In vitro and in vivo experiments have shown that drug-resistant seizures can be optogenetically treated by activating halorhodopsin to inhibit excitatory neurons, or by activating channelrhodopsin-2 to stimulate inhibitory neurons. This strategy has been used to create a closed-loop system in which the onset of a seizure is detected by an EEG device, which prompts an optical fiber to activate the opsin and suppress seizure activity. 

Although optogenetic therapy offers a high amount of precision, it is highly invasive. Furthermore, reliable methods to detect seizures are yet to be developed, attenuation limits how deep the light spreads, and tissue can become heated - altering behavior.

Optogenetics and epilepsy

Optogenetics has been used to study regions of the brain involved in Parkinson's disease, inspiring new methods of treatment. 
The optogenetic inhibition of DYSK-SPNs, a small subset of D1-SPNs, with halorhodopsin in mice has been shown to reduce involuntary movements - a side effect of L-DOPA medication. 
Optogenetic stimulation of cortical neurons projecting to the subthalamic nucleus reduces motor deficits, helping to explain the mechanism by which deep brain stimulation works.
Additionally, optogenetics has been used to identify a subset of external globus pallidus (GPe) neurons that result in long-lasting restoration of movement when stimulated.

Optogenetics and Parkinson's disease

Selective opsin expression is more difficult to implement in the peripheral nervous system, which is more spread out than the brain, to investigate pain using optogenetics. Although peripheral  organs are less stable to hold optical fibers than the skull, these devices have been adapted for use in the periphery. In the future, the optogenetic inhibition of nociceptive neurons, in vivo, could be a strategy to treat humans with chronic pain.

Optogenetics and chronic pain

Optogenetics has been applied in humans to restore vision in patients with retinitis pigmentosa, an eye disease causing severe vision impairment. A viral vector containing a channelrhodopsin protein is injected into the patient's eyeball, making their retinal ganglion cells optogenetically active. The patient wears goggles that detect changes in light intensity and send corresponding light pulses into the retina. The cited study demonstrates that the subject was able to successfully perform visual tasks with this procedure.

Optogenetics and visual restoration

* Epilepsy
* Vision restoration 
* Parkinson's disease 
* Chronic pain

University of Michigan - Ann Arbor

A genetic approach to control the activity of specific neurons by light. Optogenetics generally makes use of the selective expression of opsins, proteins that respond to certain types of light.

Optogenetics

Walker, M. C., & Kullmann, D. M. (2020). Optogenetic and chemogenetic therapies for epilepsy. Neuropharmacology, 168, 107751. https://doi.org/10.1016/j.neuropharm.2019.107751

Optogenetic and chemogenetic therapies for epilepsy (2020)

A protein and cation channel first found in green algae (Chlamydomonas reinhardtii). It opens upon stimulation by blue light, and neurons expressing ChR2 fire action potentials. The isomerization of all-trans retinal allows the channel to open, resulting in an influx of Na+ that is greater than the outflow of K+.

Channelrhodopsin-2 (ChR2)

An inward Cl- pump found in archaea. Neurons expressing halorhodopsin are hyperpolarized (silenced) in response to yellow light.

Halorhodopsin

Viral vectors (ex. adeno-associated viruses, or AAV) are a common method to transfer light-sensitive opsins into the brain for experiments involving optogenetics. By packaging opsin genes fused with cell-type specific promoters into the viral vector, the opsin is expressed in cell types of interest. Promoters must be small enough to be packaged into viral vectors. In vivo, viral vectors are delivered via stereotaxic injections.

Viral vectors in optogenetics

Optogenetics can be performed in a living organism. First, a cannula (thin tube) is surgically inserted into a brain region expressing an opsin. Then, an optical fiber that can deliver light is inserted into the cannula, allowing the experimenter to compare behavior when the light is off (neurons of interest are not stimulated) and when the light is on (neurons of interest are stimulated within milliseconds). A limitation is that implanting the optical fiber may cause physical damage.

Optogenetics in vivo

ChR2-assisted circuit mapping (CRACM) is a method of brain mapping using optogenetics. By making presynaptic neurons of interest express ChR2, the experimenter can deliver light and record which postsynaptic neurons depolarize (excitatory synapse) or hyperpolarize (inhibitory synapse). CRACM is useful in mapping long-range connections but cannot be performed in vivo.

Brain mapping with optogenetics

Optogenetic stimulation has been demonstrated to induce long-term potentiation and long-term depression, both in vitro and in vivo. It can affect locomotion, motor learning and memory consolidation.

Optogenetics and plasticity

Therapeutic applications of optogenetics

Rodents are the most widely used model organism in neuroscience and biomedical research. Rats and mice differ significantly in gene expression, social behaviors, and physiology, giving them unique advantages and disadvantages as the favorable model in any particular research. For example, mice were more commonly used due to their larger “genetic toolbox,” which includes transgenic and “knockout”/”knock-in” mice. However, adult rats typically weigh up to ten times more than adult mice. Their larger size makes surgery and other invasive procedures such as catheter insertion easier to perform, while mice are chosen for optogenetics experiments because light passes more easily through their smaller brains and can therefore reach deeper regions of the brain.

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