From observing myriad nerve cells’ activity at once, unsuspected circuitry tied to alertness

By Bruce Goldman

A study in Cell from the lab of Stanford psychiatrist, neuroscientist and bioengineer Karl Deisseroth, MD, PhD, demonstrates a new technology’s power — it helped Deisseroth and his colleagues identify hitherto-unsuspected neuronal circuity in that all-important internal brain state called “alertness.”

Deisseroth is incorrigibly inventive. Several years ago he pioneered a dazzling technology called optogenetics, whereby specific sets of nerve cells in living animals’ brains can be genetically modified so they express a light-sensitive protein on their surfaces. Not just any light-sensitive protein, but one that can be induced on command to dispose the nerve cell it sits on to either fire, or to resist the impulse to fire, at the mere flick of a light switch. Optogenetics has already revolutionized neuroscience, because it allows researchers to explore specific neural circuits in, say, mice or rats and to determine what, exactly, it is that those circuits do for a living.

A second revolutionary technology introduced a few years ago by Deisseroth’s team is called CLARITY. The name describes quite well what the new method can do: chemically transform a brain so that it becomes transparent — you can literally read a newspaperthrough it — yet maintain its structural integrity, so that all the proteins on the surfaces of its resident nerve cells, and even the DNA in their nuclei, remain in position and essentially unchanged. CLARITY also makes the brain permeable to fluorescence-tagged molecular probes that can bind to particular nerve-cell surface proteins or to their internal genetic contents; the result is a color-coded map of the innards and “outtards” of the brain’s constituent nerve cells. Wow.

I’ll leave out several equally innovative methods pioneered in the Deisseroth’s lab, except for the latest one. Called MultiMAP, it’s a way of simultaneously observing the internal activity of practically every nerve cell in a small living creature’s brain. Researchers can tag nerve cells that were most active when the animal was engaged in a certain kind of behavior. This specifies not only the most-activated brain circuits’ locations but the types of cells of which those circuits are composed.

From my release about the study:

In particular, the investigators wanted to explore the activity of the brain’s neuromodulatory circuitry. Distinct from their more binary cousins — some 98 percent of neurons in the brain act by either exciting or inhibiting downstream neurons — clusters of neuromodulatory neurons send out projections that branch throughout the brain and act less like on/off switches than like colors on an artist’s palate. Rather than excite or inhibit, they instead add nuance by secreting substances that render excitatory and inhibitory neurons more or less likely to fire under various circumstances.

The researchers tied several such circuits, first in zebrafish and then in mice, to alertness.  What applies to those two creatures — whose ancestors diverged hundreds of millions of years ago — probably applies to us humans, too.

Too much or too little alertness contributes to depression, sleep loss, anxiety, mania and post-traumatic stress disorder. Now maybe we can get closer to the root of these problems.