Tag Archives: optogenetics

Artificial skin can feel pressure, then tell your brain about it

Prosthetics has come a long way from its humble beginnings – the crude wooden legs of yore are a far cry from the technological marvels we can create to replace our limbs today. However, there is one thing that, with all our know-how, we haven’t yet been able to incorporate in them: a sense of touch. A research team from Stanford University aims to fix this shortcoming, and has developed technology that can “feel” when force is exerted upon it, then transmit the sensory data to neurons – in essence, they’ve created an artificial skin.

Image via factor-tech

Image via factor-tech

Tactile sense is a very important source of information for our brains, and having an otherwise functioning limb that doesn’t feel what it’s touching is something most of us can’t even imagine. Sit on your hand till it goes numb, then try to tie your laces – it’s frustratingly hard, and personally, I find the sensation disturbing.

Now imagine that numbness persists for your whole life. That’s what prosthetic users have to live with, a serious limitation imposed on even the most effective prosthetic. Without tactile sensitivity, it’s hard to maintain optimal motor control, and it’s impossible to know how much force you’re exerting on an object, or it’s temperature and texture, for example. To make matters worse, having a sense of touch (even the illusion of it) is one of the best ways to alleviate phantom limb pain, which affects nearly 80% of amputees.

The human skin is a superbly complex and well tuned sensory organ – so much so in fact, that we may never be capable of creating something that reacts to stimulus in quite the same way it does. But the Stanford team, led by electrical engineer Benjamin Tee, recently performed a proof-of-concept experiment that brought artificial tactile sense from the realm of sci-fi one step closer to reality. They used flexible organic circuits and innovative pressure sensors to create a skin-like interface that can sense the force of static objects. Data recorded by the device was transmitted via optogenetic to cultured mice brain cells. Their work was published in the journal Science.

The DiTact

Artificial mechanoreceptors mounted on the fingers of a model robotic hand.
Image via phys

The system, dubbed “DiTact” (Digital Tactile System) relies on low-power, flexible organic transistor circuitry, that can translate pressure into the same signals our natural mechanoreceptors generate. To make the sensors precise and to give them a wide enough range of pressure recording, the team created them out of carbon nanotubes shaped into tiny pyramidal structures.

“Our sensor was made of tiny pyramids of rubber with carbon nanotubes distributed in it,” noted study co-author Alex Chortos. “This structure was very useful because it allowed us to easily change a few things, like the distance between the pyramids, the size of the pyramids, and the concentration of carbon nanotubes in order to get the ideal pressure sensing characteristics in the right range.”

The nanostructure of the pyramids allowed the researchers to increase the sensors’ precision close to the levels of our own cutaneous receptors.

Interfacing

But just having sensors isn’t enough, all the magic happens in the brain. To create sensation, the researchers took the signals from the piezometers and transferred them via optic cables to mouse cortical neurons – as the technology is still in an early stage of development, the cells were cultured in vitro rather than use the brains of live animals.

But using the same technique, signals from a prosthesis coated with DiTact could be fed directly to the brain of a living human – optogenetics has been successfully used on live subjects before. All that is needed is for a number of neurons to be genetically altered to respond to light signals. Using a transgene obtained from certain algae strands, neurons can be made to fire electrical signals when exposed to blue light, or to yellow light using a bacterial transgene.

However, because of the rate at which sensory information is processed by neurons, the team had to implement a few of their own changes to the classical method.

“Biological mechanoreceptors are able to produce signals as fast as several hundred electrical pulses per second,” says Chortos. “Previous optogenetic technologies were only capable of stimulating brain cells much slower than we need to mimic real mechanoreceptors.”

Luckily, Chortos knew of the work of Andre Berndt and Karl Deisseroth who developed a new type of optogenetic treatment that allows brain cells to be stimulated very rapidly so that they’re compatible with the speed of real mechanoreceptors. Using the new optogenetic proteins, the neurons were able to sustain longer intervals of stimulation, suggesting that the system could also work with other fast-firing neurons, including peripheral nerves. This, the team says, means that DiTact will likely work with live mice or humans, and the good results they’ve seen up to know means that they will test the system on a live mouse as soon as possible.

Getting a feel for the future

“We could validate that our sensor is conveying the correct information to [a live] animal by using behavioral cues, i.e. how the animal behaves in response to pressure,” said Chortos. “The ultimate test will be to attach the sensor to a human and ask them what they feel. In order to get truly natural touch sensing, we may need to modify and tweak our design.”

