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Lecture 1: General introduction and genetics
The professor starts this lecture with a case to make clear what kind of interplay underlies pathology.
It is not merely the disorder itself, there is an interaction between psychological processes and
psychosocial and physical exposure from the environment. This leads to either improved health or
diseases. However, this interaction can be controlled by an intervention and thus preventing
individuals from getting sick.
Genetics: goals of this lecture
- Explain basic principles of genetics
- Explain the complex interplay between G and E
- Describe how GxE can be studies
- Describe related clinical application and potential drawbacks of these application
Genetic mechanisms
Phenotype vs genotype
The phenotype is observable outward appearance of a cell or organisms (this is also personality
and blood group), while the genotype is the type of coding on the DNA. This goes hand in hand
with the nature versus nurture debate: what does exactly affect a person in terms of hereditary
and environment? Research shows us that we can contribute some genes to pathology, but these
genes do not necessarily result into a disease. They can be seen as a “sensitivity gene” that merely
set a threshold for the environmental factors to cross.
➔ There was a question in the lecture about the MAOA gene , this gene is recessive (see
articles of this week for more information)
Genome
Within the nucleus of a cell, you can find chromosomes, which consist of DNA. In turn, DNA consists
of genes themselves. Because the string of DNA is so long the body has come up with a solution called
histones. Histones are small orbs on which the DNA wraps itself around. This way the DNA can be
stored in a smaller space. As you know boys have an XY chromosome and girls have an XX chromosome
(a normal human being has 22 regular chromosomes and 1 sex chromosome ). All these chromosomes
together is called the genome.
Structure of DNA
The DNA consists of a sugar-phosphate group and bases (in pairs): A, T, G, and C. (see the article for
the picture). The DNA is of course double stranded and that is why the bases are in pairs. One part of
a DNA is called a gene when it (a specific base pair order) encodes for one protein. In turn, a protein
is a building block of the body ; it all starts with promotor region (which can be seen as a specific code
on the DNA) and ends with terminator regions (which is also a specific code).
Genetic variation
Genotype is an individual’s genetic constitution, overall or at specific genes. But 99% of the DNA is
similar across humans, which means that they are fixed. Therefore only 1% differs across individuals.
The differential can be the result of mutations (due to the exposure of sunlight or chemicals, which
can happen through a base change, meaning that an A, C, T, or G is changed into a different base) a
deletion of a base segment, a duplication of a base segmentation, or a whole stretch of DNA can be
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deleted or duplicated. When these changes, due to mutations, are not repaired it can lead to a change
in proteins. This can also happen through polymorphisms: a change that can be seen in a particular
population (bigger or equal than the normal 1% difference in genes), but that does not cause a major
defect in biological functioning. A single nucleotide polymorphisms (SNPs) is a DNA morphisms that
occurs when a single nucleotide (a, t, c or G) in the genome differs between members of a species or
paired chromosomes within an individual.
An variable number of tandem repeats (VNTRs) is a short nucleotide sequence that is organized as a
tandem repeat. These often have different variations amongst individuals and can therefore be used
as a biological fingerprint.
From genotype to phenotype
One speaks of mendelian inheritance when referring to the inheritance of traits controlled by a single
gene with two alleles . These genes either have a dominant or a recessive allele. Dominant means that
the factor the allele is coding for will be expressed when present, while recessive alleles can only be
expressed when it is paired with another recessive allele. Therefore we speak of two differences in
pairing: homozygous and heterozygous. Homozygous refers to the presence of either two dominant
or two recessive alleles, while heterozygous refers to a gene which has a dominant AND a recessive
allele.
Important to keep in mind, is that protein production is dynamic and continuously influenced by
various factors, for instance:
- Epistasis: the interaction between genes. Allele at one locus interferes or masks an allele at
another locus. If you have a gene for baldness it does not matter if you have an allele for red
or blond hair, while the result will be masked by the bald allele
- Epigenetics: a series of biochemical processes through which changes in gene expression are
achieved throughout the lifecycle of an organism without change in DNA sequence (genes are
switched on or off by environmental factors)
➔ Epigenome and genome difference
Epigenetics
Epigenetics is the study of how DNA interacts with smaller molecules found within cells, which can
activate and deactivate genes. As you know DNA is expressed when a gene (part of a DNA string) is
transcribed into RNA, which create proteins by using ribosomes. In turn, these proteins are what
determine the cell’s characteristics. Epigenetic changes can interfere or boots the activation of specific
genes. This is possible while a part of the DNA string gets a certain tag. All these tags withing a single
gene is called the epigenome. Interesting is that epigenetic changes survive cell division and therefore
can consists throughout the lifetime of a organism. For example the embryotic stem cells develops
further and further (requires epigenetic memory). But also, constantly throughout the day Epigenetics
signals that come from inside the cell or neighbouring cells but can also come from the exterior.
