Optogenetics

Optogenetics (from Greek optikós, meaning

'seen, visible') is a biological technique which
involves the use of light to control cells in living
tissue, typically neurons, that have been
genetically modified to express light-sensitive
ion channels. It is a neuromodulation method
that uses a combination of techniques from
optics and genetics to control and monitor the
activities of individual neurons in living tissue—
even within freely-moving animals—and to
precisely measure these manipulation effects in
real-time.[1] The key reagents used in
optogenetics are light-sensitive proteins.
Neuronal control is achieved using optogenetic
actuators like channelrhodopsin, halorhodopsin,
and archaerhodopsin, while optical recording of
neuronal activities can be made with the help of
optogenetic sensors for calcium (GCaMP),
vesicular release (synapto-pHluorin),
Neurotransmitter (GluSnFRs), or membrane
voltage (Arc Lightning, ASAP1).[2] [3] Control (or
recording) of activity is restricted to genetically
defined neurons and performed in a
spatiotemporal-specific manner by light.

In 2010, optogenetics was chosen as the

"Method of the Year" across all fields of science
and engineering by the interdisciplinary
research journal Nature Methods.[4] At the same
time, optogenetics was highlighted in the article
on "Breakthroughs of the Decade" in the
academic research journal Science.[5] These
journals also referenced recent public-access
general-interest video Method of the year video
and textual SciAm summaries of optogenetics.

History
The "far-fetched" possibility of using light for
selectively controlling precise neural activity
(action potential) patterns within subtypes of
cells in the brain was thought of by Francis
Crick in his Kuffler Lectures at the University of
California in San Diego in 1999.[6] An earlier use
of light to activate neurons was carried out by
Richard Fork,[7] who demonstrated laser
activation of neurons within intact tissue,
although not in a genetically-targeted manner.
The earliest genetically targeted method that
used light to control rhodopsin-sensitized
neurons was reported in January 2002, by Boris
Zemelman (now at UT Austin) and Gero
Miesenböck, who employed Drosophila
rhodopsin cultured mammalian neurons.[8] In
2003, Zemelman and Miesenböck developed a
second method for light-dependent activation
of neurons in which single inotropic channels
TRPV1, TRPM8 and P2X2 were gated by
photocaged ligands in response to light.[9]
Beginning in 2004, the Kramer and Isacoff
groups developed organic photoswitches or
"reversibly caged" compounds in collaboration
with the Trauner group that could interact with
genetically introduced ion channels.[10][11]
TRPV1 methodology, albeit without the
illumination trigger, was subsequently used by
several laboratories to alter feeding, locomotion
and behavioral resilience in laboratory
animals.[12][13] [14] However, light-based
approaches for altering neuronal activity were
not applied outside the original laboratories,
likely because the easier to employ
channelrhodopsin was cloned soon
thereafter.[15]

Peter Hegemann, studying the light response of

green algae at the University of Regensbug, had
discovered photocurrents that were too fast to
be explained by the classic g-protein-coupled
animal rhodopsins.[16] Teaming up with the
electrophysiologist Georg Nagel at the Max
Planck Institute in Frankfurt, they could
demonstrate that a single gene from the alga
Chlamydomonas produced large photocurents
when expressed in the oocyte of a frog.[17] To
identify expressing cells, they replaced the
cytoplasmic tail of the algal protein with the
fluorescent protein YFP, generating the first
generally applicable optogenetic tool.[15] Zhuo-
Hua Pan of Wayne State University, researching
on restore sight to blindness, thought about
using channelrhodopsin when it came out in
late 2003. By February 2004, he was trying
channelrhodopsin out in ganglion cells — the
neurons in our eyes that connect directly to the
brain — that he had cultured in a dish. Indeed,
the transfected neurons became electrically
active in response to light.[18] In April 2005,
Susana Lima and Miesenböck reported the first
use of genetically-targeted P2X2
photostimulation to control the behaviour of an
animal.[19] They showed that photostimulation
of genetically circumscribed groups of neurons,
such as those of the dopaminergic system,
elicited characteristic behavioural changes in
fruit flies. In August 2005, Karl Deisseroth's
laboratory in the Bioengineering Department at
Stanford including graduate students Ed
Boyden and Feng Zhang (both now at MIT)
published the first demonstration of a single-
component optogenetic system in cultured
mammalian neurons,[20][21] using the
channelrhodopsin-2(H134R)-eYFP construct
from Nagel and Hegemann.[15] The groups of
Gottschalk and Nagel were first to use
Channelrhodopsin-2 for controlling neuronal
activity in an intact animal, showing that motor
patterns in the roundworm Caenorhabditis
elegans could be evoked by light stimulation of
genetically selected neural circuits (published in
December 2005).[22] In mice, controlled
expression of optogenetic tools is often
achieved with cell-type-specific Cre/loxP
methods developed for neuroscience by Joe Z.
Tsien back in 1990s[23] to activate or inhibit
specific brain regions and cell-types in vivo.[24]

