Luminous paths in the brain

Thanks to a new indicator molecule, scientists can now observe the activity of single nerve cells on a long-term basis

The brain determines who we are, what we do and how we perceive the world around us. And so it is not surprising that man has always been fascinated by the brain. To understand how the brain functions, one must be able to interpret the "language" of the nerve cells, i.e. the pattern of their electrical activity. However, it is difficult to filter out the signal of any one particular cell from the signals of thousands of neighboring cells. To track the activity of a single neuron over a period of many weeks is practically impossible. But precisely these observations would be invaluable to investigate how the response properties of single cells change during the course of an illness, during development and aging or during learning processes. Up until now, such research was nothing more than a pipe dream.

Tracking down cell activity

In the last few years, however, research methods have been greatly improved and refined. The development of specific fluorescent dyes, for instance, meant that the activity of individual nerve cells could be rendered visible. These dyes are based on synthetic calcium indicators which alter their brightness when bound to calcium. Calcium is present in all nerve cells and the free calcium concentration changes when, for example, a nerve cell passes on an electrical impulse. Artificially introduced into a cell, such calcium indicators can therefore render the cell's electrical impulses visible. In addition, the presence of the fluorescent dye in the cell causes the latter to stand out from the mass of nerve cells and so it is clearly visible with all its ramifications. Using modern 2-photon-microscopy, the activity and anatomy of the cells in question can thus be studied directly in the brain. However, these artificial dyes tend to leak out of cells within a short time, preventing long-term observation.

Genetically encoded calcium indicators are a good alternative to synthetic dyes. These molecules are proteins produced by genetically altered nerve cells. When the nerve cell is active, the indicator molecules emit a yellowish hue; otherwise they are bluish. It is therefore no longer necessary to penetrate the cell and inject a dye to render cell activity visible. However, here too, there is a problem: In comparison to the artificial dyes, the genetically encoded indicator molecules did not respond unless the changes in the calcium concentration were considerable. And so, long-term observation of the activity of single nerve cells still amounted to no more than wishful thinking.

TN-XXL: The answer to the researchers' wish?

The wish now appears to have come true. Scientists at the Max Planck Institute of Neurobiology have successfully developed a considerably more efficient calcium indicator. This molecule, named TN-XXL, is more sensitive than its predecessors and reacts to even small changes in the activity of nerve cells. Since TN-XXL is continually being reproduced by the nerve cells, its high luminosity remains constant. And so the activity of single nerve cells can be observed over a period of many weeks in the intact brain.

Oliver Griesbeck, head of the study, reckons that "TN-XXL should cause quite a stir in neuroscience research." The unique opportunity to study the activity of individual nerve cells over a longer period of time is an important prerequisite for understanding how the brain functions and changes over time – whether in the course of its development, during aging, or when processing new information. Griesbeck also assumes that there will be applications for the new molecule in clinical research. "TN-XXL can, for example, be implemented to trace the course of diseases or the effect of medication in the body." And so it should not be long before TN-XXL gives us new insight into how our brain and body function.

[SM]