Other examples can be diet, daylight, exercise, diseases, drugs, negative life events, and social
support. Of course, these factors can be either protective or risk factors.
Epigenetic gene regulation
Environmental factors come across and cause chemical modifications to either histones or DNA which
results into changes in accessibility of the DNA transcription machinery (methyl group silences this ,
while a promotor can also be promoting the DNA). When its attached to a histone then a stretch of
DNA will be affected, otherwise it will only affect the gene it is connected to.
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Studying GxE
There are a lot of different ways in which you can study gen-environment interactions. For example:
Comparing cases (with a disease) and control, such as pedigree (=family) studies is particularly good
for a rare disease caused by rare mutations. But it is also possible to do twin studies, while they have
identical genes (monozygotic twins). Keep in mind that they also have the same environment so
nothing can solely be contributed to a single gene expression. Lastly, it is possible to study a whole
population.
You can either do a candidate gene association study or a genome wide association study. In a
candidate gene association study you evaluate an association of specific genetic variants wit
outcomes or traits of interest, selecting the variants to be tested according to explicit considerations.
While the genome wide association study (GWAS) is a study that evaluates the association of genetic
variation with outcomes or traits of interest by using 100.000 – 1.000.000 or more markers across the
genome.
Application
Medical diseases
As you might already know the down’s syndrome is 100% explained by genetics , while on the other
hand TBC can be completely explained by environmental factors (vitamin C deficit). There are different
ways in which the environmental risk factor influences the genotype -> disease pathway. Below a
possible pathway is described:
A great example can be allergy, which is often an early manifestation of immune dysregulation. It can
be considered as a classic psychosomatic disorder, which is a great example of G x E. While it is an
complex interaction and can be better understood than psychopathology (in an allergy there may be
clearer environmental factors). Allergies are socially relevant, while nearly 30% of the western
population has an allergy and it’s dramatically increasing. There are several indications that G x E
interactions in allergies are important. Because within a family the allergy rate is higher, but
environmental factors are also important. While incidence increase too rapidly to be explained
genetically by de theory of Darwin. Moreover, there are more allergies in developed countries
(hygiene hypothesis: states that early childhood exposure to particular microorganisms protects
against allergic diseases by contributing to the development of the immune system ). It can also be
influenced by psychological factors, e.g., psychosocial stress increasing incidence, probability of
symptom exacerbation, and severity of the condition.
But it is not that simple when the disease is heterogenous, this means that there are multiple genes
and multiple environmental factors that cause an allergy. Furthermore, the time window of exposure
of environmental risk, such as the time of exposure and the dose of exposure. Lastly, not all
environmental factors are usually measured, for example the protective factors that can have a
buffering influence are not measured.
Genetics contribution for an allergy is somewhere between 35 – 75 %
Psychopathology
Nearly 80% of schizophrenia can be explained by genes (and 40% to MDD). But there is a heritability
gap: twin studies seem to overestimate the genetic component, while twins also share the same
environment. Genetic component of schizophrenia and major depression would be (corrected for the
heritability gap) between 20 – 25% genetic explanation.
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G x E major depression:
Mainly based on candidate gene association studies: there are indications for higher risk of depression
when you have a 5 HTTLPR (Serotonin transporter gene) short allele x stressful life events or childhood
maltreatment. As well as the BDNF gene in combination with stressful life events.
This tells us that the role of monoamines and BDNF play an important role (see: revised monoamine
hypothesis next week). We know that antidepressants increase levels of monoamines and BDNF
expression. However, when you look at genome wide association studies you don’t see that these
genes are involved. This seems a contradiction. However, it could be explained that the GWAS are
based on a priori hypothesis, multiple genes might be important for the expression, but also studies
are often underpowered in sample size (which increases the risk of false positive finding), and
differential susceptibility averages out the impact of genes.
Other explanation: The Differential susceptibility Model
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G x E: schizophrenia
The risk of schizophrenia increases 2-3 times when one has gene vulnerability and actively uses
cannabis during adolescence. The hypothesis of schizophrenia is that cannabis triggers dopamine
release. And antipsychotic drugs supress dopamine receptors. Individuals with specific genotypes
should therefore avoid or limit cannabis use (makes sense of course).
G x E; Alcohol dependence
There are indications for genes encoding for amongst others GABA receptor times lowers parental
knowledge or higher peer group antisocial behaviour and substance availability. This makes sense
because GABA is associated with reward and inhibition process and alcohol bind with the GABA
receptors.