The primary tools for optogenetic recordings

have been genetically encoded calcium
indicators (GECIs). The first GECI to be used to
image activity in an animal was cameleon,
designed by Atsushi Miyawaki, Roger Tsien and
coworkers.[25] Cameleon was first used
successfully in an animal by Rex Kerr, William
Schafer and coworkers to record from neurons
and muscle cells of the nematode C.
elegans.[26] Cameleon was subsequently used
to record neural activity in flies[27] and
zebrafish.[28] In mammals, the first GECI to be
used in vivo was GCaMP,[29] first developed by
Nakai and coworkers.[30] GCaMP has
undergone numerous improvements, and
GCaMP6[31] in particular has become widely
used throughout neuroscience.

In 2010, Karl Deisseroth at Stanford University

was awarded the inaugural HFSP Nakasone
Award "for his pioneering work on the
development of optogenetic methods for
studying the function of neuronal networks
underlying behavior". In 2012, Gero Miesenböck
was awarded the InBev-Baillet Latour
International Health Prize for "pioneering
optogenetic approaches to manipulate neuronal
activity and to control animal behaviour." In
2013, Ernst Bamberg, Ed Boyden, Karl
Deisseroth, Peter Hegemann, Gero Miesenböck
and Georg Nagel were awarded The Brain Prize
for "their invention and refinement of
optogenetics."[32][33] Karl Deisseroth was
awarded the Else Kröner Fresenius Research
Prize 2017 (4 million euro) for his "contributions
to the understanding of the biological basis of
psychiatric disorders".

Description
Fig 1. Channelrhodopsin-2 (ChR2) induces temporally precise
blue light-driven activity in rat prelimbic prefrontal cortical
neurons. a) In vitro schematic (left) showing blue light
delivery and whole-cell patch-clamp recording of light-evoked
activity from a fluorescent CaMKllα::ChR2-EYFP expressing
pyramidal neuron (right) in an acute brain slice. b) In vivo
schematic (left) showing blue light (473 nm) delivery and
single-unit recording. (bottom left) Coronal brain slice
showing expression of CaMKllα::ChR2-EYFP in the prelimbic
region. Light blue arrow shows tip of the optical fiber; black
arrow shows tip of the recording electrode (left). White bar,
100 µm. (bottom right) In vivo light recording of prefrontal
cortical neuron in a transduced CaMKllα::ChR2-EYFP rat
showing light-evoked spiking to 20 Hz delivery of blue light
pulses (right). Inset, representative light-evoked single-unit
response.[34]
Fig 2. Halorhodopsin (NpHR) rapidly and reversibly silences
spontaneous activity in vivo in rat prelimbic prefrontal cortex.
(Top left) Schematic showing in vivo green (532 nm) light
delivery and single- unit recording of a spontaneously active
CaMKllα::eNpHR3.0- EYFP expressing pyramidal neuron.
(Right) Example trace showing that continuous 532 nm
illumination inhibits single-unit activity in vivo. Inset,
representative single unit event; Green bar, 10 seconds.[34]
 Play media
A nematode expressing the light-sensitive ion channel Mac.
Mac is a proton pump originally isolated in the fungus
Leptosphaeria maculans and now expressed in the muscle
cells of C. elegans that opens in response to green light and
causes hyperpolarizing inhibition. Of note is the extension in
body length that the worm undergoes each time it is exposed
to green light, which is presumably caused by Mac's muscle-
relaxant effects.[35]

