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10.2 Animal models in neurological research
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Do curso por Peking University
Advanced Neurobiology I
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Na lição
Techniques in neuroscience
Let's learn some prevalent techniques in neuroscience.
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Yan ZhangProfessor
School of Life Sciences, Peking University
Yulong LiResearch Fellow
School of Life Sciences, Peking University
So again, there are different ways to teach the newer techniques.
But I think SS set, the broad spec would be most
to establish both correlation and
causality at different levels.
But specifically,
we have already touched upon some aspects of the techniques in neuroscience.
For example, how different model organisms can contribute
to our understanding of neural systems like action potential.
How does it generate by the interplay of what is grade a sodium and
potassium channels, right?
But in addition, different animal models can provide
different aspects of knowledge or information.
For example, the vertebrates that are closer to human okay.
So one will expect that the information for
them is partially the non human primate can provide
information of a higher cognitive processing like emotion.
We'll study worms for emotion.
Might be a little bit more difficult because it's difficult to find, okay.
But there are some simple model organisms that can provide
to the simplicity to understand a complex development
of neuro-circuitry that can control behavior.
For example, we have already talked about a screen but
other invertebrates, butterflies that today have very sophisticated behavior and
some of their cells are huge and beautiful, right?
And this can provide the information to study how the invertebrate
nerve cells development, recognize each other and organize to process information.
Okay, if those information that obtained are conserved,
then because of their simplicity they can provide a testable principle for
people to study in a more complicated animal
models like a mouse or even some human cells.
If those principal or if those molecules
are structured and no conserved, but
I think is still useful because it provides
a vivid example that how nature evolve to use
different strategies to solve the same problem.
For example, human can smell something.
Well, butterfly can also chase some flowers.
Even if it turns out that the principles in butterfly, or
the receptors that the butterfly used to sense those odors
are completely different than humans, it provides a very
unique perspective to understand the diversity of evolution.
How different strategies, like how we evolve, so
different species in different geography conditions to deal with the same problem.
For example, how to distinguish different odors.
How to achieve the sensitivity,
how to dynamically change the sensitivity and different conditions.
And I think those are still very useful for people to understand nature.
So then a lot of times people think to understand nature that some people
they very dear to their heart
trying to understand the disease mechanism because that is related to human health.
But, a lot of study, especially research are curiosity driven, and
I think one of the curiosity is just to appreciate how nature evolves for
those different strategies.
It will be some sort of feelings
that you figure out how nature works.
And this is the amplification, zoom in.
This is a very complicated neuron
with this diversified dendrites.
And the simplicity of the invertebrates for
example, the model organism of flies and
sciaticas allows much simple genetic manipulation.
And indeed, people have already found out
the conserve principal the conserver molecules or
sometimes the almost identical for
those molecules control the nerve assembly that control human's neuronal assembly.
For example, the natural molecule
seems to be used the same way in worms and
in humans to induce axonal guidance.
And people also use special vertebrae
model organism taking advantage,
again, of their unique property.
For example, zebrafish because of these transparency that
allows much easier imaging in the live animal.
So it's very useful for the neuroscience research.
And because it is a water prey and a zebrafish is relatively small so
one can also take advantage of the genetic and
the relative cheaper to grow to culture to use that to searching for
important molecules that are important for.
Because there’s still a big difference between invertibrates and vertebrates.
And especially for zebrafish
actually lady.
She actually is a fly geneticist and after doing
her nobel prize work in flies to identify a lot of
[INAUDIBLE] important molecule for fly segmentation.
She spear head, she's becoming a pioneer in
the zebrafish field by using zebrafish along
with the community to develop into a vertebrate model
system to study or to model the human disease.
And you can see the transparency, especially people can,
in this zebrafish to make additional mutation to make a really transparent,
to eliminate the pigments.
So indeed some of my friends in Harvard was complain
to me they were using some albino mutant fish that without pigment.
And frequently what happened was that the rotation student in his lab
sink those there's no fish in that water, just dump the fish, okay.
So, they had huge trouble to maintain those fish,
because some careless rotations student couldn't see the fish inside the water,
because they are so transparent.
Okay, so, now they have to use huge labels.