Clinical applications
Knowledge on human genomics (Specific DNA profile) and environmental factors can be used to
personalized medicine. You can identify people at risk for a disease (this is called a primary
prevention), you can predict prognosis, and you can improve treatment (for example a tailored
treatment can be offered while using the drug with the least side effects “pharmacogenomics” )
Crispr-CAS9 can change the DNA which cuts a specific part of the DNA and sort out all different kind
of effects. (Watch the video in the slides, pretty useful!). Crispr is awesome while it is easy and has
low costs, it can replicate genetic basis for human diseases in a model organism and therefore is
fundamental for research, they can promote health in adults, while restoring diseased organs by
inactivating genes in diseased cells, also it is possible by editing reproductive cells or developing
embryo’s (therefore creating a healthy human when one is born). But think about ethics ! You can
figure this out for yourself.
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Lecture 2: Neuroscience
The Neuron and neurotransmission
The neuron consists of dendrites, the nucleus (in the cell body) and an axon covered in myelin sheaths
(with nodes of Ranvier and Schwann cells). Within the neuron signalling is usually done with electron
signals. Whereas, inter-neuron communication goes with chemical processes. There are some
exception in the brain, but this is very rare.
Neurotransmission
There are two different types of electrical signals: Graded potentials and all or none potentials. An all
or none potential principle refers to the fact that the neuron will either fire or will not fire at all. There
is no in-between. Graded potentials are changes in the membrane potential that do vary in size. These
potentials arise from the summation of individual actions of the ligand-gated ion channel proteins and
decrease over space and time.
Pre-synaptic all or none action potential
In rest the regular amputate is -70mV and the outside is 0 mV. When the membrane is depolarized
then at a certain point the cell membrane will reach a threshold for the Na+ channels. In the rest state,
these channels are of course closed (-55mV). A pore will open in the sodium channels and sodium ions
will enter the cell. The sodium ions are positively charged and will increase the depolarization of the
membrane (up until around +30mV , then the sodium channels close down and need time to
refractory; no more sodium will enter the cell). In the meantime the threshold of the potassium
channels have been reached and open while the sodium channels refactor. These channels are
selective for potassium and flows in the other direction. While potassium is also positively charged
the cell membrane re-polarizes and stay open until it causes an undershoot ( more negative then the
resting membrane potential).
Saltatory conduction
A saltatory conduction is an action potential that travels from node to node, which means it travels
faster. This occurs at the axon only (while dendrites are not myelinated). Depends on the density of
sodium channels , which are very high at nodes of Ranvier. Therefore, the action potentials are
generated at the nodes of Ranvier. Myelination leads to insulation, that means that there is a passive
conduction between the nodes. The action potential hops from one node of Ranvier to the other node
(it travels fast from node to node and slows down on the node itself). A saltatory conduction is
therefore fast and very efficient.
Graded excitatory/inhibitory postsynaptic potentials
The graded potentials can either be excitatory or inhibitory. An excitatory postsynaptic potential
(EPSP) depolarizes (less negative -> pushing towards the threshold) the membrane, towards the
threshold. Caused by the flow of positively charged ions into the postsynaptic cell as a result of
opening of ligand-sensitive channels. While an inhibitory postsynaptic potential (ISPS) hyperpolarizes
the membrane, away from the threshold. This will travel to the axon hillock. There it can trigger the
threshold for an action potential or not, depending on the amount of EPSP or IPSP.
A neurotransmitter provides chemical signalling across the synapse. It is synthesized and stored in the
presynaptic neuron and will only be released into the synapse when the neuron fires. This causes a
postsynaptic effect after it interacts with a receptor. Besides, there is a mechanisms for degradation
and or reuptake (see later on).
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Types of receptors
The main classes of receptors are which will be explained below. The first category are ionotropic and
metabotropic receptors. An Ionotropic receptor is a receptor and an ion-channel in one. It is a trans-
membrane protein. Upon binding of the neurotransmitter on the receptor, than the protein goes into
a confirmation changes and a pore opens so that ions can travel in or outside of the cell (depending
on the selectivity of the cell). An EPSP metabotropic receptor is only a receptor and via different steps
it activates a separate ion-channel. It is only a trans-membrane protein, but is merely a receptor. The
receptor activates another transmembrane protein (channel) , but through different steps within the
cell. Resulting in the same: a pore opens that allows cells to enter or exit the cell. Eventually this results
in either an EPSP or an IPSP
The second category is the NMDA receptor, which is a glutamate receptor (ionotropic, therefore a
channel and a receptor in one). The pore does not only attract Na+ and Ca+, but also magnesium. They
are all trying to flow inward in the cell. But magnesium is a bigger ion that calcium and sodium and
the pore is pretty small. Magnesium can act like a blockade of the pore. So even though a glutamate
binds it is possible that there is no current flow through the pore. Magnesium will diffuse toward the
outside of the cell when the voltages goes up in the cell membrane, then the NMDA receptor opens
again and the sodium and calcium will flow through again. Therefore this is also a voltage dependent
channel (and the only one).
