Watching the Brain in Action

Typical images acquired from a highly scattering structure of an adult zebrafish brain. The fluorescence image on the left has a very blurry appearance indicating that the intense light scattering in large brains makes them inaccessible by optical microscopy methods. In contrast, functional optoacoustic tomography (right) is able to provide high-resolution three-dimensional information regarding real-time neuronal activity (orange dots) in the entire scattering brain. (Source: HZM)

Typical images acquired from a highly scattering structure of an adult zebrafish brain. The fluorescence image on the left has a very blurry appearance indicating that the intense light scattering in large brains makes them inaccessible by optical microscopy methods. In contrast, functional optoacoustic tomography (right) is able to provide high-resolution 3D information regarding real-time neuronal activity (orange dots) in the entire scattering brain. (Source: HZM)

Watching millions of neurons in the brain inter­acting with each other is the ultimate dream of neuro­scientists. A new imaging method – developed by researchers at the Helmholtz Zentrum München and the Technical Univer­sity of Munich – now makes it possible to observe the acti­vation of large neural circuits, currently up to the size of a small-animal brain, in real time and three dimensions.

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 Daniel Razansky, a group leader at the Institute of Biological and Molecular Imaging (IBMI), Helmholtz Zentrum München, has now found a way to address this challenge. The new method is based on opto­acoustics, which allows non-invasive inter­rogation of living tissues at centi­meter scale depths.

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.

“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 Xosé Luis Deán-Ben. 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.

“So far we demonstrated real-time analysis on whole brains of adult animals, 24 cubic milli­meter in size,” 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. (Source: IBMI / HZM)

Reference: X. L. Deán-Ben et al.: Functional optoacoustic neuro-tomography for scalable whole-brain monitoring of calcium indicators, Light Sci Appl., online 13 october 2016; DOI: 10.1038/lsa.2016.201

Link: Institute for Biological and Medical Imaging IBMI, Helmholtz Center Munich, Neuherberg, Germany

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