Insights into the nervous system

How does the brain function?

Rapid transmission of nerve impulses

© Adapted from Rey S, Ohm H et al. eLife 2023. DOI: 10.7554/eLife.85752

Nerve bundles leading from a fruit fly’s ventral nerve cord – the equivalent of the spinal cord in humans – to the legs. The image shows sodium channel proteins (green) on the axons of the neurons, which transmit stimuli. The nuclei of glial cells light up pink. / Confocal fluorescence microscopy

Nerves carry signals, in the form of electrical impulses, from the sensory organs to the brain and from the brain to the whole body. Neurons pass on the impulses via long protrusions known as axons. In the process, voltage-gated channels open in the membrane of the axons. Charged sodium and potassium ions flow through these channels and redistribute. This creates an electrical impulse by changing the voltage across the plasma membrane. The distribution of the voltage-gated ion channels determines the speed of signal transmission. Neurons are supported by glial cells. They form an insulating layer around the axons, which is necessary for the rapid and precise transmission of stimuli.

We have shown that voltage-gated ion channels on fruit fly axons are not as evenly distributed as previously assumed. As in humans, a very large number of these channels is located at the beginning of the axons, at the site where an impulse is first generated. The ion channels are also arranged in clusters along the rest of the axon. We showed that axon-wrapping glia regulate the number and distribution of these channels, and that they form a myelin-like insulation. This suggests that, as in vertebrates, “saltatory conduction” provides the means for fast signal conduction velocity. Given these similarities, the fruit fly could serve as a model for studying the formation and regeneration of myelin. This is important for diseases such as multiple sclerosis in which the myelin sheath of the axons is damaged.

Henrike Ohm and Christian Klämbt
Institute for Neuro- and Behavioural Biology, University of Münster

A firework display of nerve cells

Lab insights

© Maite Ogueta, Uni Münster
  • This is the experimental set-up we use to explore how a fruit fly’s internal clock controls its behaviour. We measure how fruit flies with different clock or receptor genes react to external conditions such as light and temperature and how these influence the flies’ sleep-wake rhythm.
    © Uni Münster - Erk Wibberg
  • Each test tube contains a fruit fly. When the fly moves back and forth it interrupts an infrared beam, which is registered by a sensor. The number of interruptions indicates the activity level of the fly.
    © Uni Münster - Erk Wibberg
  • Under the microscope, we analyse the molecular mechanisms upon which the internal clock is based. Many of the fundamental principles of biological time measurement date back to early evolutionary stages, so experiments with fruit flies can give us some indication of how similar processes might take place in humans, too.
    © Uni Münster - Erk Wibberg
  • Certain preparations are necessary before we can examine fruit flies under the microscope. Based on wing shape or eye colour, we can distinguish between four chromosomes in fruit flies.
    © Uni Münster - Erk Wibberg
  • More than 3,000 strains of fly are kept at the Multiscale Imaging Centre in small tubes.
    © Uni Münster - Erk Wibberg
  • Each tube is labelled with the name of the genetic variant it contains. The flies reproduce rapidly and need only a little corn pulp and dry yeast as food.
    © Uni Münster - Erk Wibberg

Photoreceptor cells (pink) in the compound eye of a fruit fly. A protein involved in regulating the fly’s circadian clock lights up green. / Confocal fluorescence microscopy

Humans, animals, plants and single-celled organisms have an internal clock that is regulated by the brain. Covering a period of 24 hours, this clock controls many processes in the body, as well as behaviours such as the sleep-wake rhythm. Using the natural cycles of light and temperature, organisms synchronise their internal clock with the day-night rhythm of the external world. When for example we sit in front of an illuminated screen at night, the light suggests to the brain that it is day, and our internal clock becomes disrupted. We can investigate these processes in fruit fly, which have circadian clocks that are remarkably similar to those in humans and are controlled by the same “clock genes”. In the fruit fly, one gene that is important for signalling light information to the clock encodes the protein “Quasimodo”. This protein triggers a chain of molecular processes in the brain that set the internal clock to light. To better understand this chain of signals, we investigated where exactly this protein is located in the fly’s eye.

The compound eye of a fruit fly is made up of 800 individual facets – roughly 50 of them can be seen in this image. Each of these facets contains 19 cells, some of which are shaped like rods and cones, as in humans. These specialised sensory cells – the photoreceptors – convert light into electrical signals, helping to synchronise the internal clock with the daily alternation between light and dark. One of eight types of photoreceptor can be seen here (“R8”, rod-shaped cells coloured pink). The protein Quasimodo (green) is found in cells that are situated above the photoreceptors and form the lens of the individual facets. Of particular interest to us is the Hofbauer-Buchner eyelet (the roundish form in pink): these four cells transmit light stimuli directly to specialised pacemaker clock neurons in the brain.

