The phenomenon by which living organisms detect and perceive optogenetic stimulation. Mice can use optogenetic stimulation as a conditioned cue for a reward or punishment. Optoception is a key limitation of optogenetics, because it may result in additional behavior that is not associated with the brain region of interest.

Optoception

Fiberless optogenetics involves activating opsins with miniature light-emitting diodes (LEDs) so that light can be delivered wirelessly. Lanthanide micro-particles are transferred into the brain, along with the opsins, and exposure to near-infrared light  (NIR) leads to the activation of light-sensitive proteins in a process called upconversion.

It aims to overcome limitations of conventional optogenetics, in which the insertion of an optical fiber in traditional optogenetics causes physical damage to brain tissue and restricts the movement of animal subjects. Furthermore, NIR can reach deeper brain regions than visible light. The limitations of fiberless optogenetics include a limited battery life of the LEDs and restriction of animals' movement due to the devices' weight and size.

Fiberless 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.

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

Luo, L. (2020). Principles of Neurobiology (2nd ed.). CRC Press. 

Principles of Neurobiology, 2nd edition (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 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

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

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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