light
light-driven experiments delivered
unexpected results about how the brain
and nervous system work, elucidating
causes and effects.
“It took a few years to go from potential to fruition,” says neuroscientist
Karl Deisseroth of Stanford University,
a pioneer of the optogenetics movement.
“We’ve turned a corner.” Now, more than
500 laboratories are using optogenetics
to probe the brains of mice, fruit flies,
zebra fish and nematodes, and even to
probe human neurons growing in lab
dishes, to “get to the neural code for complex things, such as reward,” he says.
Optogenetics may help neuroscience
mature as a scientific discipline, says
Gero Miesenböck, a neuroscientist at
the University of Oxford in England and
a founding father of the field. With the
advent of optogenetics, he says, “neuro-
science is now finally catching up to the
widely held standards of proof in other
fields of biology and chemistry to help
establish causality.”
Light-responsive molecules used in
optogenetics experiments have two
basic modes. Some are neuron activa-
tors. When a specific wavelength of light
shines on the cells engineered to carry
these molecules, a channel opens and
allows positively charged ions to flow
into the cell. “This happens to be the neu-
ral code for ‘on,’ ” Deisseroth says. Other
light-responsive molecules, when tickled
with the correct wavelength of light, let
negatively charged ions into the cell. The
influx of negative ions silences neurons.
Using combinations of the two types of
molecules and different wavelengths of
light, researchers can flip neurons on
and off at will to find out how neurons
interact with their neighbors.
For now, knowledge of those inter-
actions is limited to small groups of
New technology illuminates
neuronal conversations in the brain
neurons within more extensive brain
circuits. But by flipping light-controlled
switches, scientists may eventually construct a full diagram of the brain’s wiring.
“The most exciting application right
now is the ability to control the activity,
remotely and noninvasively, of neurons,”
says Herwig Baier, a neuroscientist at the
University of California,
San Francisco. “It’s like a
functional MRI, except it’s
truly functional. You can
really show causality.”
Functional MRI has
helped researchers peer
into living brains, reveal-
ing which areas of the
brain are active (SN:
12/19/09, p. 16). But optogenetics allows scientists
to manipulate neurons instead of just
observing them. Scientists can identify
specific brain circuits, such as those that
help fruit flies sing love songs or give fish
their tail swish, as well as those that push
mice into addiction or cause them to collapse into depression.
may lack the brain circuit for creating
the mating serenade.
Clyne and Miesenböck engineered
fruit flies of both sexes to carry a light-responsive protein in the neurons that
make this fruitless in male flies. A pulse of
UV light activated the neurons, causing
males to immediately beat their wings.
But female flies began to
sing sultry music (to a
fruit fly), too. The result
indicates that male and
female flies have the
same underlying brain
circuitry, a surprise to
the researchers.
“We really had no
inkling that there is a
unisex structure that
you can switch to male
or female behavior,” Miesenböck says.
“It’s really an elegant solution.”
Though Miesenböck doesn’t much
care about the love lives of fruit flies,
studying the insects may help him figure
out how the brain ticks.
He and his colleagues are using the
technology for other basic biology
problems as well. Memory studies, for
instance, usually focus on the effect
of disrupting a particular gene or use
psychological tests to try to determine
how memories are made. But neither of
those types of experiment reveals which
neuronal circuits are activated during
the memory-making process.
“These approaches, I feel, leave the
black box pretty firmly shut,” Miesenböck
says. Genetic experiments that disrupt a
gene and shut down brain cell activity
aren’t as informative as finding out what
happens when a particular circuit is activated, he says. “There are many ways you
can break something, but often there’s
only one way to make it work.”
Optogenetics
allows scientists
to manipulate
neurons
instead of
just observing
them.
Flipping the switch
In 2008, Miesenböck and colleague
J. Dylan Clyne of Yale University reported
in Cell that they had used light to manipulate a brain circuit that controls courtship behavior in the fruit fly Drosophila
melanogaster. Researchers had already
known that one form of a protein called
fruitless is made in some neurons in male
fruit fly brains and that those neurons
help regulate the wing vibrations that
create the flies’ mating songs.
This form of fruitless had been found
in males but not females, and researchers think that the protein form helps
wire males’ brains to sing courtship
songs. Females, scientists had thought,
