Scientists Turn Positive Memories On and Off in Mice — Could That Help Treat Anxiety?

"As if a shudder ran from its brain to its body": How neuroscientists learned to modulate memories in rodents

Adapted excerpt from How to Change a Memory (Princeton University Press, 2025) by Steve Ramirez.

Feelings such as anxiety can be invisible to others yet shape everyday choices — from whether to prepare for an interview to what to say on a first date. These emotions arise from many neural routes that converge on the same subjective state, and experience — encoded as memory — plays a central role in what triggers them. When these triggers begin to disrupt mood, thinking and daily functioning, clinicians may classify the resulting cluster of symptoms as a mental disorder.

From personal motivation to a lab experiment

Near the end of graduate school, Ramirez watched anxiety’s unpredictable return in his mother, who began experiencing frequent panic attacks. Motivated by her struggle, his final project asked a bold, brain-centered question: could activating positive memories inside the brain reduce anxiety- and depression-like behaviors in rodents?

The idea and its human precedent

The project drew inspiration from human research on the "undoing effect" of positive emotions. Work by psychologist Barbara Fredrickson and colleagues showed that positive emotions can accelerate physiological recovery from stress — for instance, helping cardiovascular measures return to baseline faster than neutral or sad stimuli. Ramirez and his colleagues wondered whether similar benefits could be achieved by directly reactivating positive memories at the neural level.

How the experiment worked

Ramirez and his lab partner Xu Liu used optogenetics, a method that lets researchers selectively activate genetically targeted neurons with light. They first identified hippocampal cells that encoded a positive memory and then placed mice in a standard sucrose preference test: two valves in a box, one dispensing sugar water and the other plain water. Healthy rodents typically prefer sugar water; animals exhibiting anxiety- or depression-like behaviors often show no preference.

In their first successful run, dubbed "Project X," the team turned on a blue laser to stimulate the hippocampal cells that held a positive memory. Ramirez described the mouse’s reaction as immediate: it changed posture, as if "a shudder ran from its brain to its body," then began inspecting the environment. Once it located the sugar water, it licked vigorously — consuming amounts comparable to control animals. In short, optogenetic reactivation of a positive memory restored normal, reward-driven behavior and engaged brain circuits linked to motivation and reward.

Short-term and longer-term effects

Follow-up experiments extended the finding. Undergraduate researcher Briana Chen collected a larger dataset showing that when positive memories were reactivated twice daily — chronically for about a week — mice exhibited lasting improvements on behavioral measures associated with anxiety and depression. Chronic reactivation was also associated with increased neurogenesis (the creation of new neurons), suggesting both immediate motivational effects and longer-term biological changes.

Guided by the Research Domain Criteria (RDoC) framework, which emphasizes brain-centered approaches to psychiatric symptoms, the authors argue that the biological potency of positive memories might one day inform therapeutic strategies. But they emphasize caution: these are preclinical animal studies that suggest a mechanism and potential avenues for translation, not an immediate clinical therapy.

A personal illustration

Ramirez closes with a personal memory that illustrates how fear can transform into reward: as a teenager visiting family in El Salvador, he and his mother held hands and jumped from a cliff into a pond. What began as fear became a shared memory of courage and joy — an example of how cognitive, negative valence (fear) and positive valence (reward) systems interact to produce lasting, adaptive memories.

Takeaway: In mice, optogenetic reactivation of positive hippocampal memory traces can immediately restore reward-seeking behavior and, with repeated stimulation, produce longer-lasting behavioral and cellular effects. These findings connect laboratory neuroscience with psychological theories about the restorative power of positive emotions and suggest new directions for research into memory-based interventions for mood disorders.

Adapted from How to Change a Memory: One Neuroscientist’s Quest to Alter the Past by Steve Ramirez. Copyright © 2025 by Steve Ramirez. Reprinted by permission of Princeton University Press.