“We envision our artificial mechanoreceptors making the greatest impact via integration for sensory feedback with prosthetic systems in development by other groups,” noted co-author Amanda Nguyen. “As our sensor would be mounted alongside artificial limb systems, the primary safety concerns are centered around nerve stimulation patterns and interface.”

Nguyen notes that while the early work on sensory feedback with neurally interfaced prosthetics shows great promise, we need to truly understand how to effectively and safely stimulate nerves in order to provide realistic sensory feedback.

“As a greater understanding of stimulation parameters is gained, the output of our artificial mechanoreceptor will be tuned to follow these stimulation paradigms,” she said. “With demonstrated efficacy and safety, the potential for improving the quality of life for individuals with tactile impairments can be balanced with the ethical concerns raised by neuroprosthetics. Accessibility of this type of technology in humans will grow as both our understanding of neuroscience grows and prosthetic technology advances to provide nuanced sensory perceptions.”

 

Ultrasounds were used to selectively turn on or off groups of neurons in a roundworm. Credit: Salk Institute

Ultrasounds used to control neurons in a worm’s brain for the first time

By ‘tickling’ select membrane channels you can effectively control neurons, by activating or deactivating cells. You can do this using electrical currents, like we see very well illustrated in brain-computer interfaces, light (the field of optogenetics), and sound (sonogenetics). Yes, sound. This was only recently demonstrated by researchers at Salk’s Molecular Neurobiology Laboratory who used ultrasounds to control neurons in the nematode Caenorhabditis elegans.

Ultrasounds were used to selectively turn on or off groups of neurons in a roundworm. Credit: Salk Institute

Ultrasounds were used to selectively turn on or off groups of neurons in a roundworm. Credit: Salk Institute

In optogenetics, scientists add light-sensitive channel proteins to neurons then shine a light on these to selectively open channels. This sort of technique has proven pivotal in our most recent efforts to unravel the brain’s secret. Closing and activating neurons is, after all, a quick fix to help us understand what each brain region does, like flicking switches until you find out what each does. The problem with optogenetics is that it’s invasive. If you want to study the human brain with optogenetics, you’d have to open a skull, and add an implant fitted with a fiber optic cable.

Ultrasounds (frequencies past 20,000 Hz), however, can pass through the body. In fact, the most famous use for ultrasound in medicine is the sonogram which makes  images of organs and structures inside the body.

“In contrast to light, low-frequency ultrasound can travel through the body without any scattering,” says  Sreekanth Chalasani, senior author of the study. “This is a new, additional tool to manipulate neurons and other cells in the body,” Chalasani added.

“This could be a big advantage when you want to stimulate a region deep in the brain without affecting other regions,” continued Stuart Ibsen, a postdoctoral fellow in the Chalasani lab and first author of the new work.

The ultrasounds by themselves didn’t activate neurons in the worm. First, microbubbles of gas outside of the worm were necessary to amplify the low-intensity ultrasound waves. “The microbubbles grow and shrink in tune with the ultrasound pressure waves,” Ibsen says. “These oscillations can then propagate noninvasively into the worm.” Once the ultrasound bombed gas bubbles activated motor neurons, the modified worms changed their direction of movement, the researchers report in Nature Communications.

Of course, it’s not like you can ultrasound people’s brains and mind control them because not all membrane ion channels respond to the sound waves. One channel, called TRP-4, was found to be responsive and this is what they worked with. When the mechanical deformations from the ultrasound hitting gas bubbles propagate into the worm, they cause TRP-4 channels to open up and activate the cell. What about the neurons that don’t have this particular membrane channel? Well, the scientists were able to add TRP-4 to neurons that didn’t innately have them, and hence couldn’t initially respond to ultrasounds.

From worms to humans there’s a long way, however. That’s not to say it’s impossible. In a mammal, TRP-4 could be added to any calcium-sensitive cell and microbubbles could be injected into the bloodstream. Theoretically, targeted ultrasound beams could then activate or deactivate neurons for therapeutic purposes, like fighting Parkinson’s. Sonogenetics is definitely something to follow in the future.

