In 1979, Nobel laureate Francis Crick mused about how wonderful it would be to find a way to control just one type of brain cells while leaving others untouched1. Twenty years later, seeing all the shortcomings of electrophysiology (low precision in targeting cells) and pharmacological manipulations (too slow in comparison to real neurotransmission), he went one step further and suggested that light might be the answer we’ve been looking for. The idea of switching neurons on and off like lightbulbs sounded both crazy and appealing, yet no one knew how to approach it. It took another six years for things to get real. Optogenetics was on its way.
Pioneered by Karl Deisseroth and colleagues, this method is spreading like wildfire through the neuroscience world, and for good reason: it offers an unprecedented level of temporal and cellular precision and allows us to control brain activity in real time. As the name already suggests, genetic and optical technology are at play there. Gene technology is used to make specific cells light-sensitive, that is, to make them activate (or shut down) when light falls on them, and optical methods (i.e. lasers) are used to subsequently manipulate these cells. Here’s the short version of how it comes about: first, the scientists take a gene responsible for producing light-sensitive proteins from fluorescent pond algae. They also make sure that this gene only gets expressed in the specific cells of interest (say, only dopaminergic neurons). Then this biochemical cocktail is inserted in a virus acting as a delivery service. The virus is, in turn, injected into the rodent’s brain and a fiber optic cable is placed directly upon the targeted cells.
After a couple of weeks it’s all yours — you can control someone else’s brain with a laser2. Almost like in your childhood fantasies.
This means a lot: we can manipulate specific ion channels or cells secreting a specific neurotransmitter, we can go very deep in the brain and reversibly activate a particular subset of neurons, we can perform manipulations at the real working speed of the brain, we can establish causal relationships between phenomena which were previously solely correlated. Really, it is a lot. Despite it being a pretty young field, plenty of research has already been done with optogenetics (and it was mind-blowing, both literally and figuratively).
Manipulation of memory
The optogenetic study that has produced the most fuss in the media is probably the implantation of false memories in mice3. Published in 2013, it transformed its authors, Steve Ramirez and the late Xu Liu, into neuroscience rockstars. What allegedly started as Steven Ramirez listening to Taylor Swift over a break-up and wondering how to erase his ex from memory resulted in some groundbreaking memory manipulation: he and his colleagues made a mouse believe that a traumatic experience happened in a specific environment — although it actually didn’t.
In this experiment, they let a mouse peacefully explore a box and tagged the cells recording the memory of this environment with light-sensitive proteins. The mouse was then placed in a second box where two things happened simultaneously: Light-induced activation of the first-box-memory and delivery of a painful foot shock. This way, the mouse was conditioned to associate a fearful event (e.g. electrical shock) with a memory of a place not connected to it — a false memory was created. Indeed, when placed back in the harmless box, the mouse froze in fear, seemingly waiting for the electrical shock to come. Moreover, the mouse became scared even when the first-box-memory, now falsely associated with pain, was activated in a completely new box. Even though this context bore no known dangers, the mouse seemed to remember that they had already endured some torture there. This discovery, besides being mind-blowing, could be the basis of potential PTSD treatments — perhaps in the far future we could selectively extinguish traumatic memories connected to some context, change them or replace them with new ones.
A tiny bit more detailed explanation of what Ramirez and Liu did to the mice.
Another example of laser-induced memory manipulation is reversing the emotional value of memories4. The researchers managed to make it seem that something good happened in a place where a bad event actually occurred. It was done by manipulating connections between hippocampus (“where was it?”-part), and amygdala (“how did I feel about it?”-part).
In this experiment, mice were put in a box where they received an electrical shock, forming a traumatic memory. The scientists then turned the cells storing these memories light-sensitive. After that, the mice were put in a new situation — the traumatised science martyrs got to sniff a female mouse. Simultaneously, the memory of the original box in their hippocampus was optogenetically reactivated. The researchers basically disconnected the memory of a place and the emotion associated with it (“Something bad happened here. I better freeze in the corner”) and replugged it to another emotion (“What a lady-pleasing Casanova was I in this room!”). After being returned to their original box, the mice showed no fear — this place was now remembered as the place of a romantic encounter with the lady mouse. It also worked in the opposite direction: The mice who met the female counterpart in the original location became scared after the memory of this box was artificially connected to electric shocks.
So maybe in the future this unexpected flexibility will help the veterans to unplug the sight of a battlefield from the panic and terror and to connect it to the feeling of tranquillity and happiness instead.
Or say you wanna forget your ex. One possibility is tequila. Another way would be to disturb the reconsolidation process on the cellular level. “Reconsolidation” means that whenever a memory is recalled, its neural trace becomes unstable, so that each time you remember something it needs to be saved (consolidated) all over again. At least this approach worked for mice: CA1, the region of hippocampus playing a role in reconsolidation, was optogenetically silenced in the exact moment they were recalling a fearful memory5. Next day a lot of the mice didn’t seem to remember the electric shock administered to them, carelessly strolling around the experiment box. Seems like preventing a contextual memory from being restabilized when it is being actively remembered can help to delete it. “Eternal sunshine of the mouse mind”, coming soon to the theatres!