Play media
A nematode expressing ChR2 in its gubernacular-oblique
muscle group responding to stimulation by blue light. Blue
light stimulation causes the gubernacular-oblique muscles to
repeatedly contract, causing repetitive thrusts of the spicule,
as would be seen naturally during copulation.[36]
Optogenetics provides millisecond-scale
temporal precision which allows the
experimenter to keep pace with fast biological
information processing (for example, in probing
the causal role of specific action potential
patterns in defined neurons). Indeed, to probe
the neural code, optogenetics by definition must
operate on the millisecond timescale to allow
addition or deletion of precise activity patterns
within specific cells in the brains of intact
animals, including mammals (see Figure 1). By
comparison, the temporal precision of
traditional genetic manipulations (employed to
probe the causal role of specific genes within
cells, via "loss-of-function" or "gain of function"
changes in these genes) is rather slow, from
hours or days to months. It is important to also
have fast readouts in optogenetics that can
keep pace with the optical control. This can be
done with electrical recordings ("optrodes") or
with reporter proteins that are biosensors,
where scientists have fused fluorescent
proteins to detector proteins. An example of
this is voltage-sensitive fluorescent protein
(VSFP2).[37] Additionally, beyond its scientific
impact optogenetics represents an important
case study in the value of both ecological
conservation (as many of the key tools of
optogenetics arise from microbial organisms
occupying specialized environmental niches),
and in the importance of pure basic science as
these opsins were studied over decades for
their own sake by biophysicists and
microbiologists, without involving consideration
of their potential value in delivering insights into
neuroscience and neuropsychiatric disease.[38]

Light-Activated Proteins: Channels, pumps and

enzymes

The hallmark of optogenetics therefore is

introduction of fast light-activated channels,
pumps, and enzymes that allow temporally
precise manipulation of electrical and
biochemical events while maintaining cell-type
resolution through the use of specific targeting
mechanisms. Among the microbial opsins
which can be used to investigate the function of
neural systems are the channelrhodopsins
(ChR2, ChR1, VChR1, and SFOs) to excite
neurons and anion-conducting
channelrhodopsins for light-induced inhibition.
Light-driven ion pumps are also used to inhibit
neuronal activity, e.g. halorhodopsin (NpHR),[39]
enhanced halorhodopsins (eNpHR2.0 and
eNpHR3.0, see Figure 2),[40] archaerhodopsin
(Arch), fungal opsins (Mac) and enhanced
bacteriorhodopsin (eBR).[41]

Optogenetic control of well-defined biochemical

events within behaving mammals is now also
possible. Building on prior work fusing
vertebrate opsins to specific G-protein coupled
receptors[42] a family of chimeric single-
component optogenetic tools was created that
allowed researchers to manipulate within
behaving mammals the concentration of
defined intracellular messengers such as cAMP
and IP3 in targeted cells.[43] Other biochemical
approaches to optogenetics (crucially, with
tools that displayed low activity in the dark)
followed soon thereafter, when optical control
over small GTPases and adenylyl cyclases was
achieved in cultured cells using novel strategies
from several different
laboratories.[44][45][46][47][48] This emerging
repertoire of optogenetic probes now allows
cell-type-specific and temporally precise control
of multiple axes of cellular function within intact
animals.[49]

Hardware for Light Application

Another necessary factor is hardware (e.g.

integrated fiberoptic and solid-state light
sources) to allow specific cell types, even deep
within the brain, to be controlled in freely
behaving animals. Most commonly, the latter is
now achieved using the fiberoptic-coupled
diode technology introduced in 2007,[50][51][52]
though to avoid use of implanted electrodes,
researchers have engineered ways to inscribe a
"window" made of zirconia that has been
modified to be transparent and implanted in
mice skulls, to allow optical waves to penetrate
more deeply to stimulate or inhibit individual
neurons.[53] To stimulate superficial brain areas
such as the cerebral cortex, optical fibers or
LEDs can be directly mounted to the skull of the
animal. More deeply implanted optical fibers
have been used to deliver light to deeper brain
areas. Complementary to fiber-tethered
approaches, completely wireless techniques
have been developed utilizing wirelessly
delivered power to headborne LEDs for
unhindered study of complex behaviors in freely
behaving organisms.[54]

