MANIPULATING MEMORIES AT THE FLICK OF A SWITCH

Had a bad experience with an ex? Or perhaps embarrassed yourself in public today and wish you could erase all traces of this from your mind? No problem, just right click and delete. Although such control over our brains may seem like the stuff of science fiction, Neuroscience research is getting closer to uncovering the science behind memory manipulation.

The brain is often compared to a computer, due to its storage capacity and speed of processing. Among many dissimilarities, however, is that unlike technology, the brain cannot be consciously reprogrammed for our own benefit. Not yet anyway. Imagine a world where we could select certain memories as high priority and send others to the spam folder. Where we could implant false memories in order to learn without studying, or maybe even just recover the memory of where we left our keys.

Memory manipulation could have more potential than just making day to day life easier. Many conditions are linked to problems with memory. The most well-known of these is dementia, which leads to a progressive loss of the ability to form and retrieve memories. There are also conditions resulting from an inability to forget. Post-traumatic stress is one such example, where memory of a previous traumatic experience leads to a lasting fear response. Memory control would therefore have huge therapeutic potential.

Toying with memories is no easy task however. In order to manipulate a memory, we first need to find out where it is stored within the billions of neurons in our brain. We would then need methods for specifically manipulating these cells safely. This is exactly what the research group of Nobel Prize winner Susumu Tonegawa at the Massachusetts Institute of Technology are attempting to do in mice.

Locating memories

So where would we begin to look for the location of a specific memory in the brain? Researcher Xu Liu, who worked for the Tonegawa group, compared this task to looking for a needle in a haystack, only harder; unlike a memory, a needle is something we can physically see and touch.

When a memory forms, it is stored in a small group of neurons which were activated during the experience. Each time the memory is recalled, the same neurons fire. For example, scientists have actually found a Jennifer Aniston neuron; a neuron which fired specifically when a patient saw her photo. The location of an individual memory in the brain is called an engram.

The fact that neurons fire in memory formation and recall, allowed the group to label them. When neurons fire, they leave a footprint behind them, as certain genes get switched on in response to the neuron’s activity. The researchers modified these genes to produce coloured fluorescent proteins when they become active. When a memory was formed, it appeared as a fluorescent signal in the brain.

This technique was then used to create and label a fear memory. In this case, a mouse was placed in a cage with a base that administered a mild electric shock to the mouse’s feet. After this experience, the researchers were able to see a small group of associated neurons light up; they had found the location of this specific memory. The memory was so strong that when mice were returned to the same cage the following day, they showed fear behaviour (displayed by freezing), even if no electric shocks were given (figure 1a).

The group then wondered if forcing these neurons to fire would retrigger the memory, giving the scientist’s remote control over memory recall. Specific activation only in this engram was made possible by fitting these cells with a light activated switch. Simply shining blue light on this switch leads to instant activation of the neurons. This is called optogenetics. Sure enough, turning the light on caused the mouse to freeze (figure 1b).

This work is exciting, as not only had they located a specific memory in the brain, but the scientists were also able to reactivate it at the touch of a button.

Figure 1: Memories can be specifically labelled and triggered in the lab.

a) If mice are given mild foot shocks, they freeze, and develop a fear memory of the metal cage. If returned to this cage the following day, they freeze immediately, instead of exploring, due to recall of the fear memory.

b) This fear memory can be labelled in the brain as it is formed. Forcing reactivation of the memory with light stimulation leads to memory recall, and freezing in a neutral environment.

Unlocking lost memories in Alzheimer’s

The most common symptom of early stage Alzheimer’s disease is memory loss, however, it is not known whether this is caused by a problem in forming memories, or just an inability to recall them. Mouse models of Alzheimer’s disease demonstrate that these mice also suffer with memory loss and therefore returning them to the metal cage where they received shocks the previous day does not lead to a fear response; they simply do not remember the shocks.

In fact, researchers found that the memory is formed; but that the mice just cannot access it. In order to recall a memory, neurons responding to an input (i.e. seeing the metal cage) must signal to the memory neurons and activate them. In these mice, there was a loose connection. Incredibly, stimulating the engram with light strengthened these connections, and recovered the forgotten memory. The group is hopeful that development of a more precise method for targeted brain stimulation in humans may help Alzheimer’s patients to recover lost memories.

Creating false memories

The group then played around with fear memories in an attempt to modify them. By doing so, they were able to transform a neutral memory into one of fear. These mice were allowed to explore a harmless cage (A), and form a memory of their experience. The following day they were placed in a metal cage. Replay of the memory of cage A was triggered with light whilst mild foot shocks were given. Surprisingly, when returned to cage A after 24 hours, the mice froze in fear.

The scientists had actively reprogrammed the memory of cage A, by pairing fear with the previously neutral memory. This provides evidence that memories are not set in stone. With the right tools we could directly target them for modification. Other members of the group have since succeeded in replacing negative memories with positive ones, and even in relieving the symptoms of depression in mice, by reactivating memories of positive experiences.

What does this mean for the future?

Mind control was previously just an idea explored in films such as Inception and Eternal Sunshine of the Spotless Mind. What these researchers managed to do, was to take the idea of memory manipulation and realize it using tools at the cutting edge of Neuroscience.

Steve Ramirez, a researcher in the group stated, “I see a world where editing memories is something of a reality.” But what does this mean for us? Should we be worried about the prospect of a future of mind control, or perhaps hopeful about the potential for new therapies for psychiatric conditions?

At the moment, this research is in its very early stages and experiments in humans are likely a long way off. Liu states, however, that “although we are still working with mice, it is probably a good idea to start thinking and discussing about the possible ethical ramifications of memory control.” It is memories which shape our personalities and govern our future decisions. They therefore function as an important protective mechanism.  Should we alter something which has such a profound effect on who we are?

Experiments in memory manipulation will, however, undeniably strengthen our understanding of how the brain and memory works, enabling us to understand more about, and perhaps even treat psychiatric conditions.

Time will tell whether the tools used to manipulate memories in mice will be transferrable to humans. According to Ramirez, however, “Because the proof of principle is there…the only leap left between there and humans is just technological innovation”.

Harriet Hardy is studying for a BSc in Biochemistry with German for Science

Banner image: Digital human brain, sdecoret; Graphic depicting mice, Harriet Hardy