This is your brain on integrated technology

It's only been a few months and I already want to update you with something relevant to a previous post about optogenetics. Today we're going to talk about how optogenetics is being used in parallel with other techniques in a new integrated technology that allows for the study of the brain from many different angles.

The brain in constantly changing and adapting to new stimuli. This makes it difficult to do research on. An investigator must either sacrifice an animal to see how the brain was at a discrete point in time, or study it in a living mouse, unable to manipulate and study it very easily. It acts somewhat like Heisenberg's uncertainty principle: one must sacrifice one answer in order to get another. Ideally, a scientist would want to measure brain activity in a living animal, while altering it experimentally, and do this for an extended period of time to see how it changes.

To attack this problem, researchers at MIT have developed a special way of measuring and manipulating the mouse brain. They use a thin wire that allows them to optogenetically activate cells, measure cell activity at a single neuron level, and administer drugs. This is implanted into the head of the mouse while it is awake and behaving normally. The wire also provides reliable data for as long as 2 months. With all these traits, scientists can do longitudinal studies that are physiologically relevant and give a realistic picture of long term brain activity and development.

To create these small wires, the scientists first made a large collection of tubes called a macrotube with several components. This includes materials for probing small subsets or even individual neurons, a light transporting component to optogenetically activate specific cells of interest, and hollow tubes to deliver drugs. Using a thermal drawing process, the macrotube is stretched until the collection of wires is on the order of 400 µm, slightly wider than a human hair. The organization is maintained, but every component is scaled down. The new wire is 100-200 times smaller than the original macrotube. If the idea of a thermal drawing process is a bit confusing, watching this video of how ribbon candy is made may help.

Conventional probes are rather rigid, and can cause build up of scar tissue and brain damage as the mouse moves around. Here, scientists used polymers that are more elastic to make their probes softer and more flexible. The probes did far less damage than conventional probes and allowed researchers to study the same mouse for up to 2 months. Combining these techniques, and allowing for lengthy studies lets neuroscientists investigate specific neurons as they relate to larger circuits and systems. As behaviors change, drugs are added, and cells are activated, they can determine which neurons change their firing patterns and could be responsible for system level changes. Integrative technology such as this has the capacity to change how we approach behavioral research in mice, and how we study the brain.

There is a lot of potential in this technique that may be possible in the future. When optical fibers become more advanced, we could take pictures, or even videos of the cells, to see how the dynamics of groups of neurons are changed. Although it would take far more bandwidth and potentially bother the mouse, using more than one wire at a time would allow us to see how different regions of the brain change in response similar stimuli. It could also show us how regions interact. Using this technology to look below the surface of the brain, if we can prevent severe damage, could shine a light on the inner workings of harder to study areas. This work is a big step in the field and should be explored and tinkered with in order to utilize it to its full potential.

Update:

In reponse to a comment, I thought it would be a good idea to add some data. What is fun, new science without the data to back it up? In the first figure shown here, the scientists wanted to show that they could activate neurons, the neurons would respond, and the microelectrode could record the responses. They used mice expressing channelrhodopsin driven by a thy1 promoter. Thy1 expressing cells include most neurons and many other cells outside of the brain. The figure below shows the neurons respond quickly to light activation. Upon the light stimulus, indicated by the blue dots along the top, the neurons would fire an action potential. The neurons would respond to the light stimulus up to 2 months after implantation of the microelectrode.

To show that they were able to successfully administer drugs using this system, the injected CNQX through the hallow tubes of the microtube. CNQX is an AMPA and kainate receptor antagonist, this would stop neurons from firing upon light activation. They demonstrate that before injection, they get response to optogenetic stimulation (as seen above and in the far left panel here). After CNQX injection, they see no response to light in the neurons, indicating that the drug injection worked. After an hour, the drug wore off and the neurons responded again to activation.

For more information as to how they verified that they could reliably record from single cells, you should read their paper linked below in the references. I find it well-written and straightforward.

References:

Canales, A., Jia, X., Froriep, U.P., Koppes, R.A. et al. Multifunctional fibers for simultaneous optical electrical and chemical interrogation of neuronal circuits in vivo. Nature Biotechnology, 33, 277-284 (2015).

Herrera, C.G. & Adamantidis, A.R. An integrated microprobe for the brain. Nature biotechnology, 33, 259-260 (2015).

Image credits:

The first image comes from the review paper by Herrera & Adamantidis. The images of the wire along with the data come from the Canales et al. paper in Nature Biotechnology.

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