Optogenetics
is the relatively novel method that allows for direct investigation of the
relationship between neuronal activity of specific neuronal populations and
animal behavior.
Before we
discuss what kind of findings can be achieved with this method, we must review
the basic concepts underlying optogenetics. For those who have doubts about the
creativity of scientists, this method is a clear proof that being a scientist
involves much innovation and creativity. As one could easily guess from the
name, optogenetics combines genetics and optics, and permits direct targeting
of cells of interest. The whole technique became possible with the discovery of
opsin channels – channels sensitive to light-present in a multitude of microbes,
the animal version of the channel, rhodopsin, is present in the eye and allows
for vision. A relevant type of opsin channel
to optogenetics is Chanelrhodopsin (ChR2). This channel has similar structure
and function to other channels present in the brain, and when light is shown
upon a neuron that expresses ChR2, the channels open and allow cations to flow in
the cell, producing depolarization.
The genetics
part of this method implies that genetic manipulations must be made so that ChR2
can be expressed in the neurons of interest. A special genetic component must
be expressed in the target neurons, presence of Cre recombinase- a doublefloxed
inverted open-reading-frame in the target neurons allows for the gene that codes
for ChR2 to be expressed in the neurons. Transgenic animals were created that
express Cre in specific neuronal populations, then a viral injection (adenno
associated viral vector-AAV) that carries the genetic information for ChR2 is
made in the target area- the result is an animal that expresses light sensitive
channels in a particular area of the brain.
The optic
part of the optogenetics involves a means to deliver light to the target
tissue. In order to achieve this goal, optic fiber cannulas are implanted in
the brain area of interest. These cannulas are fixed chronically on the skull
of the animal. When performing a behavioral experiment, the cannulas are
connected to a patch cable that delivers light from a laser delivery device at
a certain wavelength. The light then is sensed by the channelrhodopsin present
in the neurons, triggering a response in the cell, and consequently a behavioral
response.
Optogenetics
might seem a bit complicated, yet the applications of this method allow for
studies that were not possible before.Dr. Stephan
Steidl, professor of Psychology at Loyola University Chicago, uses optogenetics
to study the relationship between the inputs to the ventral tegmental area (VTA)
of the brain and the motivational behavior in mice.
Projections of the
dopamine neurons in VTA to limbic and cortical areas such as the nucleus
accumbens (NAc) and prefrontal cortex (PFC) of the brain have been identified
to have a significant role in behaviors that involve motivation, reward and
cognition (Omelchenko et al., 2005). Predominant
brain disorders such as addiction and depression, involve pathological dysfunction
in the performance of this task (Lammel et al., 2012). The VTA also receives inputs from other parts
of the brain, and these inputs are thought to influence the activity of the
dopamine neurons, thus affecting reward behavior. Dr. Steidl’s studies focus on
the inputs to the VTA coming from the laterodorsal tegmental area (LDTg) and the
pedunculopontine tegmental area (PPTg). With the help of optogenetics, he is
able to study the individual effects of three different types of neurotransmitters
released by these areas on the VTA, and consequently their effects on reward
behavior. Thus, insight can be gathered
about the mechanisms of the too common addictive behaviors we observe in
humans. Optogenetics is a rather innovative and efficient way to study such
specific functions in the brain.
Optogenetics
is also used to study the underlying causes of schizophrenia, brain disorder in which people have distorted
perception of reality, symptoms include hallucinations, delusions, disordered
thinking and behavior. Researchers at the
University of California in San Francisco, Elizabeth Steinberg and Ronald
Keiflin used rats as animal model to study the role of dopamine neurons in
prediction error learning. Role that is
thought to be malfunctioning in schizophrenic patients. With the help of
optogenics, the researchers manipulated the activity of dopamine neurons during
behavioral learning experiments. Findings of this study suggest that stimulation
of dopamine neurons at certain times may modify the learning from prediction
errors and could also successfully mimic a prediction error, resulting in an enduring
impact on reward-seeking behavior. These findings reveal the importance of
dopamine release at specific times in reward seeking behavior and offer direction
for therapies development to treat the symptoms of schizophrenia.
The
applications of optogenics confer a revolutionary means to study the brain and
its intricate circuitry. Hope for new treatments also arises with the use of
this new method. Thus we all should be grateful for the creativity of scientists!
Sources:
Fenno L,
Yizhar O., Deisseroth K.,The
Development and Application of Optogenetics Annual Review of Neuroscience,
Vol. 34, No. 1. (2011), pp. 389-412,
Lammel S. et
al, Input specific control of reward and aversion in the ventral tegmental
area, Nature, Vol 491, Nov. 2012
Omelchenko
N. and Sesack S., Laterodorsal tegmental projections to identified cell
populations in the rat ventral tegmental area, The Journal of Comparative
Neurology, 483:217-235, 2005
Schizophrenia Research Forum, Surprise Signals: Optogenetics Links Dopamine
to Prediction Errors, Steinberg
EE, Keiflin R, Boivin JR, Witten IB, Deisseroth K, Janak PH. A causal link
between prediction errors, dopamine neurons and learning. Nat Neurosci. 2013 May,
26 http://www.schizophreniaforum.org/pap/annotation.asp?powID=169761
Steidl, Stephan -Lecture
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