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Summary Learning Objectives Molecular Principles of Brain Disorders
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Summary learning objectives Molecular Principles of Brain Disorders.
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Lecture 1 – Etiology of braindisorders
• You understand and can explain the concept of heritability
Heritability is the variance in symptoms that can be explained by the variance in genetc factors
• You can estiate the heritability of depressiont ADHDt bipolar disordert autsit schizophrenia
Depression 40-50%
ADHD 76%
Bipolar disorders 80%
Autsm 80%
Schizophrenia 80%
• You can describe contributon of genes and environiental factors to the etology of coiplex
iultfactorial psychiatric disorders
There is an interplay in genes and environmental factors which cause the disease. A combinaton of
genetc factors with biological stressors can afect brain circuits. These impaired brain circuits can
cause endophenotypes (symptoms) and these endophenotypes can cause a disease.
• You can elaborate on the concept of coiplex genetcs and the stress – diathesis iodel
Hypothesis: mental illness is caused by multple small contributons from several genes, all
interactng with environmental stressors. So this new model is called the Stress-diathesis model: A
combinaton of environmental ris factors (stress, life events, biological stressors such as viruses,
toxins) with ris genes can cause mental illness
• You can explain biological endophenotypes and systei endophenotypes and can give exaiples
Biological endophenotypes are biologically measurable, for example cortsol levels.
System endophenotypes are symptoms, for example impulsiveness. Both are the outcome of a
fragmentzed disease. However, this model doesn’t ta e the environmental factors into account.
• You can naie environiental risk factors for psychiatric disorders in general
Pre-natal ris factors (maternal stress during pregnancy, nutritonal defciency during pregnancy,
maternal use of tobacco or alcohol), birth compilatons, abuse, neglect, poor parental care, stressful
life events, drugs.
,• You can explain HOW can environiental factors exert their infuence on the body and braint via
alteratons in the stress systei and via epigenetc iodifcatons
Environmental ris factors (e.g. poor parental care) can lead to methylaton of the promotor region
of the GR gene hereby NGFIA (transcripton factor) is not able to bind the promotor less
expression of the cortsol receptors (GR) no negatve feedbac loop of the stress system more
stress (high cortsol levels)
• You can explain the line of investgaton of the study
‘Epigenetc prograiiing by iaternal behavioura and you
can interpret the graphs and fgures of this study in detail
and with a deep level of understanding
Low maternal lic ing and grooming methylaton of the
promotor region no binding of NGFIA to the gene less
expression of cortsol receptors no negatve feedbac of
stress system more stress (high cortcosterone levels, high
anxiety and low lic ing and grooming of their own pups).
• You can explain gene-environient
interactons and give soie exaiples
In this model, the environmental
stressors are also ta en into account. So
ris genes in combinaton with major
stressors can lead to dysfuncton in brain
circuits. This leads to specifc symptom
endophenotypes (symptoms) and these
symptoms together form the disease.
,• You can explain causal loops and give soie exaiples:
Body senses stress hypothalamus secretes cortcotropin releasing hormone (CRH) onto the
pituitary gland CRH binds to the CRH receptor secreton of adrenocortcotropic hormone
(ACTH) ACTH released into bloodstream
binds to ACTH receptors on adrenal cortex
release of glucocortcoids (cortsol) binds to
cortsol receptor (GRs) GRs will translocate into
the nucleus of a cell and act as a transcripton
factor (it can do so in all body cells) efects li e
increased blood pressure, suppressing immune
system, this can be on the long term very harmful.
Therefore, this system can be shut down via a
negatve feedbac loop. These negatve feedbac
parts are in the brain in the hypothalamus,
hypophysis and hippocampus. It shuts down
producton of CRH and ACTH (its own producton).
The amount of cortsol 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 cortsol receptors!
, Lecture 2 – Depression
• You are aware that the ionoaiine hypothesis is an outdated overly siiplistc paradigi
Old hypothesis lac of serotonin
New hypothesises circuit disease
• You can elaborate on the current ideas regarding the etology of depression
1. Overactve amygdala
2. Decreased actvity PFC
3. Decreased hippocampal volume: neurogenic hypothesis
4. Overactve HPA-axis
6. Decreased levels BDNF: BDNF hypothesis
7. Brain-gut hypothesis
8. Cyto ine hypothesis
9. Disturbed circadian regulaton (chronobiological model)
all connected in complex interactons!
• You can explain brain iiaging fndingst such as increased aiygdala reactvityt decreased PFC
actvityt reducton voluie hippocaipusa their relaton to the syiptois of depression and the
effects of treatient on these fndings
Increased amygdala Depression characterized by increased and sustained emotonal reactvity.
Increased and sustained amygdala reactvity especially in response to emotonal informaton
involuntary elaboraton on negatve topics
Decreased PFC actvity increased amygdala (circuit)
Reducton volume hippocampus A decreased hippocampal volume at birth is a ris factor for
depression. Decreased head and tail of the hippocampus is a mar er for an increased chance of
getng depression. So hippocampal volume is a vulnerability mar er.
SSRI/AD can normalize all impaired brain structures.
• You can elaborate on the role of the HPA-axis in the etology of depression
Overactve HPA-axis persistent fnding in some subtypes (insomnia and weight loss) of depression.
Increased peripheral plasma cortsol concentratons. Elevated levels of CRH in brain. Reduced
glucocortcoid receptors (GC-R) cortsol receptors in hippocampus and hypothalamus. Negatve
feedbac loop unable to shut down stress system. Chronic stress via CRF / cortsol decreased
appette, weight loss, loss of libido.
• You can integrate the current ideas and explain the relaton between HPA-axist BDNF and
reduced voluie hippocaipus / PFC (Synaptogenic hypothesis of depression)
Overactve HPA high levels cortsol direct toxic efects + negatve efects via inhibiton gene
expression BDNF: results in decreased synapses + dendritc atrophy + inhibiton neurogenesis
volume reducton hippocampus.
• You can elaborate on the cytokines hypothesis and the chronobiological iodel
Constant dar ness mice (for 4 wee s) elevated levels of IL-6 depression-li e behaviour
Also: altered gene expression in hippocampus of cloc genes per2 and npas2.
And they also saw a reduced neurogenesis in hippocampus. Lin ing chronobiological and cyto ine
models and neurogenic hypothesis
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