One of the most notable recent examples of a film showcasing amnesia is Memento (2001). It tells the story of a former insurance investigator, Leonard Shelby, and his attempts to track down the man who attacked him and his wife-killing her and leaving him with a brain injury that has destroyed his ability to form new memories. Image: IMDB

Scientists light the brain of mice to recall their lost memories

A team at MIT in collaboration with the Riken Brain Science Institute in Japan activated the lost memories of mice. The findings suggest memory deficiencies like amnesia have more to do with accessing data, than storage itself. Though far from applicable to humans, the research does show that it’s possible, in theory at least, to help patients with retrograde amnesia (who’d lost their memories following a trauma or brain injury) live a normal life once more.

Shining light on lost memories

One of the most notable recent examples of a film showcasing amnesia is Memento (2001). It tells the story of a former insurance investigator, Leonard Shelby, and his attempts to track down the man who attacked him and his wife-killing her and leaving him with a brain injury that has destroyed his ability to form new memories. Image: IMDB

One of the most notable recent examples of a film showcasing amnesia is Memento (2001). It tells the story of a former insurance investigator, Leonard Shelby, and his attempts to track down the man who attacked him and his wife-killing her and leaving him with a brain injury that has destroyed his ability to form new memories. Image: IMDB

Among neuroscientists, the causes and roots of amnesia are still up for debate and the community seems to be split into two currents: those who believe it is caused by damaged brain cells (a storage problem), and those who hold that the memories themselves are blocked because of faulty connections (an accessing problem). These latest findings allude to the latter as being the leading factor of memory loss, though in practice it might actually be a combination of the two.

“The majority of researchers have favored the storage theory, but we have shown in this paper that this majority theory is probably wrong. Amnesia is a problem of retrieval impairment,” said Nobel-awarded Sususmu Tonegawa, director of the RIKEN Brain Science Institute in Saitama, Japan, said in a statement.

To pick the mice’s brains, the researchers used optogenetics – the combination of genetics and optics to control well-defined events within specific cells of living tissue. By way of an engineered virus, the researchers introduced a specific protein in those neurons that are typically activated when memories are made and stored; such a collection of neurons is called an engram. Since these proteins are sensitive to blue light, the researchers could control activity in the neurons, effectively turning them on or off at will.

The mice where separated into two groups. Electric shocks were applied in a distinct setting to induce a fear factor or bad memory. After a while, after the mice were introduced in the same room they became scared without any electric shock, signaling they were reliving the traumatic event. Then, some of the mice were injected with a drug called anisomycin which affects memory much in the same way as retrograde amnesia. When the drugged mice were placed in the same room, they showed no sign of fear or past memory of the same enclosure. However, once blue lights were shone on their brains, the mice instantly recalled their past memory, the researchers reported in Science.

This image of a mouse with blue light shone inside the brain is from a previous optogenetics research made in 2009. Back then, researchers attempted to convert bad memories into good ones. Photo: John P. Carnett/Popular Science/Getty Images A mouse used in a different optogenetics experiment in 2009.

This image of a mouse with blue light shone inside the brain is from a previous optogenetics research made in 2009. Back then, researchers attempted to convert bad memories into good ones. Photo: John P. Carnett/Popular Science/Getty Images A mouse used in a different optogenetics experiment in 2009.

Later on, brain scams performed by the team showed that the engrams in one part of the hippocampus –  primarily associated with memory and spatial navigation – were communicating with cells in another part of the hippocampus. This network was extended to include connections with other regions of the brains, including the amygdala which is where the fear response is activated. So, because other connections in the mouse’s brain – those that were not affected by the drug – contained information about the electric shock, these were re-activated once the blue light was shone.

“If you test memory recall with natural recall triggers in an anisomycin-treated animal, it will be amnesiac, you cannot induce memory recall. But if you go directly to the putative engram-bearing cells and activate them with light, you can restore the memory,” Tonegawa said.

“Our conclusion is that in retrograde amnesia, past memories may not be erased, but could simply be lost and inaccessible for recall,” he went on. “These findings provide striking insight into the fleeting nature of memories, and will stimulate future research on the biology of memory and its clinical restoration.”

While there’s much promise and insight, the same procedure is impossible for amnesic human patients, due to both technical and ethical challenges. For one, the memory that needs to be activated needs to be studied and patterned before using a brain scan. Then, you need some specific proteins injected and a blue laser fitted inside your skull. On the other hand, this opens terrain for biomedical specialists and other neuroscientists to find pathways and drugs that might declutter these connections. In those cases where memory loss is merely a matter of neuron connectivity, there’s hope these can be activated once more.

brain computer interface

Presenting the first brain-gene interface: thought-controlled protein production

You’ve heard about controlling robotic arms or prosthesis with thoughts, but what about genes? In a deceptively simple experiment, bioengineers in Switzerland combined a classical brain-computer interface with a biological implant, which effectively allowed a genetic switch to be operated by brain activity.

