Nowadays it is well recognized that most brain functions may not be comprehended through inspection of single neurons. To advance meaningfully, neuroscientists need the ability to monitor the activity of millions of neurons, both individually and collectively. However, such observations were so far not possible due to the limited penetration depth of optical microscopy techniques into a living brain.
A team headed by Prof. Dr. Daniel Razansky, a group leader at the Institute of Biological and Molecular Imaging (IBMI), Helmholtz Zentrum München, and Professor of Molecular Imaging Engineering at the Technical University of Munich, has now found a way to address this challenge. The new method is based on the so-called optoacoustics*, which allows non-invasive interrogation of living tissues at centimeter scale depths.
”We discovered that optoacoustics can be made sensitive to the differences in calcium ion concentrations** resulting from neural activity and devised a rapid functional optoacoustic neuro-tomography (FONT) system that can simultaneously record signals from a very large number of neurons”, said Dr. Xosé Luis Deán-Ben, first author of the study. Experiments performed by the scientists in brains of adult zebrafish (Danio rerio) expressing genetically encoded calcium indicator GCaMP5G demonstrated, for the first time, the fundamental ability to directly track neural dynamics using optoacoustics while overcoming the longstanding penetration barrier of optical imaging in opaque brains. The technique was also able to trace neural activity during unrestrained motion of the animals.
Tracking the wildfire
„So far we demonstrated real-time analysis on whole brains of adult animals with roughly 2x3x4 millimeter dimensions (approximately 24 mm3),“ says the study’s leader Razansky. State-of-the-art optical microscopy methods are currently limited to volumes well below a cubic millimeter when it comes to imaging of fast neural activity, according to the researchers. In addition, their FONT method is already capable of visualizing volumes of more than 1000 cubic millimeters with temporal resolution of 10 milliseconds.
Large-scale observation of neural activity is the key to understanding how the brain works, both under normal and diseased conditions. „Thanks to our method, one can now capture fast activity of millions of neurons simultaneously. Parallel neural networks with the social media: in the past, we were able to read along when someone (in this case, a nerve cell) placed a message with a neighbor. Now we can also see how this message spreads like wildfire,“ explains Razansky. „This new imaging tool is expected not only to significantly promote our knowledge on brain function and its pathophysiology but also accelerate development of novel therapies targeting neurological and neuropsychiatric disorders,” he concludes.
* Optoacoustics allows for high resolution, non-invasive, 3D imaging of living tissues. The technology uses short laser pulses that cause short-term expansion of the tissue, leading to tiny ultrasound vibrations. Those are registered with specially designed detectors, processed and converted into three-dimensional images of the interrogated tissue. To this end, the Helmholtz researchers have developed a number of optoacoustic imaging technologies for tracking hemodynamics and targeted agent delivery in a number of pre-clinical and medical imaging applications. The current work addresses significantly faster biological processes, such as neural activation.
** Nerve activation causes displacements of the calcium ions, which are transported in or out the neurons through so-called ion channels. Fluctuations in the intra-cellular calcium concentrations can be measured by means of genetically encoded calcium indicators (GECIs), which change their absorption spectrum, and consequently their color, depending on the amount of calcium present.
For his research, Razansky was awarded with highly competitive research grants from the European Research Council (ERC) and the US National Institutes of Health (NIH).
Deán-Ben, XL. et al. (2016): Functional optoacoustic neuro-tomography for scalable whole-brain monitoring of calcium indicators. Light: Science & Applications, doi:10.1038/lsa.2016.201
The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members.
The Institute for Biological and Medical Imaging (IBMI) conducts research into in vivo imaging technologies for the biosciences. It develops systems, theories and methods of imaging and image reconstruction as well as animal models to test new technologies at the biological, preclinical and clinical level. The aim is to provide innovative tools for biomedical laboratories, for diagnosis and for the therapeutic monitoring of human diseases.
Technical University of Munich (TUM) is one of Europe’s leading research universities, with more than 500 professors, around 10,000 academic and non-academic staff, and 39,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, reinforced by schools of management and education. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German „Excellence University.“ In international rankings, TUM regularly places among the best universities in Germany.
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Scientific Contact at Helmholtz Zentrum München:
Prof. Dr. Daniel Razansky, Helmholtz Zentrum München – German Research Center for Environmental Health, Institute for Biological and Medical Imaging, Ingolstädter Landstr. 1, 85764 Neuherberg – Tel. +49 89 3187 1587, E-mail: