Imagine living a life you couldn’t remember. Experience would be held hostage to the moment; constantly disappearing and reappearing as a new scene. The knowable world would stretch no farther than your perception at any given moment. All you could do is react to what lies before you, with no sense of how it got there and no anticipation for what lies ahead of it. It seems almost nightmarish to think about. Memories are a fundamental aspect of our consciousness, which makes them one of the most pressing and intriguing topics in scientific research. Among the many questions preoccupying biologists, however, one continues to stand out: how do we forget? At MIT’s Picower Institute for Learning and Memory, Susumu Tonegawa’s lab decided to focus their work precisely on that issue. Forgetting is a common phenomenon we all experience, but in patients with dementia, forgetting becomes a degenerative symptom. Currently, over five million people in the United States live with Alzheimer’s disease (AD), a form of dementia characterized by progressive memory decline (2). In early stages of Alzheimer’s, memories of episodes, or specific events, fade away first before developing into a later stage where patients lose semantic memories — skills, facts, identities, etc (2). As scientists reflect on the potential causes of forgetting, hypotheses typically fall into two possible explanations: either the memory still persists and AD patients simply can’t retrieve it, or AD patients are failing to store the memory altogether. A new study by the Tonegawa lab at the Picower Institute for Learning and Memory at MIT provides key insight on this debate of retrieval versus storage. The premise of their experiment is pretty remarkable: find the neurons responsible for storing and retrieving memories, and see if activating those cells with would resurface forgotten memories in amnesic mice with the mouse equivalent of AD (“AD mice”) (1). Researchers looked at two different age groups of mice, nine-months old and seven-months old, to see how Alzheimer’s affects memories at earlier and later stages. The mice were introduced to a distinct chamber A — with a different floor, ceiling, and scent than where they were raised — and given two shocks on their feet for 2 seconds each, causing the mice to freeze in fear. This created the fear memory that chamber A is dangerous, and whenever the mouse was in the cage, it would freeze in anticipation of that danger. The seven-month old mice still froze in the chamber an hour after the conditioning (short-term memory) but not a day after (long-term memory). The nine-month old mice on the other hand didn’t have either long-term or short-term memory, so the focus was placed on seven-month old mice to see if optogenetics can manually retrieve the lost fear memory (1). First, the researchers had to locate the memory cells and seize control of their activity. Looking at a simplified overview of their methodology, a specially designed virus was used to engineer a mouse model in which specific neurons could be selectively activated or inactivated with blue light. Basically, the viral injections introduce a gene called channelrhodopsin-2 (ChR2), which produces a labelling protein that could then bind to ion channels of specific neurons and control when they open or close by changing its own shape. If blue light is flashed over the labelled neurons, the ChR2 protein will allow the ion channels to open and activate the neurons. Without blue light, the ion channels will stay closed and the neurons won’t activate (1). Since the idea is to only label the neurons responsible for fear memory, they used optical fibers to inject their virus directly into the region of the brain they suspected was involved: the dentate gyrus (DG) of the hippocampus. For the sake of accuracy, the injection occurred a day prior to the fear training so that only the DG cells responsible for the fear memory formed during training are tagged with ChR2 (1). Putting their innovative methodology to actual practice, the researchers revealed remarkable results. While the AD mice without ChR2 did not freeze in chamber A after two days, the tagged AD mice began to freeze again when blue light was flashed. Moreover, they controlled exactly when the mice froze by randomly turning the light on and off; every time it was on, they froze (1). They could restore the fear memory that had been lost in amnesic mice at the whim of a light switch. Furthermore, the researchers were able to manipulate the memory to make the treated mice afraid of another chamber that was actually completely safe. This new chamber B had no shock-inducing capabilities, but when modified AD mice were placed inside and exposed to blue light, they started to freeze even though they had never experienced shocks in chamber B (1). By reinstating the memory of chamber A while in chamber B, researchers created a false perception of danger in chamber B. Essentially, they implanted a false memory of chamber B, making it seem as if it were dangerous when in reality it was not. More generally, the fact that the memory still existed and was retrievable suggests that the problem of forgetting in Alzheimer’s is related to impaired retrieval mechanisms as opposed to storage. If the physical memory had deteriorated — if it was no longer being stored — then activating the tagged neurons would not have changed the modified AD mice behavior. Both the tagged and untagged AD mice would have exhibited the same behavior: a failure to freeze in chamber A. If the memory itself is lost, then activating a group of neurons couldn’t change anything since these neurons no longer reference a particular moment. With nothing in storage, the neurons have no content to restore or bring back into conscious awareness. However, the fact that activation of memory neurons did succeed in reintroducing fear memory indicates that the memory is still present within the brain and retrievable. REFERENCES Roy, Dheeraj S., et al. “Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease.” Nature 531.7595 (2016): 508-512. Alzheimer’s Association. “2017 Alzheimer’s disease facts and figures.” Alzheimer’s & Dementia 13.4 (2017): 325-373.