Imagine wearing a “funny” cap fitted with electrodes and a tiny implant, then controlling your mood by thinking the perfect “pure” thoughts that would cause a cascade of feel good chemicals. If it works, this could basically work as a painkiller, so you can deliver just the right amount. Really, there’s a lot of potential floating around this thing.

brain computer interface

Image: zine.co.in

The setup went something like this: human participants wore a standard EEG cap that registered their brain activity, then a device translated this into a electrical signal and sent it to a  electromagnetic field generator. Each specific kind of brain activity thus corresponded to a certain magnetic field. In the meantime, researchers tweaked bacterial genes into kidney cells to cause them to produce light-sensitive proteins. Then, the cells were bioengineered so when they sensed light these would produce  a protein called secreted alkaline phosphatase (SEAP). The protein was chosen for no particular reason other than it is extremely easy to detect in the blood, so it fit well for demonstrative purposes. A mini-setup was made consisting of the engineered cells and a LED, all encased in a plastic pouch – this was inserted under the skin of several mice.

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The human volunteers were tasked with various cognitive activities, like playing Minecraft or meditating. These activities generated a magnetic field which activated the implant’s infrared LED, triggering SEAP production. Playing Minecraft produced moderate levels of SEAP, while meditating resulted in high levels. Interestingly enough, a third group was thought to consciously light the LEDs on or off, thereby purposely turning SEAP production on or off (Nature Communications). As you can see, by using an implant, the setup harnesses the power of optogenetics without requiring the user to have his or her own cells genetically altered. We’ll definitely hear more about this in the future.

“Controlling genes in this way is completely new and is unique in its simplicity,” explains Martin Fussenegger, Professor of Biotechnology and Bioengineering at the Department of Biosystems (D-BSSE) in Basel.

Fussenegger hopes that a thought-controlled implant could one day help to combat neurological diseases, such as chronic headaches, back pain and epilepsy, by detecting specific brainwaves at an early stage and triggering and controlling the creation of certain agents in the implant at exactly the right time.

(A) The picture on the left shows serotonin neurons in red. The middle picture shows neurons expressing light sensitive proteins in green. The picture on the right is an overlay of the previous two pictures, showing in orange light sensitive proteins selectively expressed in serotonin neurons. (B) Blue light illumination, 500 microsecond pulse, shown in blue line, induced spontaneous action potentials in the serotonin neuron for approximately 10 seconds. The yellow light illumination, 500 microsecond pulse, shown in yellow line, stopped spontaneous action potentials.

The key to patience lies within serotonin

Image: Flickr Creative Commons

Image: Flickr Creative Commons

Either when someone’s late for a date or you need to queue in line, our patience becomes tested. Some people handle the waiting better than others, leading us to the idea that patience is a virtue that differs from person to person. But what is it exactly that helps us remain patient, and why do some people remain unfazed even when faced with hours, days even of waiting? The answer might lie in serotonin – one of the most widespread neutransmitter believed to influence a variety of psychological and other body functions. An imbalance in serotonin levels, for instance, has been linked with depression.

The finding came after Japanese researchers at the  Neural Computation Unit at the Okinawa Institute of Science and Technology Graduate University used a new technique called optogenetics, where they use light to simulate specific neurons with precise timing.

Serotonin: rewarding patience

Serotonin is involved in a wide array of bodily and cognitive functions. Of the approximately 40 million brain cells, most are influenced either directly or indirectly by serotonin. This includes brain cells related to mood, sexual desire and function, appetite, sleep, memory and learning, temperature regulation, and some social behavior. In classic neuroscience, serotonin was believe to signal punishment and inhibit behaviors, however the opposite might be the case. Serotonin enriching drugs have been shown effective at treating depression, while previous optogenetic stimulation studies have shown that it’s linked with rewards. Also, research conducted by the same Japanese researchers found that inhibiting serotonin neurons causes impulsive behavior.

