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Translational Neuroscience Summary (MED-MIN6)
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This summary encompasses the whole minor MED-MIN16. I only used this summary, together with the practice exams to finish this minor with a high grade.
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Introduction lectureTwo ways of research to understand and treat the brain:
1. Fundamental research: this research depends on animal models and is the most efficient
research, but also invasive (you harm the animals). There are genetic modifications (KO or
knock in). experiments are usually harmful or fatal.
2. Clinical research: has to rely on human subjects. Very limited set of methodologies
applicable. Study groups are very heterogeneous (every human eats and lives differently). It
depends on the results from basic research (the animal models)
How to link fundamental and clinical research: you have to know to which extent the human and
animal physiology is compatible. After that you have to mimic human neurological disorders in
animal models. Then you have to link molecular and cognitive aspects.
In translational neuroscience they first look at the patient: diagnostics, phenotype and now even
genotype. When they for instance find an interesting gene they go to fundamental and preclinical
research (animal models) to look at the same gene. They use pharmacology to rescue the phenotype
of the animal and then go further into clinical research to make a medicine to help the patient.
Bootcamps day 1
Intracellular has more K+, but less Na+ and Cl- than extracellular environment.
When there are many K+ and Cl- on the left, K+ will go to the right (channels too small for Cl- to go
through) via diffusion energy. Then there will be an electrical energy that wants the K+ back because
the right is now positively charged, but the diffusion energy is still higher. At some point when more
K+ goes through the channels, the diffusion energy is the same as the electrical energy: an
equilibrium has been reached. This is how a membrane potential is made up, there are only very few
ions that are displaced. There is no or a very small change in the concentrations (gradient).
The right equation is the simplified version at body
temperature. The left equation is the Nernst
equation. The z is the charge of the molecule, R is
the gas constant, T is the temperature and F is also a constant, [X]o is the concentration of the ion on
the outside, [X]i is on the inside.
The more extreme the gradient, the more extreme is the equilibrium potential.
If Vrmp is more positive, you have a depolarization. When it is more negative, you have a
hyperpolarization. Vrmp is dependent on potassium, then chloride and then a little on sodium.
Calcium has no effect on Vrmp. The impact on Vrmp is defined by the ion specific membrane
permeability.
This formula is the Goldman
equation. P is the permeability of
the ions through the membrane.
The higher the permeability, the higher the impact on the membrane potential.
When putting an electrode in the cytosol of brain cells, the substance in the electrode has the same
characteristics so that the cytosol values will not change.
When the electrode touches the cell membrane, it will apply a little bit of suction. The part that is
bound to the electrode will be ripped apart and the electrode can measure whether the cell
hyperpolarizes or depolarizes. It can also control the cell by giving or taking certain ions.
In a network, neurons that are not involved in an action create their own activity. This will be a
random spike.
,The extracellular signals are typically in the microV range, intracellular in mV range. Extracellular
recordings also allow recordings of synaptic transmission.
Fs is the number of samples per second. When there is a wave of 10 Hz and you have fs of 9 Hz, you
get a slower sinus in the computer program, this is called aliasing. This simply happens because fs of
9 Hz will give different points on the next waves.
Noise is everything else that is present in the signal. The recordings from electrophysiological signals
contain a considerable amount of noise. Noise has a way higher frequency than the signal (it is way
more compact), a computer can suppress the noise by using a low-pass filter.
A good measurement for the amount of noise is the RMS (root mean square) of the amplitude. First
for each sample you take the square (everything becomes positive) of the average. Then the root, so
root mean square.
Signal-to-noise ratio (SNR): RMS (signal)/RMS (noise).
So you can filter the noise when the noise and signal have different frequencies. But if they have the
same frequency: you do a lot of recordings when measuring a bit of activity. When the recordings are
always the same, it is a signal, otherwise it is noise. The noise will cancel when taking the average of
the recordings.
The RMS of the noise is the same as the standard deviation.
Depolarization is a sharp transition, repolarization is more spread out along the axon. Consequently,
repolarization generates less current and does not contribute much to potentials at a distance, what
you see at a distance is only depolarization.
The compound action potential is the action potential of all the axons together at a certain place.
Downstream the action potential signal gets broader and less high, this is because different axons
have different speeds so the further away you go, the more different the action potentials will be
and thus the CAP will be broader and less high.
More membrane means more current and a larger signal, this is why the signal of a muscle is way
higher than from a nerve.
Normally the motor units will not fire synchronously, unless you stimulate the motor units electrically
in some point of the body.
SNAP (sensory nerve action potential) is the measurement of the action potential of a nerve, CMAP
(compound muscle action potential) is the measurement of the action potential of a muscle.
You can only measure the action potential of the pyramidal cells because they are the only ones that
are ordered in the brain.
Bootcamps day 2
Axons will only give their signals to the dendrites, not to the soma or other axons.
If you record the postsynaptic neuron with the patch clamp method and make an action potential in
the presynaptic neuron, you can see that an excitatory postsynaptic response will go up in the graph
,and will thus be a depolarization, the current graph will go down. Inhibitory postsynaptic response
goes down (hyperpolarization) and current graph will go up.
Glutamate is the main excitatory neurotransmitter, GABA is the main inhibitory neurotransmitter.
Paired whole cell recording: put two patch clamps on two neurons that communicate with each
other to look at the activity. If you for instance stimulate cell 2 and measure cell 1 (the postsynaptic
side) to look whether there will be a depolarization or hyperpolarization.
