Molecular Principles of Brain Disorders
Introductiecollege 28/10
Study powerpoints and literature on canvas.
,Etiology of mental traits and conditions
In the past there was a tendency to explain disease via nurture.
Brain plasticity causes everything around you to be able to modulate your brain wiring and
behaviour. Most brain disorders are complex and multifactorial disorders.
Studying twins gives a clear image because they spend the same time in the womb en
monozygotes share 100% same dna. These studies give us an inside in the role of genes.
There are so many riskfactors which could contribute but the largest role is gene factors. It is
very difficult to find all the risk genes and all the possible combinations.
Too simplistic: Classic theory:
single abnormal gene→ abnormal gene product→ neuronal malfunction → mental illness
Then what is the pathway from gene to phenotype? These are new hypotheses:
1. Complex genetics or diathesis-stress model (this lecture)
2. Differential susceptible to environment hypothesis (lecture neurobiology of resilience)
3. Balancing selection hypothesis (lecture mental illness creativity)
Stress- diathesis model
Mental conditions are caused by multiple small contributions
from several genes, all interacting with environmental stressors.
People can have a genetic predisposition and in combination
with environment.
So you inherit the risk but not the disease itself. There are even
genes that prevent you from having the disease. COMPLEX
Endophenotype approach
Path from gene to mental illness. So genotype to phenotype
which sounds easy but is very complex. There are
intermediaries between the genotype and the phenotype so the
gene and the disease/behaviour.
Endophenotypes are measurable inheritable variables closely
linked to the disease. Two types:
Bio endophenotypes: Measurable biological phenomena
- Electrophysiological response to startle
- Neuroimaging response to information processing
- Activation of certain brain circuit
symtom/system endophenotypes: single symptoms associated
with mental disease/condition
- Insomnia
- Executive dysfunction
- Hallucinations
- Poor fear conditioning
- Anhedonia
genes>molecules> circuits>infomation processing>single
symptom> full syndrome of mental condition
,Psychiatric symptoms are increasingly linked to malfunctioning specific brain circuits.
Environmental factors
Altered gene expression via stress system and epigenetics.
There are individual (genetic), relationship and environmental factors.
pre/peri natal risk factors: maternal stress, nutrional deficiency, drugs are important
riskfactors. Also abuse, infections, trauma, stress, etc.
This system needs to be able to shut down. It uses cortisol that controls the stress system by
binding to brain cortisol receptors which is a protein in the hypothalamus. Negative feedback
loop. When there are not enough receptors it causes your stress system to get hyperactive.
Not enough receptors could be due too much early life stress causing life long overactive
HPA axis so less gr = less negative feedback to shut system down. Dan kan je dus niet
zoveel aan als normaal. Hpa axis.
Epigenetics
Life experiences → literally change person's mind
Chemically coating the DNA. ease or block access to genes on DNA. coating alters gene
expression, but not genetic code. Environmental programming of gene expression.
Epigenetic changes by unravelling the chromosome.
variation in maternal care affects HPA axis responses to stress
in offspring. Parenting practices can profoundly shape a child's
development and mental health.evidence via epigenetics.
READ ARTICLE FOR EXAM focus on f1, f4, f5
Maternal care in rat world is licking and grooming. Low
maternal care causes less gr expression so high corticosterone
levels, high anxiety. High licking maternal and grooming
causes a lot of gr expression glucocorticoid receptor causing
low corticosteroid levels, low anxiety which is healthy.
, ADHD & Neurodiversity
Children diagnosed with adhd don’t all have it for their entire life. We see more and more
adults being diagnosed with adhd.
Is the brain of people with adhd different compared to people without adhd? What causes
these differences?
Brain structures that could be impaired in people with ADHD:
- Prefrontal cortex (less inhibitory control, more impulsive)
- Cerebellum & caudate nucleus (motor hyperactivity)
- Corpus callosum (less communication hemispheres)
- BUT most imaging studies underpowered (less than 20 subjects in group)
+
Do not memorise location so right of left, dorsolateral bla bla bla. But do know the regions so
the ones above.
Mega analysis from 2017 measuring brain volumes
shows more reliable results because huge group. It
shows smaller effect sizes between patients with adhd
and healthy controls which is the 0 line.
The brain of children with adhd matures slower but
catches up in the end.
Largest effect in amygdala: also in ADHD to emotional
regulation problems.
Emotional regulation problems often present in patients
with ADHD, but these disease characteristics have not
(yet) been included into the official DSM criteria
Volume differences clustered in children and no
differences at group level were reported in adults
Most pronounced effects in childhood + delayed peaks of subcortical volume maturation:
model of ADHD as a disorder of brain maturation delay.
Scientist want to follow people from birth till death to investigate whether adhd will disappear
and why it happens or why it develops.
GENETIC FACTORS
ADHD has a high heritability. About 75% is genetic and 25% is due to environmental factors.
It is difficult to pin point the risk genes or risk factors. There are a lot of genes that increase
the risk by a small chance, but together they make it huge. This makes it difficult. There are
weak associations with DAT gene and DRD4 gene, but they only explain 3% pf phenotypic
variation from the whole 75%.
NON GENETIC FACTORS
Severe early deprivation so problems with family structure is the biggest risk factor for
ADHD, this is part of psychosocial adversity. Also dietary factors and environmental toxins
and pre and perinatal factors have influence. Pp 21
Introductiecollege 28/10
Study powerpoints and literature on canvas.