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The mice who saw the light

Figure 1. Control of serotonin neural activity by light. (A) The picture on the left shows serotonin neurons in red. The middle picture shows neurons expressing light sensitive proteins in green. The picture on the right is an overlay of the previous two pictures, showing in orange light sensitive proteins selectively expressed in serotonin neurons.  (B) Blue light illumination, 500 microsecond pulse, shown in blue line, induced spontaneous action potentials in the serotonin neuron for approximately 10 seconds. The yellow light illumination, 500 microsecond pulse, shown in yellow line, stopped spontaneous action potentials.

(A) The picture on the left shows serotonin neurons in red. The middle picture shows neurons expressing light sensitive proteins in green. The picture on the right is an overlay of the previous two pictures, showing in orange light sensitive proteins selectively expressed in serotonin neurons.
(B) Blue light illumination, 500 microsecond pulse, shown in blue line, induced spontaneous action potentials in the serotonin neuron for approximately 10 seconds. The yellow light illumination, 500 microsecond pulse, shown in yellow line, stopped spontaneous action potentials. (fig. 1) Image: OIS

The researchers genetically engineered mice so that they produced light-activated molecules only in neurons that produce serotonin (fig. 1), then inserted an optical fiber in the backs of each brain. Five such mice were trained to performed a reward-delayed task, meaning they would receive a tasty treat if they waited at a hole. The game came in various stages; the mouse had to wait for 3 seconds, 6 seconds, 9 seconds or … infinity. The last stage meant that the mouse would never receive a reward – the ultimate patience test. To be sure the mice were actually patiently waiting, each mouse was trained to hold its nose in the hole while waiting for the reward. The researchers call this posture a ‘nose poke’.  Ok, let’s move further.

No prior signal was released that would notify the mice how long the waiting would be, and the waiting periods themselves were shuffled at random.

Figure 2. Effect of serotonin activation on waiting for delayed reward  The mouse easily could wait for 3 and 6 seconds to receive delayed food. When the duration was 9 seconds, the failure in waiting significantly increased. When serotonin neurons were activated with light stimulation during the 9-second delay, the number of reward wait failures significantly decreased.

Figure 2. Effect of serotonin activation on waiting for delayed reward
The mouse easily could wait for 3 and 6 seconds to receive delayed food. When the duration was 9 seconds, the failure in waiting significantly increased. When serotonin neurons were activated with light stimulation during the 9-second delay, the number of reward wait failures significantly decreased.

In half of the trials, researchers stimulated serotonin neurons by shining a light through the optical fiber while the mice were waiting. The mice had no problem waiting for 3 or 6 seconds to receive the food, but from 9 seconds onward the rodents became fed up – and it wasn’t food. When serotonin neurons were stimulated with the light, the researchers found that the failure rate over 9 seconds significantly decreased (fig. 2).

Figure 3. Effect of serotonin activation on waiting time during reward omission  In the 25% of trials, a food pellet was not presented no matter how long the mice waited. Without serotonin neuron stimulation, the mice waited 12 seconds on average. The waiting time was significantly extended to about 17.5 seconds on average with the stimulation of serotonin neurons.

Figure 3. Effect of serotonin activation on waiting time during reward omission
In the 25% of trials, a food pellet was not presented no matter how long the mice waited. Without serotonin neuron stimulation, the mice waited 12 seconds on average. The waiting time was significantly extended to about 17.5 seconds on average with the stimulation of serotonin neurons.

In 25% of the trials, the researchers really messed with the mice’s heads – the food wasn’t rewarded no matter how long they had to wait. During these trials, mice with no serotonin stimulation waited on average 12.0 seconds, while those with serotonin neuron optical stimulation waited on average 17.5 seconds (fig. 3). For control purposes, the researchers were careful to shine light in serotonin neurons at different timing when the mouse did not have its nose poked in the food hole. They found that these mice behaved the same as in unstimulated cases. This suggests that serotonin doesn’t inhibit motor functions and, at the same time, that serotonin neurons promotes patience for delayed rewards.

“Our previous studies have shown that serotonin levels increase when waiting for delayed rewards. We have also shown that inhibiting serotonin neurons leads to an inability to wait for a long time,” explained Drs. Kayoko Miyazaki and Katsuhiko Miyazaki. “By using light to stimulate neurons at specific times, this study has proven serotonin’s role in patience during delayed reward waiting, underlining serotonin’s much greater role than previously thought.”