The final classification type is based on their location: post-synaptic or presynaptic. The easiest
location is the postsynaptic receptor (when the action potential arrives the neurotransmitter is
released and binds to these postsynaptic receptors; the transmembrane receptors). While the
presynaptic receptors reacts when there is an overflow in the synaptic cleft of a specific ion. There are
two different subtypes: auto and hetero. An auto presynaptic receptor is activated by a
neurotransmitter origination from its own terminal It will therefore be only activated when there is
too much of the ion in the cleft. They will inhibit their own excretion of ions within the presynaptic
neuron (kind of like a negative feedback loop). While an hetero synaptic receptor is a receptor that is
located on the same place as an auto presynaptic receptor, but only gets activated by a
neurotransmitter from a different neuron. And thereby another neuron may modulate the
neurotransmitter release of a particular synapse.
Mechanisms for degradation or reuptake
Let’s say the neurotransmitter is outside the cell (it cannot stay here forever). If we want to stop this
signal there are different enzymes outside the neurons that will degrade (cut) the neurotransmitters
in different pieces and therefore it is no longer possible for them to bind to postsynaptic receptors.
There are also reuptake transporters (in the pre synaptic terminal) that will escort the pieces back to
the presynaptic terminal to be used again later on. (this is not a 100% efficient process, so there will
be some new neurotransmitters created somewhere)
➔ Psychotropic drugs often inhibit these actions (SSRI, Ritalin, MAO-I).
Psychopharmacology: Pharmacokinetics and pharmacodynamics
Definition
Psychopharmacology is the study of drugs that affect the central nervous system, behaviour,
cognition and or affect. A drug (pharmakon) is a non-food chemical substance that has known
biological effects on humans or other animals. This chemical substance is used in the treatment, cure,
prevention, or diagnosis of a disease or used to otherwise enhance physical or mental well-being
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Drug names and labels
I am convinced that you do not need to know the chemical name of drugs (if you do want to know the
chemical name see slide 22), however here are some brand names and generic names of the same
drug:
Brand (trade) name Generic name
Prozac Fluoxetine
Ritalin Methylphenidate
Ambien Zolpidem
Valium Diazepam
Percoset / Percodan Oxycodone
Pharmacokinetics and dynamics
Kinetics refers to (the science about) how the body affects the drug (inactive and excrete). While
dynamics refers to how the drug affects the body. This can go through protein (receptor) binding,
neurotransmission or cellular, brain functioning, psychological behaviour, cognition and or affect).
Pharmacokinetics
The first step of pharmacokinetics is absorption. The fastest route of administration is through Iv or
inhalation. After this the drug needs to be distributed. A drug can either be hydrophilic or lipophilic,
which is important for the distribution. The distribution of the blood brain barrier is very important (if
it affects the brain or not), but also binding of the drug in general. Furthermore, after being distributed
the drug is metabolised in the liver and eventually excreted in through the kidneys (it can be used for
drug screening in urine). The half-life is always calculated in the linear part of the curve (after the peak
administration there is an linear decrease).
Pharmacodynamics
Pharmacokinetics almost always effects chemical neurotransmission, which can be during the
production or the neurotransmission itself. But also by blocking precursors or the speed of how fast
they are stored or released from the vesicles and so on. The synapse is the goldmine for the
pharmaceutical industry lol
Dose response curve
A dose response curve is a curve that indicated how much of a drug is needed for a certain response.
A dose response curve can differ for one drug. For example oxycontin needs more ug/Ml for
respiratory depression, while it needs less for analgesia (pain killing). Only in high doses it can lead to
respiratory depression and you don’t want that to happen of course. This is the difference between
the side effects and the desired effect, while keeping in mind the safety. But keep in mind that there
can be a habituation (tolerance for a specific drug) and they need more of the drug to feel the effects.
Being addicted to oxycodone can therefore lead to respiratory depression.
Mood disorders
There are around 550k patients in the Netherlands with Major Depressive disorders and around 90k
patients with bipolar disorders. Today we only talk about MDD.
Depression and the brain
The same brain structures of emotions are affected by depression, and by monoamine
neurotransmitters. These monoamine neurotransmitters are serotonin, noradrenaline and dopamine.