Expression of Optogenetic Actuators

Optogenetics also necessarily includes the

development of genetic targeting strategies
such as cell-specific promoters or other
customized conditionally-active viruses, to
deliver the light-sensitive probes to specific
populations of neurons in the brain of living
animals (e.g. worms, fruit flies, mice, rats, and
monkeys). In invertebrates such as worms and
fruit flies some amount of all-trans-retinal (ATR)
is supplemented with food. A key advantage of
microbial opsins as noted above is that they are
fully functional without the addition of
exogenous co-factors in vertebrates.[52]
Technique

Three primary components in the application of

Optogenetics are as follows (A) Identification or synthesis of
a light-sensitive protein (Opsin) such as Channelrhodopsin-2
(ChR2), Halorhodopsin (NpHR), etc... (B) The design of a
system to introduce the genetic material containing the
opsin into cells for protein expression such as application of
Cre-Recombinase or an Adeno-Associated-Virus (C)
Application of light emitting instruments.[55]

The technique of using optogenetics is flexible

and adaptable to the experimenter's needs. For
starters, experimenters genetically engineer a
microbial opsin based on the gating properties
(rate of excitability, refractory period, etc..)
required for the experiment.

There is a challenge in introducing the microbial

opsin, an optogenetic actuator, into a specific
region of the organism in question. A
rudimentary approach is to introduce an
engineered viral vector that contains the
optogenetic actuator gene attached to a
recognizable promoter such as CAMKIIα. This
allows for some level of specificity as cells that
already contain and can translate the given
promoter will be infected with the viral vector
and hopefully express the optogenetic actuator
gene.
Another approach is the creation of transgenic
mice where the optogenetic actuator gene is
introduced into mice zygotes with a given
promoter, most commonly Thy1. Introduction of
the optogenetic actuator at an early stage
allows for a larger genetic code to be
incorporated and as a result, increases the
specificity of cells to be infected.

A third and rather novel approach that has been

developed is creating transgenic mice with Cre-
Recombinase, an enzyme that catalyzes
recombination between two lox-P sites. Then by
introducing an engineered viral vector
containing the optogenetic actuator gene in
between two lox-P sites, only the cells
containing the Cre-Recombinase will express
the microbial opsin. This last technique has
allowed for multiple modified optogenetic
actuators to be used without the need to create
a whole line of transgenic animals every time a
new microbial opsin is needed.

After the introduction and expression of the

microbial opsin, depending on the type of
analysis being performed, application of light
can be placed at the terminal ends or the main
region where the infected cells are situated.
Light stimulation can be performed with a vast
array of instruments from light emitting diodes
(LEDs) or diode-pumped solid state (DPSS).
These light sources are most commonly
connected to a computer through a fiber optic
cable. Recent advances include the advent of
wireless head-mounted devices that also apply
LED to targeted areas and as a result give the
animal more freedom of mobility to reproduce
in vivo results.[56][57]

Issues
Although already a powerful scientific tool,
optogenetics, according to Doug Tischer &
Orion D. Weiner of the University of California
San Francisco, should be regarded as a "first-
generation GFP" because of its immense
potential for both utilization and
optimization.[58] With that being said, the
current approach to optogenetics is limited
primarily by its versatility. Even within the field
of Neuroscience where it is most potent, the
technique is less robust on a subcellular
level.[59]
Selective expression

One of the main problems of optogenetics is

that not all the cells in question may express
the microbial opsin gene at the same level.
Thus, even illumination with a defined light
intensity will have variable effects on individual
cells. Optogenetic stimulation of neurons in the
brain is even less controlled as the light
intensity drops exponentially from the light
source (e.g. implanted optical fiber).

Moreover, mathematical modelling shows that

selective expression of opsin in specific cell
types can dramatically alter the dynamical
behavior of the neural circuitry. In particular,
optogenetic stimulation that preferentially
targets inhibitory cells can transform the
excitability of the neural tissue from Type 1 —
where neurons operate as integrators — to Type
2 where neurons operate as resonators.[60] Type
1 excitable media sustain propagating waves of
activity whereas Type 2 excitable media do not.
The transformation from one to the other
explains how constant optical stimulation of
primate motor cortex elicits gamma-band (40–
80 Hz) oscillations in the manner of a Type 2
excitable medium. Yet those same oscillations
propagate far into the surrounding tissue in the
manner of a Type 1 excitable medium.[61]