 

By further exploring the effect of serotonin, the researchers hope to decipher the neuronal network behind mental disorders and behaviors involving serotonin. Findings appeared in the journal Current Biology.

Caenorhabditis elegans (C. elegans) is a small (about 1 mm long as an adult), free living nematode (round worm). Simple as it is, it can be regarded as a prototype to study biological locomotion in various fluid environment.

Of mind control: scientists manipulate worm and take control of its behavior

In a remarkable feat of science, scientists at Harvard University have surpassed seemingly insurmountable technological challenges have managed to take over the behavior of a lab worm. Using precisely targeted laser pulses at the worm’s neurons, scientists were able to direct it to move in any directions they wanted, and even trick it in thinking there’s food nearby. These fantastic results provide an important milestone in the quest to understand how sensory information is transmitted into behavior.

Caenorhabditis elegans (C. elegans) is a small (about 1 mm long as an adult), free living nematode (round worm). Simple as it is, it can be regarded as a prototype to study biological locomotion in various fluid environment.

Caenorhabditis elegans (C. elegans) is a small (about 1 mm long as an adult), free living nematode (round worm). Simple as it is, it can be regarded as a prototype to study biological locomotion in various fluid environment.

The researchers used the favored lab testing specimen, the common Caenorhabditis elegans (C. elegans) worm, to test their theories, which they genetically altered in order for its neurons to give off fluorescent light, allowing them to be tracked during experiments. Also, genes in the worm were altered to make its neurons sensitive to light, so they could be stimulated with pulses of light – this is optogenetics.

“If we can understand simple nervous systems to the point of completely controlling them, then it may be a possibility that we can gain a comprehensive understanding of more complex systems,” said team leader Sharad Ramanathan, an Assistant Professor of Molecular and Cellular Biology and of Applied Physics. “This gives us a framework to think about neural circuits, how to manipulate them, which circuit to manipulate and what activity patterns to produce in them.

“Extremely important work in the literature has focused on ablating neurons, or studying mutants that affect neuronal function and mapping out the connectivity of the entire nervous system. ” he added.

“Most of these approaches have discovered neurons necessary for specific behavior by destroying them. The question we were trying to answer was: Instead of breaking the system to understand it, can we essentially hijack the key neurons that are sufficient to control behavior and use these neurons to force the animal to do what we want?”

Taking over a worm’s brain

Targeting the worm’s neurons with laser pulses, however proved to be an incredible challenge. The researchers manage to overcome the difficulties they faced though, like developing a movable table which keeps the worm centered to the laser beam no matter how fast or in what direction it might move, and implementing a custom-built computer hardware and software to insure the laser pulses fire at the required split-second speeds – once every 20 milliseconds, or about 50 times a second.

“The goal is to activate only one neuron,” Ramanathan said. “That’s challenging because the animal is moving, and the neurons are densely packed near its head, so the challenge is to acquire an image of the animal, process that image, identify the neuron, track the animal, position your laser and shoot the particularly neuron”

They discovered that controlling the dynamics of activity in just one interneuron pair (AIY) was sufficient to force the animal to locate, turn towards, and track virtual light gradient. What was mind blowing, for me to learn at least, was that the scientists didn’t only manipulate the worm’s behavior, but its senses also. They proved this by tricking the worm’s brain into believing food was nearby, causing it to make a beeline toward the imaginary meal.

“By manipulating the neural system of this animal, we can make it turn left, we can make it turn right, we can make it go in a loop, we can make it think there is food nearby,” Ramanathan said. “We want to understand the brain of this animal, which has only a few hundred neurons, completely and essentially turn it into a video game, where we can control all of its behaviors.”

Before you form any modern Manchurian candidate paranoia influenced ideas, consider that C. elegans has one of the most primitive brains, as far as complex organisms are concerned – boosting a disappointing 302 neurons. It’s impossible for a similar set-up to render similar results for a snake, let alone a human. Still, the Harvard researchers intend of improving their system and test on more complex organisms.

Findings were published in the journal Nature.

An image of a transgenic mouse hippocampus.

Memories are stored in specific brain cells, MIT Inception-like research finds

An image of a transgenic mouse hippocampus.

An image of a transgenic mouse hippocampus.