,Etiology of mental traits and conditions
In the past there was a tendency to explain disease via nurture.
Brain plasticity causes everything around you to be able to modulate your brain wiring and
behaviour. Most brain disorders are complex and multifactorial disorders.
Studying twins gives a clear image because they spend the same time in the womb en
monozygotes share 100% same dna. These studies give us an inside in the role of genes.
There are so many riskfactors which could contribute but the largest role is gene factors. It is
very difficult to find all the risk genes and all the possible combinations.
Too simplistic: Classic theory:
single abnormal gene→ abnormal gene product→ neuronal malfunction → mental illness
Then what is the pathway from gene to phenotype? These are new hypotheses:
1. Complex genetics or diathesis-stress model (this lecture)
2. Differential susceptible to environment hypothesis (lecture neurobiology of resilience)
3. Balancing selection hypothesis (lecture mental illness creativity)
Stress- diathesis model
Mental conditions are caused by multiple small contributions
from several genes, all interacting with environmental stressors.
People can have a genetic predisposition and in combination
with environment.
So you inherit the risk but not the disease itself. There are even
genes that prevent you from having the disease. COMPLEX
Endophenotype approach
Path from gene to mental illness. So genotype to phenotype
which sounds easy but is very complex. There are
intermediaries between the genotype and the phenotype so the
gene and the disease/behaviour.
Endophenotypes are measurable inheritable variables closely
linked to the disease. Two types:
Bio endophenotypes: Measurable biological phenomena
- Electrophysiological response to startle
- Neuroimaging response to information processing
- Activation of certain brain circuit
symtom/system endophenotypes: single symptoms associated
with mental disease/condition
- Insomnia
- Executive dysfunction
- Hallucinations
- Poor fear conditioning
- Anhedonia
genes>molecules> circuits>infomation processing>single
symptom> full syndrome of mental condition
,Psychiatric symptoms are increasingly linked to malfunctioning specific brain circuits.
Environmental factors
Altered gene expression via stress system and epigenetics.
There are individual (genetic), relationship and environmental factors.
pre/peri natal risk factors: maternal stress, nutrional deficiency, drugs are important
riskfactors. Also abuse, infections, trauma, stress, etc.
This system needs to be able to shut down. It uses cortisol that controls the stress system by
binding to brain cortisol receptors which is a protein in the hypothalamus. Negative feedback
loop. When there are not enough receptors it causes your stress system to get hyperactive.
Not enough receptors could be due too much early life stress causing life long overactive
HPA axis so less gr = less negative feedback to shut system down. Dan kan je dus niet
zoveel aan als normaal. Hpa axis.
Epigenetics
Life experiences → literally change person's mind
Chemically coating the DNA. ease or block access to genes on DNA. coating alters gene
expression, but not genetic code. Environmental programming of gene expression.
Epigenetic changes by unravelling the chromosome.
variation in maternal care affects HPA axis responses to stress
in offspring. Parenting practices can profoundly shape a child's
development and mental health.evidence via epigenetics.
READ ARTICLE FOR EXAM focus on f1, f4, f5
Maternal care in rat world is licking and grooming. Low
maternal care causes less gr expression so high corticosterone
levels, high anxiety. High licking maternal and grooming
causes a lot of gr expression glucocorticoid receptor causing
low corticosteroid levels, low anxiety which is healthy.
, ADHD & Neurodiversity
Children diagnosed with adhd don’t all have it for their entire life. We see more and more
adults being diagnosed with adhd.
Is the brain of people with adhd different compared to people without adhd? What causes
these differences?
Brain structures that could be impaired in people with ADHD:
- Prefrontal cortex (less inhibitory control, more impulsive)
- Cerebellum & caudate nucleus (motor hyperactivity)
- Corpus callosum (less communication hemispheres)
- BUT most imaging studies underpowered (less than 20 subjects in group)
+
Do not memorise location so right of left, dorsolateral bla bla bla. But do know the regions so
the ones above.
Mega analysis from 2017 measuring brain volumes
shows more reliable results because huge group. It
shows smaller effect sizes between patients with adhd
and healthy controls which is the 0 line.
The brain of children with adhd matures slower but
catches up in the end.
Largest effect in amygdala: also in ADHD to emotional
regulation problems.
Emotional regulation problems often present in patients
with ADHD, but these disease characteristics have not
(yet) been included into the official DSM criteria
Volume differences clustered in children and no
differences at group level were reported in adults
Most pronounced effects in childhood + delayed peaks of subcortical volume maturation:
model of ADHD as a disorder of brain maturation delay.
Scientist want to follow people from birth till death to investigate whether adhd will disappear
and why it happens or why it develops.
GENETIC FACTORS
ADHD has a high heritability. About 75% is genetic and 25% is due to environmental factors.
It is difficult to pin point the risk genes or risk factors. There are a lot of genes that increase
the risk by a small chance, but together they make it huge. This makes it difficult. There are
weak associations with DAT gene and DRD4 gene, but they only explain 3% pf phenotypic
variation from the whole 75%.
NON GENETIC FACTORS
Severe early deprivation so problems with family structure is the biggest risk factor for
ADHD, this is part of psychosocial adversity. Also dietary factors and environmental toxins
and pre and perinatal factors have influence. Pp 21