Nonetheless, it remains difficult to target opsin

to defined subcellular compartments, e.g. the
plasma membrane, synaptic vesicles, or
mitochondria.[59][62] Restricting the opsin to
specifiic regions of the plasma membrane such
as dendrites, somata or axon terminals would
provide a more robust understanding of
neuronal circuitry.[59]

Kinetics and synchronization

An issue with channelrhodopsin-2 is that its

gating properties don't mimic in vivo cation
channels of cortical neurons. A solution to this
issue with a protein's kinetic property is
introduction of variants of Channelrhodopsin-2
with more favorable kinetics.[55][56]

Another one of the technique's limitations is

that light stimulation produces a synchronous
activation of infected cells and this removes
any individual cell properties of activation
among the population affected. Therefore, it is
difficult to understand how the cells in the
population affected communicate with one
another or how their phasic properties of
activation may relate to the circuitry being
observed.

Optogenetic activation has been combined with

functional magnetic resonance imaging (ofMRI)
to elucidate the connectome, a thorough map of
the brain’s neural connections. The results,
however, are limited by the general properties of
fMRI.[59][63] The readouts from this
neuroimaging procedure lack the spatial and
temporal resolution appropriate for studying the
densely packed and rapid-firing neuronal
circuits.[63]

Excitation spectrum
The opsin proteins currently in use have
absorption peaks across the visual spectrum,
but remain considerable sensitivity to blue
light.[59] This spectral overlap makes it very
difficult to combine opsin activation with
genenetically encoded indictors (GEVIs, GECIs,
GluSnFR, synapto-pHluorin), most of which
need blue light exciation. Opsins with infrared
activation would, at a standard irradiance value,
increase light penetration and augment
resolution through reduction of light scattering.

Applications
The field of optogenetics has furthered the
fundamental scientific understanding of how
specific cell types contribute to the function of
biological tissues such as neural circuits in vivo
(see references from the scientific literature
below). Moreover, on the clinical side,
optogenetics-driven research has led to insights
into Parkinson's disease[64][65] and other
neurological and psychiatric disorders. Indeed,
optogenetics papers in 2009 have also provided
insight into neural codes relevant to autism,
Schizophrenia, drug abuse, anxiety, and
depression.[41][66][67][68]

Identification of particular neurons

and networks

Amygdala

Optogenetic approaches have been used to

map neural circuits in the amygdala that
contribute to fear conditioning.[69][70][71][72] One
such example of a neural circuit is the
connection made from the basolateral
amygdala to the dorsal-medial prefrontal cortex
where neuronal oscillations of 4 Hz have been
observed in correlation to fear induced freezing
behaviors in mice. Transgenic mice were
introduced with Channelrhodoposin-2 attached
with a Parvalbumin-Cre promoter that
selectively infected interneurons located both in
the basolateral amygdala and the dorsal-medial
prefrontal cortex responsible for the 4 Hz
oscillations. The interneurons were optically
stimulated generating a freezing behavior and
as a result provided evidence that these 4 Hz
oscillations may be responsible for the basic
fear response produced by the neuronal
populations along the dorsal-medial prefrontal
cortex and basolateral amygdala.[73]

Olfactory bulb

Optogenetic activation of olfactory sensory

neurons was critical for demonstrating timing in
odor processing[74] and for mechanism of
neuromodulatory mediated olfactory guided
behaviors (e.g. aggression, mating)[75] In
addition, with the aid of optogenetics, evidence
has been reproduced to show that the
"afterimage" of odors is concentrated more
centrally around the olfactory bulb rather than
on the periphery where the olfactory receptor
neurons would be located. Transgenic mice
infected with channel-rhodopsin Thy1-ChR2,
were stimulated with a 473 nm laser
transcranially positioned over the dorsal section
of the olfactory bulb. Longer photostimulation
of mitral cells in the olfactory bulb led to
observations of longer lasting neuronal activity
in the region after the photostimulation had
ceased, meaning the olfactory sensory system
is able to undergo long term changes and
recognize differences between old and new
odors.[76]

