Optogenetics: Controlling Brain Activities with Light
By Sirius Lee 李揚
Have you read the article The Amazing Cephalopods from our previous issue? We introduced to you how large and thick axons from marine organisms like squids have contributed to our understanding of nerve impulse. This time, we are excited to present to you another useful technique in the study of neuroscience. In earlier days of research, scientists struggled to control a single type of cell in the brain without altering other variables in the vicinity [1]. Previous techniques which involve electrodes to stimulate neurons and record signals were not ideal because they failed to target specific cell types and electrical recording could be affected by simultaneous stimulation at the same site [1]. Administration of drugs to control neurons is possible but drugs act slowly [1] and may lead to unwanted side effects [2]. In recent years, scientists have invented a novel technology which can overcome the problems above. They were inspired by the discovery of bacteriorhodopsin found in archaea and its sensitivity towards light [3]. Voila! Welcome to the era of optogenetics.
Breaking down the word, “opto” indicates “optical”, while “genetics” implies the modification of the genetic material. With a specific set of neurons in mind, their genome could be rewritten by editing techniques such that the cells would express the newly inserted gene encoding the light-sensitive bacteriorhodopsin. By exposing the genetically modified organisms to the light of specific wavelengths, scientists could therefore switch on or off neurons, similar to a video gamer when they use their remote control to command the avatar.
The haloarchaeal bacteriorhodopsin was the first to be discovered. This membrane protein pumps protons (H+) from the cytoplasm to the extracellular fluid when activated by photons. Since its initial discovery in 1971, researchers also discovered two other classes of light-responsive proteins, halorhodopsin in 1977 and channelrhodopsin in 2002 [1]. Yellow light-activated halorhodopsin is a chloride pump which actively pumps negative chloride ions (Cl–) into the cell upon excitation by yellow light; and blue light-activated channelrhodopsin is a cation channel which allows positive ions to flow into the cell under concentration gradient upon excitation by blue light [1, 4]. It is known that a neuron fires when it is depolarized, such as when positive ions rush into the cell. Therefore, by expressing suitable light-sensitive proteins and exciting them with suitable colors of light, one could excite or inhibit a neuronal cell by manipulating the ion flow [4]. With the key to instructing the networks of genetically modified neurons, causal links between neuronal activities and molecular or behavioral outcomes can be established.
Optogenetics has quickly become a gold standard for neuroscience research. For instance, neuroscientists could first use a pharmacological agent (drug), tetrodotoxin, to inhibit neuronal activity in hippocampal slices in vitro (footnote 1), and then repeat the experiment through light-directed inhibition on transgenic mice expressing halorhodopsin in vivo to confirm the neuronal activity-dependent expression of a key protein [5]. In terms of clinical use, researchers have explored the therapeutic use of optogenetics, expanding its functionality. Promising results recently published in Nature Medicine support such an approach in restoring partial vision to a patient suffering from a neurodegenerative eye disease, retinitis pigmentosa [6]. In the study, viral vector containing channelrhodopsin gene was injected into a patient’s eye to genetically engineer the retinal cells in fovea. Meanwhile, researchers designed a pair of goggles which could detect the light intensity of the surroundings, and convert the information to light signal for stimulating the channelrhodopsin expressed in the retinal cells. With the aid of the goggles, retinal cells were appropriately activated and partial vision of the patient could be restored.
It could not be more amazing when nature’s terrific designs can be harnessed and transformed into powerful tools in our pursuit of science. This wisdom of using optogenetics has brought us one step closer to illuminating the neural circuitry of our brains, or perhaps, given us the key to untangling all mysteries in neuroscience.
1 In vivo & in vitro: In vivo means “within the living” literally in Latin. It often refers to experiments conducted in or on a living organism, as opposed to in vitro, meaning “in glass (labware)”.
References:
[1] Deisseroth K. Optogenetics. Nat Methods. 2011;8(1):26-29. doi:10.1038/nmeth.f.324
[2] Hartsough LA, Park M, Kotlajich MV, et al. Optogenetic control of gut bacterial metabolism to promote longevity. Elife. 2020;9:e56849. doi:10.7554/eLife.56849
[3] Oesterhelt D, Stoeckenius W. Rhodopsin-like protein from the purple membrane of Halobacterium halobium. Nat New Biol. 1971;233(39):149-152. doi:10.1038/newbio233149a0
[4] Yizhar O, Fenno LE, Davidson TJ, Mogri M, Deisseroth K. Optogenetics in neural systems. Neuron. 2011;71(1):9-34. doi:10.1016/j.neuron.2011.06.004
[5] Wang Y, Fu WY, Cheung K, et al. Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus. Proc Natl Acad Sci U S A. 2021;118(1):e2020810118. doi:10.1073/pnas.2020810118
[6] Sahel JA, Boulanger-Scemama E, Pagot C, et al. Partial recovery of visual function in a blind patient after optogenetic therapy. Nat Med. 2021;27(7):1223-1229. doi:10.1038/s41591-021-01351-4