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Memory Engineering – How Fiction Slowly Becomes Reality
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       Memory engineering has been a darling of futuristic fiction for decades. Whether it’s a spine-chilling manipulation tool in George Orwell’s 1984 or a cure for heartbreak in Michel Gondry’s film Eternal Sunshine of the Spotless Mind, the ability to control memory has always been fascinating.

Memory Engineering,long-term potentiation,molecular neuroscience,depression-inducing memories

We cling to our unchangeable memory as a proof of sanity, and many people fear the day when brainwashing is at the press of a button, Men in Black-style. However, several recent developments in neuroscience show that day may not be so far, but memory engineering could turn out to be more useful than scary, offering new ways to treat Alzheimer or post-traumatic stress disorder.


       Even back in the 1960s, there was evidence that nerve stimulation and forming certain proteins are important building blocks in the complex process of memoryy formation and retention. Researchers Terje Lømo and Timothy Bliss demonstrated that stimulating neurons at 100 times a second can strengthen synapses, while the 10 times stimulus used as a control was neutral. The process called long-term potentiation (LTP) was believed to be the physical basis of memory. Decades later, John Lisman, biology professor at Brandeis University, discovered that the protein enzyme CaMKII is required for changing synaptic strength. In 2011, Lisman and his colleagues showed that a complex of CaMKII and another molecule, NMDAR, is proportionately related to the strength of the synapse – the more of the complex, the stronger the synaptic connections. Lisman worked on slices of rat hippocampus, a part of the brain involved in memory, but recent studies have gone further, using living mice.


       Last year, a set of experiments led by neuroscientists Steve Ramirez and Xu Liu from the Massachusetts Institute of Technology (MIT) used mind-blowing molecular neuroscience techniques on mice to capture specific memories and alter them, later following how the rodents behaved according to their ”implanted” artificial memories. The basic mechanism is simple: once you identify and label the neurons that were active during a specific experience, all you need is a biological ”switch” that enables you to operate them, turning them on and off as you please.  The mice were genetically modified for the experiment, so that their neurons would produce a molecular label whenever they were fully active, as well as an ”on” switch, also on a molecular level. Once active, the neurons would glow red thanks to the label, a molecule called Channelrhodopsin which makes neurons light-activated. This means that the specific ”engineered” neurons could now be activated by shining a light on them, thus awakening the specific fragment of past experience they have previously stored. Moreover, the researchers found a way to switch the entire system on and off, using a common antibiotic, doxycycline – whenever they introduced doxycycline in the rodents’ diet, the labelling process stopped. When doxycycline was later removed, neuron labelling continued, thus enabling the scientists to activate the process only for specific periods of time in their experiments.

Memory Engineering,long-term potentiation,molecular neuroscience,depression-inducing memories  

       At first, mice were given no doxycycline. As they explored a new arena, neurons from the hippocampus became labelled, allowing the researchers to later activate them by light. Then the process was stopped by introducing the antibiotic into their diet. Now the team had a grip on a particular mental representation – the experience of the newly explored space. Now the truly interesting part began. Experimenters moved the mice to a new setting and reactivated the memory of the first space they explored by using light onto their brains, and then used electrical shocks to associate it with fear. When they returned to the original setting, mice were almost paralyzed with fear, even though no shocks were ever given in that particular space.


       The second experiment used a two-room arena, and researchers only associated one of them with the fear of electrical shocks by giving them doxycycline when exploring the other one. After the fear-conditioning, mice returned to the two-room arena, allowed to explore it freely. Unsurprisingly, they showed an obvious preference for the room not associated with fear. The team had basically altered their behaviour and worldview, and one cannot help but wonder what will happen when such techniques find human applications. Apart from the brainwashing scenario, what if scientists could one day strengthen the fading memories of elderly Alzheimer’s sufferers? What if traumatized soldiers returning home from the battlefield with crippling PTSD could be cured by erasing anxiety and depression-inducing memories and neutralizing specific trigger-situations, allowing them to live a normal life?  A new study from the University of California in San Diego delves even deeper into the relationship between brain cell connections and strenghtening or weakening particular memories. “We can form a memory, erase that memory and we can reactivate it, at will, by applying a stimulus that selectively strengthens or weakens synaptic connections,” said Dr. Roberto Malinow, neurosciences professor and senior researcher of the study.