The reversal potential is the potential at which mV it will change from depolarization to
hyperpolarization. In the ppt you can see this for a certain EPSP (somewhere between -10 and +10)
and IPSP.
NMDA and non-NMDA receptors are the most abundant receptors on the post synapse that let ions
go through. Normally Ena (small permeability) is positive, Ek (strong permeability) and Ecl (mild
permeability) are negative which means that Vrmp is negative. When the non NMDA channels open,
you change the permeability for sodium and potassium (these channels will only let sodium and
potassium go through). The P for sodium will become extremely large and become the same as that
from potassium. The reversal potential will lay in the middle between those two. The membrane
potential will go up because of the permeability of sodium but will not reach the reversal potential
because chloride will pull the membrane potential a bit down.
However, NMDA channels also use calcium as a player and Eca is way higher than Ena. The
permeability of Ca2+ will go up and will pull together with Na+ on the membrane potential, only K+
will pull it down. The ENMDA is +28 mV (reversal potential) but because Cl- is still a player, the
membrane potential will go down.
Glutamate can open the NMDA channels but there is a Mg2+ plug that can be removed with a high
force of energy. When the action potential comes, the Mg2+ will be removed and the ions can flow
through to get a depolarization.
GABA is the inhibitory neurotransmitter. Measuring the activity can be done with the paired
recording of two neurons. GABAA is the fast neurotransmitter, it is the classic mechanism. The GABA-
gated Cl- channels will open when GABA binds. The Cl- will go into the cell which leads into a
hyperpolarization. The permeability of Cl- will increase which means that the membrane potential
will go down.
In the brain, GABA is inhibitory. But in development, GABA is excitatory (only depolarizations). The
excitatory GABA will decrease with age and will be 0 at 1-2 yrs. Many brain diseases are caused
because the GABA isn’t excitatory in the first years of development.
GABA channels only use Cl- so cells can play with the chloride gradient. The Ecl lays close to Vrmp so
it can change a lot in the cell. In immature brains chloride ions are pumped outside of the cell which
means that Ecl will go up and the Vm will go up (permeability will increase), there will be a
depolarization.
Besides EPSP and IPSP you also have miniature postsynaptic events. This happens when there is no
action potential but one of the vesicles will still open and neurotransmitters will go to the post
synapse. This is called action potential independent neurotransmitter release. This amount can be
calculated and when you see a lot of miniature postsynaptic events on the graph, you know that a lot
of axons are bound to the neuron. This will give you a global idea of the network integration.
Supragranular stimulation has a lot of electrodes in a part of the brain. You stimulate one neuron
and look where the action potential will go to, this information can be used.
LFPs (local field potentials) is the sum of all the dendritic synaptic activity?
, Epigenetics is the way how DNA structures are organized. During development, stem cells are the
same. they have a certain epigenetic signature that can be changed when the stem cells are
differentiating into other cells but they lose the signature so that the differentiated cells can not
differentiate into other cells.
0.2% of the entire genome can be variable in humans. Most variation is common, but there are also
rare variations that even can be unique to a single person.
Mutations are lower than 1% in the population, polymorphisms are higher than 1% and are fixated in
evolution.
Karyotyping is the determination of the genomic structure. Years ago this was done with
microscopes, then microarrays were used where there are probes with around 20 bases that are
complementary to the normal DNA. When the normal DNA will not bind, you know that there is a
mutation.
Trio screening: look at the affected child and the healthy parents. The mutation that only one child
has is called de novo mutation.
SNPs in ORF: missense variants (amino acid substitution), nonsense variants (codon will change into a
stop codon), frameshifts (new codon is added so the frames of three codons will shift) and splice
sites (normal splicing of introns is affected in pre-mRNA).
Exon junction complexes hold the exons together after splicing. They will be removed when the
ribosome has moved over the mRNA. The mRNA will have a polyA tail at the end when translation
happens.
SNPs outside ORF: affect promotor, affect RNA stability, affect splicing or affect epigenetic control
Lecture 1
Glial cells are meant for the support and protection of neurons (astrocytes, microglial cells,
oligodendrocytes, schwann cells, ependymal cells).
Microglial cells eat unwanted factors in the brain to protect the neurons.
Astrocytes have very broad end feet with which they cover the capillaries. They form the blood-
brain-barrier. They determine which substances are going to the neurons. They produce the nerve
growth factors for the growth of neurons.
Oligodendrocytes have very long extensions and wrap them around the dendrites to form an
isolation barrier.
CNS is the brain and spinal cord, PNS is the cranial nerves (arise from the brain) and spinal nerves
(arise from the spinal cord).
CNS: are located in the skull and vertebral column, they are protected by bones and three brain
membranes. Surrounding the brain there is CSF (cerebral spinal fluid) which will protect your CNS
against hard movements.
CNS is like a triptych: it consists out of three parts. Sensory information (afferent) is going in and
stored into the cortex, information that is going out has an efferent/motor output (afferent neurons,
interneurons, efferent neurons)
The brain consists for 99.9% out of interneurons.
CNS has gray matter (outer layer) which is also called the neocortex where all the neuronal cell
bodies are located. It consists out of six layers with different functions. Inside the brain is the white
matter. In the white matter (all the axons with myelin sheets) you can also find the gray matter
which are groups of cell bodies (basal ganglia). They are important for initiation and starting of
movement.
In the spinal cord the white matter is on the outside and gray matter on the inside.
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