Nucleus accumbens

Optogenetics, freely moving mammalian

behavior, in vivo electrophysiology, and slice
physiology have been integrated to probe the
cholinergic interneurons of the nucleus
accumbens by direct excitation or inhibition.
Despite representing less than 1% of the total
population of accumbal neurons, these
cholinergic cells are able to control the activity
of the dopaminergic terminals that innervate
medium spiny neurons (MSNs) in the nucleus
accumbens.[77] These accumbal MSNs are
known to be involved in the neural pathway
through which cocaine exerts its effects,
because decreasing cocaine-induced changes
in the activity of these neurons has been shown
to inhibit cocaine conditioning. The few
cholinergic neurons present in the nucleus
accumbens may prove viable targets for
pharmacotherapy in the treatment of cocaine
dependence[41]
Cages for rat equipped of optogenetics leds commutators
which permit in vivo to study animal behavior during
optogenetics' stimulations.

Prefrontal cortex

In vivo and in vitro recordings (by the Cooper

laboratory ) of individual CAMKII AAV-ChR2
expressing pyramidal neurons within the
prefrontal cortex demonstrated high fidelity
action potential output with short pulses of blue
light at 20 Hz (Figure 1).[34] The same group
recorded complete green light-induced
silencing of spontaneous activity in the same
prefrontal cortical neuronal population
expressing an AAV-NpHR vector (Figure 2).[34]

Heart

Optogenetics was applied on atrial

cardiomyocytes to end spiral wave arrhythmias,
found to occur in atrial fibrillation, with light.[78]
This method is still in the development stage. A
recent study explored the possibilities of
optogenetics as a method to correct for
arrythmias and resynchronize cardiac pacing.
The study introduced Channelrhodopsin-2 into
cardiomyocytes in ventricular areas of hearts of
transgenic mice and performed in vitro studies
of photostimulation on both open-cavity and
closed-cavity mice. Photostimulation led to
increased activation of cells and thus increased
ventricular contractions resulting in increasing
heart rates. In addition, this approach has been
applied in cardiac resynchronization therapy
(CRT) as a new biological pacemaker as a
substitute for electrode based-CRT.[79] Lately,
optogenetics has been used in the heart to
defibrillate ventricular arrhythmias with local
epicardial illumination,[80] a generalized whole
heart illumination[81] or with customized
stimulation patterns based on arrhythmogenic
mechanisms in order to lower defibrillation
energy.[82]

Spiral ganglion

Optogenetic stimulation of the spiral ganglion in

deaf mice restored auditory activity.[83]
Optogenetic application onto the cochlear
region allows for the stimulation or inhibition of
the spiral ganglion cells (SGN). In addition, due
to the characteristics of the resting potentials
of SGN's, different variants of the protein
Channelrhodopsin-2 have been employed such
as Chronos and CatCh. Chronos and CatCh
variants are particularly useful in that they have
less time spent in their deactivated states,
which allow for more activity with less bursts of
blue light emitted. The result being that the LED
producing the light would require less energy
and the idea of cochlear prosthetics in
association with photo-stimulation, would be
more feasible.[84]

Brainstem
Optogenetic stimulation of a modified red-light
excitable channelrhodopsin (ReaChR)
expressed in the facial motor nucleus enabled
minimally invasive activation of motoneurons
effective in driving whisker movements in
mice.[85] One novel study employed
optogenetics on the Dorsal Ralphe Nucleus to
both activate and inhibit dopaminergic release
onto the Ventral Tegmental Area. To produce
activation transgenic mice were infected with
Channelrhodopsin-2 with a TH-Cre promoter
and to produce inhibition the hyperpolarizing
opsin NpHR was added onto the TH-Cre
promoter. Results showed that optically
activating dopaminergic neurons led to an
increase in social interactions, and their
inhibition decreased the need to socialize only
after a period of isolation.[86]

Precise temporal control of

interventions

The currently available optogenetic actuators

allow for the accurate temporal control of the
required intervention (i.e. inhibition or excitation
of the target neurons) with precision routinely
going down to the millisecond level. Therefore,
experiments can now be devised where the light
used for the intervention is triggered by a
particular element of behavior (to inhibit the
behavior), a particular unconditioned stimulus
(to associate something to that stimulus) or a
particular oscillatory event in the brain (to
inhibit the event). This kind of approach has
already been used in several brain regions:

Hippocampus

Sharp waves and ripple complexes (SWRs) are

distinct high frequency oscillatory events in the
hippocampus thought to play a role in memory
formation and consolidation. These events can
be readily detected by following the oscillatory
cycles of the on-line recorded local field
potential. In this way the onset of the event can
be used as a trigger signal for a light flash that
is guided back into the hippocampus to inhibit
neurons specifically during the SWRs and also
to optogenetically inhibit the oscillation itself[87]
These kinds of "closed-loop" experiments are
useful to study SWR complexes and their role in
memory.