Manipulation of social behavior
Another important domain being actively investigated with optogenetic technology is social behavior. Aggression, anxiety, sniffing females: We share a lot of important social behaviors with rodents (well, maybe not the last one. Except if you’re really drunk). Understanding the cellular bases of behavioral dysfunctions and tweaking them is very important for such disorders as ASD (autism spectrum disorders) or schizophrenia.
One of these studies took a detailed look at amygdala and found two distinct neuronal subpopulations in its medial part6. One (inhibitory) is responsible for different social behaviors (e.g. aggression) and the second one (excitatory) initiates asocial ones (e.g. repetitive self-grooming). When researchers artificially activated the inhibitory subpopulation, the stimulated mouse went from Dora the Explorer to the Incredible Hulk: It relentlessly attacked its fellow comrade the millisecond the light went on. Whereas when the excitatory cell subpopulation was activated, the mouse just forgot about protecting it’s territory from an intruder and went totally hippie and relaxed.
Mouse Hulk in action. From http://authors.library.caltech.edu/49515/20/mmc1.mp4
It was by far not the only study trying to understand what the exact neural underpinnings of aggression are. The hypothalamus, the small region governing basic functions such as hunger, body temperature and mating, was also shown to have a hot-tempered cell cluster7. Optogenetic stimulation of the hypothalamus part with a very long name (ventrolateral area of the ventromedial hypothalamus) turned the male mice into blood-thirsty vikings, attacking other males, females and even inanimate objects. Untangling this circuitry could answer a wide array of questions: How does the brain control aggression? Are some people hard-wired to be violent? Can we alleviate aggressive behavior?
From the other extreme of the spectrum, anhedonia and social withdrawal in depression were explored as well8. In depressed mice, stimulation of medial prefrontal cortex (mPFC), the region responsible for functions like decision-making and emotional regulation, made them, well, less-depressed and more socially active. They started to go out and have fun again (which in mouse world means interaction with other mice) and seemed to enjoy life more (eating more sucrose is their savoir vivre). This rapid way of relieving symptoms compares favourably with currently common antidepressants which take weeks or even months to start working.
And this is just the beginning. Optogenetics is taking baby steps right now; imagine what a full-blown sprint would look like. It will take decades of refining the technique, understanding the underlying targets and having discussions about ethical aspects, but then we might actually end up with something (even more) astonishing. So far the only human optogenetic study aims to restore sight to the blind9; maybe in fifty or hundred years (given that we avoid Trump presidency and the Earth still exists) patients with chronic pain, depression or obsessive-compulsive disorder will casually walk around with cables going out of their heads. Or maybe optogenetics will only be used for fundamental brain research whose results will be later translated into other forms of therapy like deep brain stimulation. Who knows? The only thing we can do to find out is to boldly go where no man has gone before, as Captain Kirk has put so nicely10.
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- Crick, F.H. (1979) Thinking about the brain. Sci Am, 241, 219–232.
- Pastrana, E. (2010). Optogenetics: Controlling cell function with light. Nature Methods Nat Meth, 8(1), 24-25. doi:10.1038/nmeth.f.323
- Ramirez, S., Liu, X., Lin, P., Suh, J., Pignatelli, M., Redondo, R. L., . . . Tonegawa, S. (2013). Creating a False Memory in the Hippocampus. Science, 341(6144), 387-391. doi: 10.1126/science.1239073
- Redondo, R. L., Kim, J., Arons, A. L., Ramirez, S., Liu, X., & Tonegawa, S. (2014). Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature,513(7518), 426-430. doi:10.1038/nature13725
- Lux, V., Masseck, O. A., Herlitze, S., & Sauvage, M. M. (2015). Optogenetic Destabilization of the Memory Trace in CA1: Insights into Reconsolidation and Retrieval Processes. Cereb. Cortex Cerebral Cortex. doi:10.1093/cercor/bhv282
- Hong, W., Kim, D., & Anderson, D. (2014). Antagonistic Control of Social versus Repetitive Self-Grooming Behaviors by Separable Amygdala Neuronal Subsets. Cell, 158(6), 1348-1361. doi:10.1016/j.cell.2014.07.049
- Lin, D., Boyle, M. P., Dollar, P., Lee, H., Lein, E. S., Perona, P., & Anderson, D. J. (2011). Functional identification of an aggression locus in the mouse hypothalamus. Nature, 470(7333), 221-226. doi:10.1038/nature09736
- Covington, H. E., Lobo, M. K., Maze, I., Vialou, V., Hyman, J. M., Zaman, S., . . . Nestler, E. J. (2010). Antidepressant Effect of Optogenetic Stimulation of the Medial Prefrontal Cortex. Journal of Neuroscience, 30(48), 16082-16090. doi:10.1523/jneurosci.1731-10.2010
- Retrieved September 13, 2016, from http://www.nature.com/news/light-controlled-genes-and-neurons-poised-for-clinical-trials-1.19886
- Star Trek Original Series Intro (HQ). Retrieved September 13, 2016, from https://www.youtube.com/watch?v=hdjL8WXjlGI