When the brain deems an experience meaningful enough, it will transfer that information from short-term storage, where typically information like where you put your car keys or the phone number of a person you just met gets stored temporarily, to your long-term memory, offering the possibility to be accessed at a later time. Neurologists claim this recording is made in the brain by strengthening the connections between groups of neurons that participate in encoding the experience, a pattern of connections which is referred to as an engram. These engrams will typically stay dormant unless they’re stimulated by a cue, which will evoke the event back into memory.

This explains why a song playing in the background might instantly transport you back to a special event tied to the track or the sweet scent of a freshly baked pie might transport you back in time to when you were a child. There are a myriad of such “anchors” dispersed though out our neural network, however the existence of engrams beyond their hypothetical nature has been debated for a while, as their exact mechanism and location has been a focus of persistent research for many decades. Now, a recent research conducted by scientists at MIT which made use of optogenetics demonstrates that memories are indeed stored in specific brain cells.

“We demonstrate that behavior based on high-level cognition, such as the expression of a specific memory, can be generated in a mammal by highly specific physical activation of a specific small subpopulation of brain cells, in this case by light,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience at MIT and lead author of the study reported online today in the journal Nature. “This is the rigorously designed 21st-century test of Canadian neurosurgeon Wilder Penfield’s early-1900s accidental observation suggesting that mind is based on matter.”

A breakthrough in neuroscience

Dr. Penfield is one of the most influential figures in neurosurgery, a pioneer in the field whose legacy includes, among others, the first maps of the sensory and motor cortices of the brain showing their connections to the various limbs and organs of the body, still used today, unaltered. He was a man inherently concerned with the various subterfuges of the human mind, and dedicated his life to understanding how the brain works and whether there is any scientific basis that might acknowledge the existence of the human soul. One of his most groundbreaking works is the elaboration of the Montreal Procedure, a controversial surgery in which he treated epilepsy patients by severing nerve cells in the brain where the seizures originated. The operation would take place under local-anesthesia, as the patient’s collaboration was deemed indispensable. Penfield would destroy only the affected nerve cells by the disease, as he stimulated the brain with tiny jolts of electricity and observed the patient’s response. While probing nerve cells in the hippocampus, the region of the brain responsible for memory formation and storage, some patients would report vivid and complex recollections of past events.

Many discussions followed around these sort of events, but until now, it wasn’t scientifically proven that the simple reactivation of nerve cells in the hippocampus could cause memory recall.

To test their hypothesis, the MIT researchers identified the particular brain cells in the hippocampus that were active only when a mouse was learning about a new environment. They then proceeded in identifying which genes were activated in those cells, and added the gene for channelrhodopsin-2 (ChR2), a light-activated protein used in optogenetic indispensable for the present research, to a genetically engineered mouse.

“We thought we could use this new technology to directly test the hypothesis about memory encoding and storage in a mimicry experiment,” says co-author Xu Liu, a postdoc in Tonegawa’s lab.

“We wanted to artificially activate a memory without the usual required sensory experience, which provides experimental evidence that even ephemeral phenomena, such as personal memories, reside in the physical machinery of the brain,” adds co-author Steve Ramirez, a graduate student in Tonegawa’s lab.

Inception: fear induced on command

The scientists next labelled a population of hippocampal dentate gyrus neurons, using tiny optical fibers to deliver pulses of light to the neurons. Finally, the mice were introduced to an environment and were left to accustom themselves for a few minutes of exploration. A mild food shock was induced all of sudden, which caused the mice to fear the particular environment. The brain cells activated during this fear conditioning became tagged with ChR2. Later, the mice were introduced in a totally different environment, with an obviously different maze and of another smell, and were left there to explore. A pulse of light was triggered onto the neurons involved in the first experience, which lead to the fear memory getting switched on; the mice quickly entered a defensive, immobile crouch. This is called fear conditioning.

“Our results show that memories really do reside in very specific brain cells,” Liu says, “and simply by reactivating these cells by physical means, such as light, an entire memory can be recalled.”

Activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific.

“This remarkable work exhibits the power of combining the latest technologies to attack one of neurobiology’s central problems,” says Charles Stevens, a professor in the 
Molecular Neurobiology Laboratory at the Salk Institute who was not involved in this research. “Showing that the reactivation of those nerve cells that were active during learning can reproduce the learned behavior is surely a milestone.”

The method may also have applications in the study of neurodegenerative and neuropsychiatric disorders. “The more we know about the moving pieces that make up our brains,” Ramirez says, “the better equipped we are to figure out what happens when brain pieces break down.”

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