Cellular biology/cell signaling

pathways

Optogenetic control of cellular forces and induction of

mechanotransduction. Pictured cells receive an hour of
imaging concurrent with blue light that pulses every 60
seconds. This is also indicated when the blue point flashes
onto the image. The cell relaxes for an hour without light
activation and then this cycle repeats again. The square inset
magnifies the cell's nucleus.

The optogenetic toolkit has proven pivotal for

the field of neuroscience as it allows precise
manipulation of neuronal excitability. Moreover,
this technique has been shown to extend
outside neurons to an increasing number of
proteins and cellular functions.[58] Cellular scale
modifications including manipulation of
contractile forces relevant to cell migration, cell
division and wound healing have been
optogenetically manipulated.[88] The field has
not developed to the point where processes
crucial to cellular and developmental biology
and cell signaling including protein localization,
post-translational modification and GTP loading
can be consistently controlled via
optogenetics.[58]

Photosensitive proteins utilized in

various cell signaling pathways

While this extension of optogenetics remains to

be further investigated, there are various
conceptual methodologies that may prove to
immediately robust. There is a considerable
body of literature outlining photosensitive
proteins that have been utilized in cell signaling
pathways.[58] CRY2, LOV, DRONPA and PHYB are
photosynthetic proteins involved in inducible
protein association whereby activation via light
can induce/turn off a signaling cascade via
recruitment of a signaling domain to its
respective substrate.[89][90][91][92] LOV and PHYB
are photosensitive proteins that engage in
homodimerization and/or heterodimerization to
recruit some DNA-modifying protein,
translocate to the site of DNA and alter gene
expression levels.[93][94][95] CRY2, a protein that
inherently clusters when active, has been fused
with signaling domains and subsequently
photoactivated allowing for clustering-based
activation.[96] Proteins LOV and Dronpa have
also been adapted to cell signaling
manipulation; exposure to light induces
conformational changes in the photosensitive
protein which can subsequently reveal a
previously obscured signaling domain and/or
activate a protein that was otherwise
allosterically inhibited.[97][98] LOV has been
fused to caspase 3 to produce a construct
capable of inducing apoptosis upon light
stimulation.[99]

Optogenetic temporal control of

signals

A different set of signaling cascades respond to

stimulus timing duration and dynamics.[100]
Adaptive signaling pathways, for instance,
adjust in accordance to the current level of the
projected stimulus and display activity only
when these levels change as opposed to
responding to absolute levels of the input.[101]
Stimulus dynamics also can trigger activity;
treating PC12 cells with epidermal growth
factor (inducing a transient profile of ERK
activity) leads to cellular proliferation whereas
introduction of nerve growth factor (inducing a
sustained profile of ERK activity) is associated
with a different cellular decision whereby the
PC12 cells differentiate into neuron-like
cells.[102] This discovery was guided
pharmacologically but the finding was
replicated utilizing optogenetic inputs
instead.[103] This ability to optogenetically
control signals for various time durations is
being explored to elucidate various cell
signaling pathways where there is not a strong
enough understanding to utilize either
drug/genetic manipulation.[58]

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External links
Optogenetics Resource Center , maintained
by the Deisseroth lab.
Synthetic Neurobiology Group, MIT , the
portal of the Boyden lab.
OpenOptogenetics.org , an optogenetics wiki,
and its companion blog .
Molecular Neurogenetics and Optophysiology
Laboratory ,"Optogenetic activation and
silencing recordings of individual prefrontal
cortical neurons in vivo and in vitro.
Sohal lab portal
Nurmikko lab portal
 Lab of Dr. Zhuo-Hua Pan
Optophysiology at the Tyler lab
Video: Ed Boyden on Optogenetics -- selective
brain stimulation with light (SPIE Newsroom,
April 2011)

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