Our forgotten memories are still in our heads

December 02, 2015

So what if I told you: mad scientists have unlocked the secret to probing lost memories in our brains. Well, I hope you got excited, because I’m practicing writing clickbait titles. But that is an extreme extension of a paper published earlier this year in Science out of the Tonegawa lab.

Let’s step back a moment to appreciate some amazing research done in the past couple years in the realm of false memories. It was a popular science story a few years ago when neuroscientists first succeeded in creating a “false memory” in a mouse (Ramirez et al, Science, 2013). Essentially, the experimenters made the mouse think that a certain cage was scary without the mouse ever having a frightening experience in that cage. Usually, we would ingrain this memory using a classical conditioning paradigm, pairing a mouse being in a certain cage (neutral, conditioned stimulus) with the experience of a foot shock (unconditioned stimulus). Therefore, when the mouse enters the cage on a later day, it will freeze because apparently that’s what mice do when they’re scared. Instead, researchers have recently started performing classical conditioning by stimulating the neurons that encode the memory of a certain cage (neutral, conditioned stimulus) with a foot shock (unconditioned stimulus) while the mouse was in a different cage. This resulted in the mice being afraid of the cage encoded by the stimulated neurons, even though they were never actually shocked when in that cage. The neurons that the experimenters stimulated were in the dentate gyrus of the hippocampus, a brain region heavily associated with memories of contexts. To make this idea more concrete, I massacred one of their figures below in an attempt at a visual aid.

TOP. First, the mouse was in cage A (red triangle). Second, the mouse was in cage B in which it received foot shocks while its neurons that encode cage A were stimulated. Afterward, these mice were exposed to cage A again as well as a novel cage (cage C). BOTTOM. After this classical conditioning, mice were specifically afraid of cage A (blue). The gray bars are from control mice. (Ramirez et al, Science 2013, Figure 2F)

Now that we know that we can stimulate neurons associated with a memory (“engram cells”) in order to reactivate that memory, there are a lot of cool experiments we can run. In their paper, Tomás Ryan and his labmates used a drug, Anisomycin, to give the mice amnesic symptoms, i.e. forget their recently made memories. In this case, the researchers labelled the cells corresponding to the cage in which fear conditioning was performed. They found that the mice who were given this amnesic drug were less afraid (compared to non-amnesic mice) when the mice returned to this cage that they had previously had shocked feet in. Therefore, the amnesic mice had essentially forgotten that this cage is scary.

However, something unexpected happened when they stimulated the cells in the amenic mice’s dentate gyrus that were active when initially encoding the fear memory (see figure below). When these cells were stimulated, this revived the fear response, and the amnesic mice exhibited freezing. In other words, the experimenter brought back a forgotten memory to these mice by stimulating their neurons directly. This was surprising because these cells were critical for a memory that had shown to be forgotten. Therefore, we could have expected that stimulation of these cells would no longer evoke a fear memory. But they do.

TOP. First, the mouse was in cage A (blue). Second, the mouse was in cage B (red) in which it received foot shocks while its activated neurons were labelled. One group of mice received an amnesiac drug after this classical conditioning. Afterward, these mice were 1) exposed to cage B again, and 2) their neurons that encode cage B were stimulated while in cage A. BOTTOM. The amnesic mice were not afraid of cage B after training. However, they were afraid when the neurons that encode cage B were stimulated. (Ryan et al, Science, 2015, Figure 3B)

Aside: One experiment that would have been nice to see is how the overall activity of the labelled engram cells (measured with c-fos expression) compared in the amnesic mice compared to controls. I would expect relatively lower c-fos expression in these engram cells for the amnesic mice compared to controls. I’m pretty sure they didn’t do this experiment, but maybe I missed it in the supplement. Second, I would be interested in if the results would be at all different if the engram cells were labelled prior to the fear conditioning experiment. If the amnesic mice lacked a fear response to the stimulation of these engram cells, then that would imply that the engram cells need to be labeled at the time of conditioning in order to be functionally connected to cells that correlate with fear expression, probably in the amygdala.

The result highlighted above implies that after forgetting the fearful memory in a specific cage, the amnesic mice used a new ensemble of neurons to re-encode that previously forgotten context. To extend this to humans, when we forget a memory due to problems with retrieval and then re-encode it, we now have two traces of that memory in the brain, just we were not able to reactivate the former at the time of encoding of the latter. This is a reminder that neurons do not have any intrinsic meaning in themselves (e.g. a Pamela Anderson neuron), but rather contribute to the conscious percept through the specific integration of their inputs and their downstream projections.

An even cooler (far-distant future) prospect of this work is the ability for us to re-activate our forgotten memories. Wouldn’t it be great if you could always remember the lyrics to Blank Space and serenade your friends, even though the lyrics now only seem to come to you while singing in the shower? Well, whenever you need to remember something, just label those cells with a light-activated cation channel and activate your implanted fiber optic cable whenever you want to recall that memory! Maybe in its early stages, this technology will be limited so you can only hold one item in this memory system at a time, like Ctrl+C, Ctrl+V. And if you adopt the first generation, that protein expression probably won’t be reversible, so this one memory you choose to encode first will become the single most important memory of your life. If that’s the case, I know I would just be listening to TSwift’s 1989 album throughout that entire encoding period.

Future students will be genetically modified as cfos-TTA lines and live on a diet of doxycycline except on the days of their tests in which they also get viral injections of AAV9-TREChR2 into their hippocampus, right by their fiber optic cable implant. Sounds like a computer is more efficient at this though, so let’s just convert our neural activity to a silicon substrate and call it a day. Maybe in year 2400. Screw you, Kurzweil, the Singularity is not that near.

To be a little bit less ridiculous, I believe there could sooner be alternative strategies to reactivate seemingly lost memories. Hypnosis is a popular example that has claimed (and I have always been skeptical) that it can be used to make people remember scenes of a crime. I’m starting to believe there might be some merit to this idea. By altering the brain state (such as by changing the rhythms of the brain), some neural circuits may become more commonly activated, thus more likely eliciting conscious recall of a specific memory. Maybe we’ll develop a strategy to stimulate our brains in many ways in order to produce a diversity of brain activations and widen our search for a lost engram.

By the way, I only touched on a small part of that paper, so you should also check out their reported differences between control and amnesic mice in terms of the engram cells’ synaptic plasticity. Also check out this nice recent review of engram cells by Susumu Tonegawa.