Maite Ogueta and Ralf Stanewsky
Institute for Neuro- and Behavioural Biology, University of Münster

Making nerve fibres visible

Lab insights

© Bastian Maus, Uni Münster
  • The Multiscale Imaging Centre is home to a state-of-the-art magnetic resonance imaging (MRI) scanner that we use for mice and rats. It is much smaller than clinical scanners – but also much more powerful.
    © Uni Münster - Michael Kuhlmann
  • The core element of our small-animal MRI is a strong 9.4-tesla superconducting magnet. It is 100,000 times more powerful than the Earth’s magnetic field. Normally the magnet is shielded by a housing – this was removed for the purposes of the photograph.
    © Uni Münster - Michael Kuhlmann
  • The magnet’s stray field is shielded for safety reasons, as the magnetic forces could interfere with electrical devices such as cardiac pacemakers or magnetically attract metallic objects.
    © Uni Münster - Michael Kuhlmann
  • A Faraday cage has been set up in another lab at the MIC. It prevents electromagnetic radiation, such as that generated by mobile phones, from interfering with the MRI. A hybrid device that combines MRI with positron emission tomography (PET) is installed there.
    © Uni Münster - Michael Kuhlmann
  • Looking through a window at the small-animal PET-MRI at the MIC. Our team is developing new ways of taking images of the inside of the body to answer biomedical questions.
    © Uni Münster - Michael C. Möller
  • To achieve the optimal imaging contrast in the MRI to address a particular research question, we can vary a number of physical parameters (MRI sequences). An important part of our work also involves translating the complex data into meaningful images.
    © Uni Münster - Michael Kuhlmann

Nerve fibres in the brain of a mouse following a stroke. Healthy nerve fibres are shown in the right half of the brain (gold). We used a computer to segment the corpus callosum (purple) in the left half of the brain and underlaid it with the brain’s anatomy (grey). The corpus callosum connects the two halves of the brain. The stroke has damaged tissue, creating a gap in the fibre structures. / 3D image created by diffusion-weighted magnetic resonance imaging (MRI)

The brains of mice and humans can be studied in great detail using MRI. To create images, the MRI scanner generates powerful magnetic fields to which the hydrogen atoms in water and fat molecules in our body tissues react (“magnetic resonance”). The number and chemical environment of the atomic nuclei differ between tissues, thereby generating image contrasts. The imaging method shown here tracks the way water molecules move in the brain. Water molecules are in constant, random movement – a phenomenon that can be observed for example when tea is brewing and the water and tea particles blend of their own accord (diffusion). In the brain, the water molecules diffuse along the nerve fibres. By tracking their movements, we can draw conclusions about the structure and course of the nerve fibres.

The structure of the corpus callosum allows us to assess how seriously the link between the two brain halves has been damaged, for example by a stroke, and how well the healing process is progressing. Our study aimed to discover how physical activity and diet affect the brain structures in mice following a stroke. The nerve fibres of the corpus callosum became compacted and altered their cellular structure. Diffusion-weighted MRI is a clinically established method that makes it possible to investigate nerve fibres also in patients. The research work conducted here serves as the basis for the later development of a clinical routine. The extremely high resolution of and degree of detail in the 3D structures can so far be achieved only after measurement times of approximately eight hours. To this end, the brain, which is still encased here in cranial bone, was removed before the experiment. In a pilot study, we will now compare the findings we obtained in mice with data obtained with stroke patients.

Bastian Maus
Clinic for Radiology, University of Münster
The study is a joint project with Frederike Straeten and Antje Schmidt-Pogoda, Department of Neurology at Münster University Hospital.

Creating images of brain activity

© Hui-Fen Chen, Bruno Pradier; background c57bl/6j model by Janke AL et al. 20th Annual ISMRM Scientific Meeting and Exhibition 2012. https://imaging.org.au/AMBMC/Model/

Active regions (coloured signals) in the mouse brain in response to a pain stimulus. The image shows the average from ten female mice. The red area represents a brain region that is active in all animals. / Functional magnetic resonance imaging (fMRI) – overlaid with an anatomical MRI image of a typical mouse brain (grey).

Various parts of our brain work together in a very specific way. We use functional MRI to examine these brain networks in mice. Those areas of the brain that are active require particularly large amounts of oxygen – this changes the flow and volume of blood there, and thus also the level of oxygen supply. We can use fMRI to visualise this haemodynamic response to the activity of the nervous system as it unfolds. Since the same imaging technique can also be used in humans, it is very likely that findings obtained in mice can be used for clinical applications. We study different forms of epilepsy and types of pain, for example. If we better understand brain activity under such conditions, this can help refine diagnoses and therapies.

The image shown here is based on the clinical observation that women are at higher risk than men of developing chronic pain after surgery. We are investigating the mechanisms underlying this phenomenon. In this study, we measured brain activity in female and male mice in response to tactile stimuli applied to the animals’ hind paws. This allowed us to study hypersensitivity following a surgical procedure simulated by a skin incision. During the experiment, the mice are anaesthetised. To compare measurements across different animals, we first synchronise the data with a reference image. We then calculate how the stimuli correlate with activity in different areas of the brain over time. We found that brain activity – under the same conditions of pain processing – is more pronounced in female mice than in their male counterparts, meaning that higher sensitivity can be objectively measured in female mice. On this basis we can further explore the sex-specific mechanisms by which pain is processed and how different medications might help. Incidentally, the stimulus applied to the right hind paw is reflected in the left hemisphere of the brain because each half of the body in animals and humans is associated with the opposite half of their brain.

Bruno Pradier and Lydia Wachsmuth
Clinic for Radiology, University of Münster
The research into pain processing is a joint project conducted with Esther Pogatzki-Zahn and Daniel Segelcke, Department of Anaesthesiology, Intensive Care and Pain Therapy at Münster University Hospital.