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There is one main finding within all studies: When you use medication that decreases monoamine
neurotransmitters availability it can cause depression and vice versa.
This led to the monoamine hypothesis of depression: deficiencies in the monoamine
neurotransmitters is sufficient to cause depression (and the underlying cause of MDD). However,
there is a problem with this hypothesis. The so called “lag time or therapeutic delay”: after the drug
induced changes in the neurotransmitter availability, it takes weeks before the changes in symptoms
occur. This problem led to the revised monoamine hypothesis (depression is the result of neuronal
degeneration of the hippocampus and the prefrontal cortex, because the monoamine don’t produce
enough BDNF) that states that the antidepressant not only increase the monoamine availability but
also downregulate the presynaptic auto receptors and stimulate the formation of BDNF (see below
for bdnf). This reinstates normal cell functioning. So the lag time is basically the reinstalling of the
presynaptic auto receptors and the formation of BDNF. Only after this there will be a positive effect
of the medication.
BDNF
Brain derived neurotropic factor are important proteins that ensures cell survival and receptor and
new neuron growth. When this doesn’t happen the neurons in the hippocampus and the frontal cortex
can’t communicate with each other. A cause may lay in chronic stress.
Categories of antidepressant medications
The most well-knows classification of antidepressants are the selective serotonin reuptake inhibitors
SSRIS that increase the availability of serotonin by blocking the serotonin transporter. The most well-
known SSRI Prozac and leaves serotonin longer in the synaptic cleft. There are also serotonin-
norepinephrine reuptake inhibitors (SNRI) that increase the availability of serotonin and
norepinephrine and in some cases even dopamine., by blocking transports. This means that they are
less selective in blocking. Furthermore, there are tricyclic antidepressant that increase the availability
of serotonin and norepinephrine by blocking their respective transporters and block acetylcholine
receptors (no idea why that helps for some depressed patients; this is often a last resort when SSRI’s
and SNRI’s does not work). The last category is monoamine oxidase inhibitors (MAOIS), that increases
the availability of monoamine neurotransmitter via the inhibition of the enzyme MAO. This enzyme
cuts the neurotransmitter into pieces and reassembled in the vesicle again. This cutting process gets
inhibited and therefore the re-uptake goes faster, leaving more neurotransmitters in the presynaptic
neuron. But MAO is also present in the liver for breaking down different substances , so it can lead to
side effects if a patient does not follow a strict diet.
Problems with antidepressants
There are some problems with antidepressant treatment, it might lead to a suicidality in adolescents
and there are some question of the efficacy of the antidepressant treatments. Some researchers claim
that these antidepressants don’t do that much compared to placebo.
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Lecture 3: Neuroendocrinology
Neuroendocrinology talks about the brain and hormones. This is of course a two way interaction.
While the brain can be a source and a target of hormones.
A hormone can be seen as a “public announcer” for the whole body, while it influences a lot of areas
in the whole body itself (for example during stress).
Pituitary = hypofyse ( in dutch)
Hereby a take-home message before the lecture even starts. The brain controls the activity of the
peripheral glands (which releases endocrine hormones) and in turn these gland affect the brain (e.g.
cortisol can cause or aggravate a disease). Furthermore, the hypothalamus is also a major source in
releasing hormones. The hypothalamus decides based on the information from man other brain
regions. The pituitary is the major route (either tropic or stimulating hormones). The peripheral glands
in turn affect the brain.
Glands make hormones; hormones coordinate processes
In the bottom of the brain sits the hypothalamus. The hypothalamus governs the peripheral glands
(adrenal, ovary testis and thyroid glands). Basically it works like a cascade: the hypothalamus makes
hormones that affect the pituitary and in turn the pituitary makes hormones that affects other cells in
the body. But the hypothalamus does directly influence the uterus and the kidney. The hypothalamus
can be seen as the starting point.
Pituitary (ACTH) – Adrenal Axis (Cortisol)
The pituitary makes ACTH, while the adrenal axis makes
cortisol. Research shows that the level of cortisol and
ACTH reacts kind of the same. ACTH works first, about 10
minutes later the cortisol levels on about the same level
of ACTH. Therefore pituitary -> Adrenal Axis. See the
picture for an easier overview.
Hypothalamus – pituitary axis
Of course the pituitary needs to know when to release ACTH. In the
picture you can see the end of the brain: in the bottom you can see a
blood-vessel system. In there they release a releasing (the so called
corticotropin releasing hormone: CRH) hormone towards the anterior
pituitary. Therefore the hypothalamus neurons are responsible for
activation of the pituitary “creation” of new hormones (like ACTH).
