Lasers Switch Bad Memories to Good in Mice

By Emily WaltzPosted 27 Aug 2014 | 17:25 GMT

Photo: John P. Carnett/Popular Science/Getty Images

A mouse used in a different optogenetics experiment in 2009.

Researchers have discovered a way to use a laserto manipulate memories in mice. In experiments

,scientists at the Massachusetts Institute ofTechnology found that they could change theemotions associated with a memory from negativeto positive and vice versa. The researchers reliedon optogenetics, a sophisticated genetic tool thatuses a laser to control neurons that have beensensitized to light.

reported today in (http://dx.doi.org/10.1038/nature13725)

Nature

Optogenetic techniques

for more than a decade to control animal behavior and map neuronal networks, and havethe potential to offer insight into maladies such as Parkinson's disease, addiction, depression, and spinalcord injuries. The technique involves injecting into the brain a virus that contains genetic constructs thatsensitize neurons to light, and then manipulating the neurons using a laser that delivers light via opticalfibers.

have been usedexperimentally

(http://spectrum.ieee.org/biomedical/diagnostics/integrated-implant-makes-it-easier-to-control-the-brain-with-light)

The MIT study presents a clever application of optogenetics. "This study shows how optogenetics could beused in a new way, to target plasticity and rewire circuits in the brain," said Roger Redondo, a co-author ofthe report, in an email to . It was an ingenious application of the technology, wrote TomonoriTakeuchi and Richard Morris, neuroscientists at the University of Edinburgh, in the U.K., in an

.

IEEE Spectrum

accompanying article in (http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13745.html)

Nature

The study also sheds light on which parts of the brain's circuitry are responsible for the malleability ofemotional memory. It has long been apparent that emotional associations with memories can be changed,but the neuronal mechanisms and brain circuits that enable this were unknown. In fact, doctors haveeffectively used manipulation of emotional memory in psychotherapy to treat maladaptive behaviors. TheMIT researchers wanted to know the scientific basis for how this is possible.

In a set of experiments, male mice were subjected to situations that produced fear (a small electric shock tothe foot) or pleasure (interaction with a female mouse) and the memory neurons that were activated duringthose experiences were labeled. The mice were then put into a rectangular testing arena and the neurons

associated with the fear or pleasure experiences were optogenetically reactivated with light whenever themice entered a target side of the test arena. As expected, mice with fear memories avoided that area of thearena, and mice with pleasure memories lingered.

The researchers than attempted to reverse the positive or negative emotion associated with the memory. Todo this, they took the animals to a new place, and allowed the fear-conditioned mice access to a female whileoptogenetically reactivating the fear neurons. They also subjected the pleasure-conditoned mice to footshocks while reactivating the pleasure neurons with the lasers. "The assumption here is that associations inthe brain are formed between neurons that are active at the same time," said Redondo during a pressbriefing held yesterday. "If this is right, we should be forcing neurons associated with fear . . . to link up withnew neurons expressing the pleasure of spending time with a female."

The experiment worked. The next testing day, the mice were put into the rectangular testing arena again,and the animals that previously had run away from the light from the laser were now spending more timenear that side of the arena, while those that had lingered near the target side were now running away. Inother words, the result suggests that the mice that had been given foot shocks now "remembered" theexperience positively and the mice that had spent time with a female "remembered" it negatively.

In further experiments, the MIT scientists determined that the neural circuits that were malleable werelocated in the brain's hippocampus in a region called the dentate gyrus. "We think their application ofoptogenetics was ingenious because they were able to reactivate a specific place memory representationfrom the training and later change its association from bad to good, or vice versa," said Takeuchi. But theremay be limitations to the strategy, he noted in his article in , "notably when sequences of neural firingare the essence of the memory" such as when the memory is of a musical tune or a sequence of actions.

Nature

Optogenetics is pretty invasive, with viruses, genetic constructs and hardware implants all going into thebrain. And then there's the bioethical considerations. So far the technique has only been tested in animals.Slightly less invasive variations, including

, have beenproposed, but would still require some kind of an implant.

wireless optogenetics(http://spectrum.ieee.org/biomedical/devices/injectable-optoelectronics-for-brain-control)

Because of these limitations, the authors were careful not to gush about potential therapeutic applications inhumans. "It's a bit far-fetched at the moment because we don't have the proper technology," said co-author , a Nobellaureate, during the press briefing.

Susumu Tonegawa (http://www.nobelprize.org/nobel_prizes/medicine/laureates/1987/)

The hope is that, if the technique can prove effective and safe, emotional memory manipulation could helpwith afflictions like severe depression and post-traumatic stress disorder.

In the press briefing, a reporter brought up a theoretical mad scientist scenario in which bad guys arezapping the memories of people against their will. Tonegawa laughed, and said: "We have no intention . . . touse this kind of technology in order to alter normal, healthy people's minds or cognition. If there is anyapplication of this in humans it is for pathological conditions—to reduce the suffering in people who havethese psychiatric disorders." Added Redondo: "In any case, the media is much better than neuroscientists atchanging memories of a series of events."

Fair enough.