PATRIZIA KROK, MICHAEL MEI, and NICK ROBINSON
Understanding the brain’s ongoing processes at the cellular level not only promises to help determine the physiological
basis of cognition, but also nurtures the
hope of curing brain diseases that are
currently difficult or impossible to treat.
Achieving this understanding—that is,
determining the brain’s functional network structure and how that structure
links to cognition and behavior—
requires the ability to record the activ-
ity of large numbers of neurons, and
to manipulate and probe that activity.
In groundbreaking experiments, neu-
roscientists from the group of Professor
Michael Häusser at University College
London have succeeded in observing
and controlling the activity of defined
cell types at an unprecedented level by
way of optogenetics. The work leverages important new developments in
light-sensitive probes and genetically
encoded activity sensors, plus novel optical hardware, that together enable re-
cording and manipulation of neural circuit activity—with single-neuron and
single-action potential precision—us-
ing only light in the intact brain.
The underlying experimental loop
includes behavioral tasks, imaging
of activity patterns in the brain, and
replaying those same pat-
terns in the identified spe-
cific functional neurons
(see Fig. 1). The research-
ers’ success has advanced
the concept of cellular-res-
olution functionally de-
fined optogenetics from
the status of “dream experiment” to
“real application,” enabling a deeper
insight into neuronal communication.
Deep-tissue imaging and
Although the basic mechanism of neural
activity is well understood, the complex
interconnection of specific neurons or
groups of neurons, and the behavioral
pattern they are linked to, are not—and
thus require novel and interdisciplin-
ary techniques of investigation.
Häusser’s team has managed to
observe the activity of >1000
single neurons simultaneously,
while manipulating the activity
of 100 targeted neurons to determine
the extent to which their action is re-
producibly linked to a behavior.
Neurons communicate with one an-
other through electric potentials that
migrate as signals along the cell mem-
brane. The level of positively and neg-
atively charged ions present in and
around the cells control their activity.
When an action potential is triggered,
calcium (Ca2+) ions flow through chan-
nels in the membrane into the neuron.
Häusser and his team genetically mod-
ified the brain of a mouse by inserting
two different proteins: a calcium-sen-
sitive fluorophore and a light-sensitive
ion channel. The ion channel inserted
into the cell membrane can be optically triggered to cause sodium (Na+) ions
to flow into the cell, resulting in a neural action potential. The action potential then opens voltage-gated Ca2+ chan-
nels, and Ca2+ ions flow into the cell and
increase the fluorescence. Because the
fluorescence is easily visible, it is easy
to confirm success of the stimulation—
and thus neural activity.
In collaboration with Thorlabs, the
Häusser group developed a setup for in
vivo photoactivation of specific neurons
Once an unattainable concept,
defined optogenetics has arrived—
promising deep insight into the causal
relationships between neuronal
operations and behavior.