Turning on happy memories can reverse depression

Scientists have cured the symptoms of depression in mice by using optogenetics to artificially activate neurons associated with positive memories.

This suggests a potential treatment pathway for depression through the manipulation of the brain cells where memories are stored.

Susumu Tonegawa, the Picower Professor of Biology and Neuroscience and principal investigator of the study, said: "Once you identify specific sites in the memory circuit which are not functioning well, or whose boosting will bring a beneficial consequence, there is a possibility of inventing new medical technology where the improvement will be targeted to the specific part of the circuit."

This approach should have fewer side effects than current antidepressants, whose functions affect multiple areas across the whole brain. Although optogenetic intervention is a long way from being used in treatments for humans, the type of analysis that this research gives us helps inform where to target therapies for certain disorders.

Manipulating Memories

Professor Tonegawa and his colleagues at the RIKEN-MIT Center for Neural Circuit Genetics have previously shown that they can label and reactivate brain cells that store specific memories, plant false memories and switch the emotional associations of a particular memory. In the recent research, they wanted to see if they could exploit these abilities to treat depression.

To do this, the researchers gave the mice a pleasurable experience (all of the mice were male and were given time to spend with a female). At the same time, the cells in the hippocampus that were storing the memory of this experience were labelled with a light-sensitive protein which when activated causes the neurons to fire.

They then induced depression-like symptoms (e.g. giving up quickly when faced with a difficult situation or being unable to enjoy activities that are usually pleasurable) in the mice by exposing them to chronic stress.

Mice that were placed in conditions to test for these symptoms had dramatically improved responses after activation of the neurons that stored the enjoyable memory. They behaved similarly to mice who had never been depressed.

To begin with this only happened as long as the memory stayed activated. However, further investigation found that with repeated activation over time (15 minutes, twice per day, for days) a comparable effect could be achieved.

Memories beat the real thing

Incredibly, this false activation of their memory was much more effective than allowing the mice to experience the pleasurable situation again.

If there were a way to stimulate specific brain circuits in humans, then it might be possible to achieve the same effects seen in this study. A more targeted form of deep-brain stimulation might accomplish this.

Deep-brain stimulation is currently used as a treatment for depression, Parkinson's disease and obsessive-compulsive disorder among other diseases, but is crude and activates large chunks of the brain.

Steve Ramirez, lead author of the paper, said: "You could imagine in the future that if you could target deep-brain stimulation not to patches of brain but to specific sets of cells that we think are holding onto a positive memory, then it offers a new therapeutic avenue."

Paper Reference

Ramirez S, Liu X, MacDonald C J, Moffa A, Zhou J, Redondo R L, Tonegawa S (2015) Activating positive memory engrams suppresses depression-like behaviour Nature 522:335-339 doi: 10.1038/nature14514