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Translating the brain’s signals

July 24, 2015

Brain cells use pulses of electricity to communicate with one another, forming the circuits that underlie everything from your ability to recognize objects to your most cherished memories. By placing an electrode near the cell body of a neuron, we can listen to it “speak” to its neighbor cells. This valuable data gives us insight into how and when different cells send signals, helping us learn their intricate language.  

But since there are many different types of neurons, being able to selectively listen to just a particular cell type—or at least being able to discern the different types of cells under observation—is critical. This becomes even more challenging as researchers collect data from hundreds, or sometimes thousands, of cells at the same time.

Ulf Knoblich and Lu Li“To understand the circuits that underlie brain function, we need to see them working in their natural habitat,” says Ulf Knoblich, a research scientist at the Allen Institute for Brain Science. “This means we need a reliable way to listen to multiple cells in the brain at the same time, even if it means not listening to them directly, but finding another way to take those measurements."

One indication that a cell has fired a signal is the presence of calcium ions, which flood into a neuron when a spike occurs. The concentration of calcium ions can be captured in a microscope thanks both to indicators that become fluorescent in the presence of calcium and to transgenic mice that express those indicators in certain cells. This makes calcium data an ideal stand-in for electrical data when scientists need to capture information about a specific type of cell.  

But there is a catch. If we need to know how far to travel in miles but we only have the distance in kilometers, we can perform a simple calculation that lets us convert from one to the other. Because calcium is not a direct indicator of electrical behavior—just a correlated event—we need a similar way to convert calcium signal data back into electrophysiological data.

Knoblich and scientist Lu Li, the Advanced Physiology team within the interdisciplinary Cell Types program at the Allen Institute, are working to create a custom rig that records both calcium and electrophysiological data at the same time from the same cells. Their goal is to come up with a way to reliably convert one type of data into another by carefully characterizing how calcium activity and electrophysiological behavior are related.

The challenge is more than scientific: it’s also logistical. Trying to situate all the pieces to capture multiple types of data at once is like playing a microscopic game of Tetris.

“This is a highly challenging project, with enormous technical obstacles to simply conducting the experiment,” explains Li, lead of the Advanced Physiology program. “We are essentially trying to create a Rosetta stone that will allow us to translate between the languages of electrical and calcium signals. To do that, we need to insert a tiny probe onto the same cell that we’re also trying to image using a sophisticated microscope. Only a handful of groups around the world can manage all these pieces at once, and we are one of them.”

Li and Knoblich are still working on crafting their rig in order to perfect the data they collect. Once they do, they’ll have a powerful way to ask bigger questions of groups of cells, eventually gaining insight into phenomena we can witness outside a microscope, like sensation and perception.

“This kind of translation requires expertise from a number of different fields, from electrophysiology of cells to hardware and software development,” says Knoblich. “We hope that working as a team will get us to the point where we can use calcium data to gain meaningful insights about how the brain’s intricate circuits function.”

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