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Summary master course Animal models for neurological disorders

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Radboud Universiteit Nijmegen (RU)

All material from the master course animal models for neurological disorders. Summarized are the lectures, assignments, and self study. All material summarized with accompanying figures. It contains all material given in the Biomedical Sciences Master course.

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Summary Animal models for neurological disorders
Biomedical Sciences Master Course

Radboud University, Nijmegen

Made by: Georgia Graat

,Rules in animal models

Animal models have been discussed as long as they have been used. There are three reasons why
the use is still popular and needed at the moment.

1. The law dictates that new drugs should be tested for efficacy and safety in animals before
they are tested in humans
2. It gives a detailed mechanistic understanding of health and (brain) disease and therefore
ultimately the design of new treatments
3. It gives a better fundamental understanding of (neuro)biology

There are several reasons why animals give an increased mechanistic understanding of diseases
compared to human studies.

1. More invasive and thus more detailed measurements
a. In humans we can only look at genes, systems and the behavior. In animals we are
allowed to study cells and circuits with invasive techniques and even killing
2. Enhanced experimental control considering environment, genetic manipulations, drug
intake, age, timing of events
3. More invasive and precise manipulations e.g. genes
a. With which we can study causality of factors

One important aspect in animal studies is that you should always choose the best animal species for
the purpose of your experiment. Zebrafish and fruit flies are used as very simple animal species.
More advanced and more often used are rodents. The advantages of the mouse over rat are that
genetically modified mice way more common are, they are cheaper (less space and faster breeding),
and they are inbred. The advantages of the rat over the mouse are the bigger size (more tissue),
more social, more easy to handle, higher cognitive functions, and outbred (increased genetic
variance). However, rat manipulations mainly exist of behavioral toxicology.

Behavioral studies include around 8 to 15 mice per group. Control groups in animal studies can be
many different things: not having the disease of interest, not getting the same treatment, not getting
neurological stimulation, not receiving e.g. stress-inducing shocks. Control groups still have to be
exactly the same in terms of species and genetic constructs, and always have to perform the same
behavioral tests.

Animal models are used to model the ‘’human’’ psychopathology, assuming obtained findings in the
animal are informative on the human situation. Animal models will, however, only be useful when
they are valid models and represent the human pathology in the way needed to study it. As animals
and humans are not alike in all ways, the validity of similarity has to be good enough to study
animals as if we are studying humans. Justification for animal models is based on their distinctiveness
and similarities from humans.

1. Construct (etiological) validity
a. Similar cause
b. The degree to which an animal model mimics the etiological or causal processes that
lead to the disease in patients
c. Problem: cannot know if the animal model has construct validity if the mechanism in
the patient is unknown

2. Face validity

, a. Correct outcome measure
b. The degree to which an outcome measure in animals reflects what it reports to
measure meaning if the outcome of the test actually says something about the factor
of interest
c. Problem: evaluation is subjective
3. Predictive validity
a. Similar outcome (prediction for outcome)
b. The degree to which outcome measures in animals are predictive of outcome
measures in the targeted patient population
c. Problem: there are substantial individual differences in responsivity between
humans. Especially in drugs this is a problem. Further, several drugs are not specific
for the treatment of one disorder

Very important in animal studies is the translational value of the animal-derived data. There is a
constant public debate going on whether it is ethical to use animal models. The limitations of animal
models are for example that the disease of interest can almost never be exactly replicated, some
animals are studied and sacrificed eventually for nothing if the data cannot be used or if the data is
not translatable enough, animals can be harmed in the process, time-consuming and expensive tests,
animal models often do not show the toxicity outcomes as seen in humans, and animals can only be
checked on certain behavior with experimental tests (not asked
how they feel or what they are doing) and thus the interpretation
of behavior and emotions is always subjective. Still, some diseases
can never be solved and some medications can never be made if
we remove animal models from research. The alternatives at the
moment are not yet good enough to replace them. To improve
animal work, more quality and predictive values of the work
should be guaranteed, transparency of the work has to be
improved, and integration of different animal genders and more
naturalistic settings should be done.

The current rules state that researchers first have
to do an animal welfare course and achieve their
article 9. When they want to start an animal
study, they have to write a DEC application, that
will be checked and approved by the local animal
welfare body. The animal welfare body works
with the research institute and already helps you
write the study application. They send it to the
DEC (dier experimenten commissie) and these
send it to the CCD (centrale commissie
dierproeven). Both ethical committees have to
approve that the answer is more important than
how much the animals will suffer. The project license with ethical approval is approved after the DEC
approves. You can write the work protocol after which only has to be checked by the IvD (instantie
voor dierwelzijn) that approves the experiments and ensures not too much harm to the animals.

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