Scientists under the leadership of the University of Bonn have harnessed rabies viruses for assessing the connectivity of nerve cell transplants: coupled with a green fluorescent protein, the viruses show where replacement cells engrafted into mouse brains have connected to the host neural network. A clearing procedure which turns the brain into a ‘glass-like state’ and light sheet fluorescence microscopy are used to visualize host-graft connections in a whole-brain preparation. The approach opens exciting prospects for predicting and optimizing the ability of neural transplants to functionally integrate into a host nervous system. The results have been published in “Nature Communications”.
Many diseases and injuries result in a loss of nerve cells. Scientists are working on tackling this challenge by transplanting neurons. In Parkinson’s disease, for instance, this is attempted with implanted dopamine-producing nerve cells.
The key question for such techniques is whether the implanted cells actually connect with the existing neural network of the host brain and thus compensate the functional loss. “Previous methods only provided an incomplete or very small-scale insight into the functional integration of implanted neurons in the brain,” says Prof. Oliver Brüstle from the Institute of Reconstructive Neurobiology at the University of Bonn and LIFE & BRAIN GmbH.
Exploiting viral spreading across neurons
Together with scientists of various disciplines at the University of Bonn and cooperation partners from Cologne and Chicago (USA), the team led by Prof. Brüstle developed a new technique: “This enables the connection of implanted cells in the entire brain to be visualized in high resolution.” The basis of this technology is provided by genetically altered rabies viruses.
The researchers are exploiting the fact that these viruses spread backwards via nerve cell junctions – called synapses. The genetically altered rabies virus, which is no longer dangerous to humans, carries a fluorescent protein. Upon infection of the graft, the transplanted neurons turn green. At the same time, the ‘green’ virus spreads backwards across established synapses to connected host neurons, which are also turning green.
A three-dimensional nerve circuit diagram across a transparent brain
To visualize the labeled cells, the team first employed a special clearing procedure. “This technique makes it possible to turn the brains completely transparent – almost as glass,” says Dr. Martin Schwarz from the Bonn Department of Epileptology, who perfected this technique. The transparent brain is then studied layer by layer, similar to computer tomography, using what is known as a light sheet fluorescence microscope, which Prof. Ulrich Kubitscheck and his team at the Institute for Physical and Theoretical Chemistry at the University of Bonn developed specifically for this purpose.
“With this technique, the brain is scanned in high resolution in over 1,000 virtual optical sections; the data is then reconstructed three-dimensionally,” explains Prof. Kubitscheck. “As the implanted neurons and the recipient’s nerve cells connected to them light up green, a three-dimensional brain map can be created that delineates all the recipient cells connected to the transplant – the graft connectome,” says Dr. Jonas Doerr, who first-authored the study together with Martin Schwarz.
As the brain tissue itself becomes invisible after the clearing procedure, the researchers in a last step aligned the fluorescent maps with neuroanatomical data generated via magnetic resonance tomography of mouse brains. “Similar to cities on a globe, all of the cells marked in green can thus be allocated to distinct anatomical territories,” says Prof. Mathias Hoehn from the Max Planck Institute for Metabolism Research in Cologne, whose group conducted these calculations.
Great potential for the development of nerve cell transplants
“Our findings show that the transplanted neurons integrate in a remarkably region-specific manner into the different transplant sites,” reports Prof. Brüstle. The researchers hope that the new approach will be particularly useful for studying and optimizing the ability of neuronal transplants to connect with the host brain before they are used for clinical therapy. As a next step, they plan to use the rabies system to investigate how human dopamine-producing cells can be best wired into the brain of mice with induced Parkinson-like symptoms.
Publication: Whole-brain 3D mapping of human neural transplant innervation, Nature Communications, DOI: 10.1038/ncomms14162
Prof. Oliver Brüstle
Institute of Reconstructive Neurobiology
University of Bonn
LIFE & BRAIN GmbH
Tel. +49 (0)228/6885500
Johannes Seiler | idw - Informationsdienst Wissenschaft
Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University
Direct conversion of non-neuronal cells into nerve cells
03.07.2018 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
17.07.2018 | Information Technology
17.07.2018 | Materials Sciences
17.07.2018 | Power and Electrical Engineering