. Slow-acting pathway → Endocrine system → Cortisol (slow-acting and long-lasting)
Hypothalamus and Pituitary gland are important → HPA (hypothalamic pituitary-adrenal) axis.
HPA (hypothalamic pituitary-adrenal) axis:
Body senses stress → hypothalamus secretes
corticotropin releasing hormone (CRH) onto the
pituitary gland → CRH binds to the CRH receptor
→ secretion of adrenocorticotropic hormone
(ACTH) → ACTH released into bloodstream →
binds to ACTH receptors on adrenal cortex →
release of glucocorticoids (cortisol) → binds to
cortisol receptor (GRs) → GRs will translocate into
the nucleus of a cell → and act as a transcription
factor (it can do so in all body cells) → effects like
increased blood pressure, suppressing immune
system, this can be on the long term very harmful.
Therefore, this system can be shut down via a
negative feedback loop. These negative feedback
parts are in the brain in the hypothalamus, hypophysis and hippocampus. It shuts down production
of CRH and ACTH (its own production). The amount of cortisol receptors (GRs) can vary between
individuals since it is a protein and coded by the DNA. A healthy stress system (HPA axis) is a stress
system with plenty of brain cortisol receptors!
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