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“The cell activity can be modulated as desired“

Epilepsy Research in the Brains of Mice: “The cell activity can be modulated as desired“


Photo: Heinz Beck

Professor Heinz Beck; © private

What exactly happens in the brain during an epileptic seizure? And can this knowledge help in finding better therapies for patients in the future?

Professor Heinz Beck from the University of Bonn, Germany, wants to find the answers to these questions and together with Caesar – Center of Advanced European Studies and Research – researches the brain of transgenic mice to be able to better understand epilepsy at the network level. Professor Beck, to be able to better understand the epilepsy disease, in the future you want to investigate nerve cells in the brain of mice that can be stimulated using light. Neuronal signals can thus be studied in vivo in a freely moving mouse. For this experiment, the animals among other things are outfitted with a special kind of “top hat. “
What kind of planning was required prior to these experiments?

Heinz Beck: I need to go a little further back for this, since the brain is a very complex organ with several trillion nerve cells that are connected to each other to where every nerve cell receives several tens of thousands of signals from other nerve cells. In addition there are very many different types of nerve cells in the brain, which differ in terms of their characteristics and their connection. Up to now this made brain research very difficult, since to be able to determine what a certain class of nerve cells is doing in an intact animal, you would have to be able to switch these on and off selectively. So far this was not possible in a freely moving animal. Now Karl Deisseroth and Peter Hegemann have developed a method that basically enables us to do precisely that. We have established this method which makes use of the possibility to express light-sensitive channels specifically in certain types of cells. These channels, so-called channelrhodopsins, originally stem from light-sensitive protozoas, which for instance are able to swim towards a light source. The interesting thing is that precisely those channels that are light-sensitive and due to the light virtually produce electricity, can be embedded into the cells. This way the activity of the cell can be quickly and specifically modulated as desired. Additionally, we have the genetic technology at our disposal to express these channels only in very specific cells. Does this mean that in the run-up mice are bred so they can be used for these experiments? So we are dealing with so-called transgenic mice?

Beck: That is correct. We follow a relatively complicated strategy with genetically modified animals. The light-dependent ion channels are being inserted into their nerve cells. Through this a specific subgroup of cells becomes light-sensitive in the brain of the mouse. Needless to say, normally the brain is not reached by light beams. That is why we implant a fiber optic strand, with which we can activate these cells – so as to be able to study the effects on the behavior of the animals. According to this, the mouse has a small electrode in the brain?

Beck: Correct. We need it to measure the nerve cell activity in the freely moving animal, while we conduct the light stimulation at the same time. We were able to technically develop the test set-up in collaboration with our colleagues from Caesar . We have developed an assembly that precisely meets our requirements. For example, an electrode was devised that can transfer nerve cell activities with a total of 16 electrodes. The so-called optode or optrode, a small LED glass fiber, enables us to ‘expose‘ specific locations in the brain. Since the animal is supposed to move freely, this happens telemetrically. This means that the measured data is wirelessly transmitted to a receiver, from which it can be collected and analyzed. This way we reach our goal to be able to manipulate and measure nerve cell activity in a freely moving animal.

Photo: Modell of a mouse with backpack

The cylinder on the head of the mouse optically stimulates the neurons in the brain. The signals are transmitted through a cable to a backpack and sent wirelessly to the computer; © caesar What kind of problems occurred during the development?

Beck: One problem is the extreme miniaturization. We can only do these experiments on mice, since we need transgenic mouse models for the cell-specific expressions. This would not be possible with a rat, but mice are small! That is to say, the mouse must be able to wear the headset that we developed during the experiment. And of course it doesn’t make sense if we have a full telemetry test set-up, yet the mouse has so much weight on its head to where it no longer can move around freely. How do you plan on later making the step from mouse to human being?

Beck: That is a somewhat difficult question. Although to my knowledge there are many people that also want to use these light-based stimulation approaches in human beings, among others the co-developer of this method Karl Deisseroth from Stanford University. However, you need to be aware of the fact that you then have to express the light-sensitive channels into the brains of patients to be able to manipulate the neurons with light. And I believe that this actually presents a certain inhibition threshold.

In addition there are a number of problems involved with making the expression cell-specific. At the moment we work with transgenic mouse models, but in humans you would have to approach this entirely differently. However, I think the advantage of this method is that in combination with the different procedures and the anatomical, biomolecular and genetic methods, for the first time we have the chance to understand the complex network in the brain. This alone for instance is an enormous advantage for developing pharmaceutical products, to where you can say that our research is already paying off. After all, the problem in developing neuropharmaceutical products is that we actually do not entirely understand the brain’s method of operation and the problems that arise during the disease at the cellular network level, respectively. How did you end up choosing this test set-up, particularly for the area of epilepsy research? Are there special opportunities in this area?

Beck: Fact is that the disease pattern and the development of the technology mutually stimulated themselves so to speak. The main symptom of epilepsy is epileptic seizures. And these seizures are, on a cellular level, a networking phenomenon par excellence, since they correlate on a cellular level with a pathologically synchronous neural ensemble activity. And if you are interested in what exactly happens in the brain, you also need to know the baseline activities in a normal brain – this meaning to understand the specifics, the basic motives of the networks themselves. And only then can you understand how seizure activity can be generated in such a network. Actually we can only develop pharmaceutical products this way.

Especially in epilepsy there only is one drug for instance that was developed on the basis of a pathophysiological cause. All other antiepileptic drugs were either developed on the basis of relatively global beliefs that are not necessarily right, or on the basis of animal models which mirror human diseases, but very incompletely. Thus the reject rate is very high. So there are a lot of drugs that fail in clinical testing. What kind of data would you like to gain from these tests and what type of experiment will you conduct?

Beck: Although the in vivo experiments are still in the developmental phase, basically you can obtain data on single cell activity from the measuring electrodes through mathematical methods. Then you virtually see when a cell discharges and when it produces an output signal, which then permits a signal transmission to other nerve cells. You can then measure this in ten, twenty or more cells via an electrode assembly. The simultaneous light-based stimulation of certain genetically defined cell types then permits you to determine how these cell types affect the behavior of the neural population in vivo. This is a big opportunity to find out how different types of nerve cells are cross-linked with one another in an intact brain.

Photo: Picture of an optrode

The picture shows the structure of an optrode: On the left in the overall view, on the right in magnification. Fiber optic and LED are stuck in a pit. The light is directed to the tip of the optrode. The sixteen gold electrodes are located on two levels and are separated by a SiO2-conductor; © caesar When will you be able to start the first experiments?

Beck: At the moment, we are still in the development phase. However, we figure that in a few short weeks we will receive a prototype from Caesar, which we then are able to implant in a test mouse.



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