       Malinow and his colleagues worked on a similar mechanism, but this time using a state-of-the art technique – optogenetics. Neurons of rats have been made sensitive to light through genetic engineering – a gene that produces a light-sensitive protein was inserted into a virus, which was later injected into specific brain cells. Then scientists stimulated these neurons with optical lasers. At the same time, an electrical shock was applied on their foot. Soon enough, the rats started associating the optical stimulation with pain, and began to show fear at every stimulation. The team then discovered a chemical change in the nerve synapses that have been stimulated, which shows that the specific memory has been strengthened on a molecular level.


       Next, Malinow and his team stimulated the same neurons differently – using a low-frequency optical pulse sequence, known for its ability to weaken synapses, the memory was “erased” and rats no longer showed a fear response to the triggering situation, which proves that the association with pain was gone. However, the most striking discovery was that re-stimulating the same nerves with high-frequency light pulses strengthened the memories, making the rats fearful once again, even when the electrical shock was not even applied. Selective removal and predictable reactivation of a specific memory is therefore no longer just a science fiction plot device. Speaking of potential clinical applications in humans, Malinow explained how the beta amyloid peptide that accumulates in the brains of Alzheimer's disease patients has the same weakening effect on synaptic connections as the low-frequency stimulation used to erased rats’ memories. Since this experiment showed it is possible to reverse the process, it may be possible to use it someday to counteract some of the effects of Alzheimer's.

Memory engineering  

       A Dutch team has made important discoveries using electric shock therapy. Electroconvulsive therapy (ECT) uses electrode pads placed on the scalp to induce seizures. Despite its negative reputation, ECT is sometimes still used as a last-resort for severe depression, combined with anaesthesia and muscle relaxants. A study led by Marijn Kroes, a neuroscientist from Radboud University Nijmegen, found that strategically timed ECT shocks could target and disrupt a disturbing memory.  The memory reconsolidation theory states that memories are taken out of “mental storage” when they are accessed and “re-written” over time, and studies suggest that memories are vulnerable to alteration or even erasure during this process. Kroes’ team investigated this hypothesis in patients undergoing ECT for severe clinical depression, by testing their ability to recall two disturbing slide-show narratives. Later after showing them, experimenters asked them to recall only one of the two, by partially replaying it. At this moment, when the reactivated memory undergoes reconsolidation and is thought to be vulnerable, patients received ECT. The next day, they were given a multiple-choice memory test, and results were significantly worse at recalling details from the the reactivated story, while memories of the other story remained unaltered. "The ability to permanently alter these types of memories might lead to novel, better treatments," says Kroes.


       The US Military is also interested in the subject – for the past few years, the Defense Advanced Research Projects Agency (DARPA) has been working on a memory stimulator, an implant sending electrical pulses to the brain much like the pacemaker works on the heart. The wireless, implantable neural-interface device is still in development and has not been tested on humans yet, but researchers were able to extend short-term memory in animals by stimulating the hippocampus. "If you have been injured in the line of duty and you can't remember your family, we want to be able to restore those kinds of functions," says program manager Justin Sanchez. However, the device was also used to manipulate the behaviour of monkeys by confusing them on what they remembered, raising numerous ethical questions. Where would a soldier stop if he knows he doesn’t have to live with the memory of his actions?   “When you fool around with the brain, you are fooling around with personal identity. The cost of altering the mind is you risk losing sense of self”, warns Arthur Caplan, a medical ethicist at New York University’s Langone Medical Center. Controversy aside, benefits could be colossal.

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Published by Andreea Dobre


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