Science Focus (Issue 23)

Optogen et i cs : Controll i ng Bra i n Act i v i t i es wi th L i ght 光遺傳學:運用光控制腦部活動 By Sirius Lee 李揚 Have you read the a r t i c l e The Amaz i ng Cephalopods from our previous issue? We introduced to you how large and thick axons from mar ine organi sms l ike squids have contr ibuted to our understanding of nerve impulse. This time, we are excited to present to you another useful technique in the study of neuroscience. In ear l ier 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 inspi red by the discovery of bacteriorhodopsin found in archaea and its sensitivity towards light [3]. Voila! Welcome to the era of optogenetics. Break ing down the word, “opto” indicates “optical”, while “genetics” implies the modification of the genet ic mater ial . With a speci f ic set of neurons in mind, their genome could be rewritten by editing techniques such that the cel ls would express the newly inser ted 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 di scover y in 1971, researchers al so di scovered two other classes of l ight- respons ive 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 lightsensitive 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. Optogenet ics has quick ly 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 suffer ing 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 power ful 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)”.