There is a fish inside.
Please take care of it, okay?
And you can see in the live fish different part of
the brain, resemble eyes, heart brain okay.
And as I said, mice, rats, and nonhuman
primates are closer comparing with fish.
So especially the non human primate.
The recent development of genetic manipulation tools
allowed people to do the genetic manipulation in non human primates, and
this opens up a new window to study The higher cognitive function in the primates.
And again, human itself can also provide good
experimental examples if you follow the ethical procedure.
For example the psychology test frequently use human as an example
coupled with this recent development of brain imaging.
So one can couple with the human's response with the image data in
different brain region, or using some special normal activation
method in humans to study, at a human level, the neuronal functions.
And geneticist's techniques, because of the conservation of DNA,
all living organism provides a unique,
powerful, scalable techniques.
Those two allowing, observing, or perturbing the system
to study biosciences, including neuroscience.
The reason neuroscience is more complicated actually motivate
a lot of scientists, including the book’s author, Dr. to develop them.
To develop more sophisticated techniques
to answer the neuronal questions.
For example, how to achieve a single cell labyrinth,
biogenetic technique, to label a single neuron, it’s morphology.
For example, how to just predict
one gene in one neuron in the brain
to study whether there is a cell autonomous effect.
For example, some guided molecule is serving as a receptor
to guide to the molecule to guide to the neuron to grow, or
it's working as a non cell autonomous function to secrete
from adjacent cell to attract or repel a neuron to grow.
Because of the sophistication of the complicated,
complex of neural anatomy when requires this sophisticated
technique just to manipulate a single neuron in a rare
type background to get a very specific answer.
And there's other ways, for example, how to label one single
neuron in its entire connecting neuron in the brain.
That also recently been developed by the genetic technique.
And the genetics can be separated as
the full genetics, or reverse genetics.
This sounds like we are going to have a genetics class, which can itself last for
one or two semesters.
And the full genetics is that you don't know which gene might be important for
some functions.
So you can sort of randomly mutate [INAUDIBLE] and
then identified the outcome, and
then sequencing to find out which gene responsible for that.
Whether [INAUDIBLE] genetic is you have already some idea which gene or
which pathway might be.
Then you just diverted testing by perturbing looking out mutating them and
then to look at the phenotype that's responding to those mutations.
And the phenotype could be at a cell level or
at a behavior level and then you will start a different aspect.
The mutagenesis process, the important part is that
usually to achieve the phenotype understanding,
most of the single point rotation will be recessive.
So if there are mutation alone, we will not have phenotype.
And therefore, they need to achieve the homozygous
to observe the phenotype for most of the mutations.
And reverse genetics that people will use different ways to perturb the gene and
one of the powerful way and we discuss is so
that no cut in the old days using the combination
which is increasingly being replaced.
So this is combination you can generate some reactors and
then that allow yourself to have selection marker to select for the.
Because the efficiency is relatively low, so
[INAUDIBLE] to have a selection marker select for
those [INAUDIBLE] for the recent development of the reverse
genetics is that allow more sophisticated manipulation.
There is the conditional manipulation meaning that
one can introduce specific creed dependent,
recombinant dependent allele into a gene and
using a specific, tissue specific expression of this recombinase.
One can only manipulate in a specific tissue, those genes so
they can further achieve the tissue specificity.
And this tissue specificity,
again this is showing how this technique wise is being done
in the embryonic stem cell through this modification,
and then you transplant those modified cells into the.
For example, to create those genetically
modified reverse genetics engineered mouse.
And then more recent development of genome added into a,
for example, the system because it can using this
base parent dependent of cutting to generate double string break.
So you can much highly increase the efficiency.
So this revolutionized the whole thing by allowing one
to start it those animals that you don't have the cultural ES cell.
You can still achieve this genetic modification.
So that expanded the animal models that one can have the genetic manipulation.
And previously, one has to rely on the ES cell because efficiency is so
low so you have to culture tens of thousands of ES cell the screen for
those and then allow them to survive and to enrich them.
But now the efficiency can be much higher, so one can just simply inject and
then screen with 100 cells rather than 10,000 cell okay.
So it doesn't require the culture ES cell system to have this genetic modification.
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