Why depressed brains are so negative: they may store more bad memories

Could we erase bad memories? Scientists unlocked the brain’s filing cabinet of negative flashbacks in mice – and may someday treat depression by blocking them

  • People with depression tend to think and recall things in a negative light
  • Scientists at McGill University looked to how we store memories to work out why
  • Mice bred to be depression-prone had more brain cell-units of negative memories 
  • Reactivating these bits of memory storage triggered depressive symptoms 
  • If we could insulate these cells from being turned back on in depression-prone people, we could block some of their symptoms, the scientists think 

Depression-prone people may naturally form and store more negative memories than others, that are just waiting to be triggered by conflict, a new study suggests.

Researchers from McGill University studying mice that were more susceptible to depression found they stored more units of bad memories in their brains and were more likely to have these memories reactivated and start behaving as if they are depressed.

People who are depressed can hardly help but to see everything – past memories and present experiences alike – in a negative light, and scientists hope that finding differences in how their brains store information on a cellular level may explain why.

Mice may not have the complex range of experiences that make human life what it is, but their brains are structured very similarly to ours, suggesting that people who are susceptible to depression may form and recall more bad memories than others. 

And scientists think that they could target those memory-units so that recall would be less intense and ease depression symptoms, or even zap the memories all together, in the style of Eternal Sunshine of the Spotless Mind.  

Mice that are prone to depression form more bad memory cells, called engrams, than more resilient animals, and these get reactivated to cause depression symptoms, a new study found. The phenomenon may explain depressed patients’ relentlessly negative outlooks and how to target and even erase those memories – as is done to Kate Winslet in Eternal Sunshine Of The Spotless Mind – to treat depression  


Philosophers once thought that the brain was basically a filing cabinet for storing, organizing and retrieving information – including memories.

We now know that there are several types of memory, and that each is encoded into the mind in a number of ways.

But those philosophers weren’t entirely wrong.

One of the ways that memories of experiences get recorded in our brains is in the form of neuron clusters, called engrams.

These sets of brain cells live in the hippocampus, like little units of memory.

They’re first lit up when we have an experience, and then can be turned back on when something triggers the memory.

For pleasant memories, that reactivation can make you feel washed in positive feelings all over again when you encounter such a trigger.

But negative memories work the same way, meaning a trigger can yank you back into pain or sadness.

The hippocampus is a hotspot not just for memory, but for depression, too.

Brain scans of depressed patients show that this area of the brain is abuzz with activity – much more so, and more constantly than we would see someone without depression.

The McGill team suspected that if the hippocampus was being lit up in depression, that might mean these negative memories were getting reactivated at a cellular level, causing those that have a lot of bad memories stored up to recall them and to do so with more intensity than others.


To test that theory, they put mice through a rather harrowing process.

They essentially let each of their test mice get beat up by a bigger, stronger, more aggressive mouse on several occasions. 


In recent years, scientists have increasingly looked to psychedelic drugs as promising therapies for treatment-resistant mental illness. 

Currently, such mind-altering drugs are largely illegal in the US. 

But ongoing clinical trials suggest that drugs once beloved by hippies and club kids might have medical benefits, too. 

Scientists are investigating: 


The club drug and tranquilizer has been in tests for treating depression for several years. 

In March 2019, the US Food and Drug Administration approved the first nasal spray version of the drug. 

Ketamine works much more quickly than traditional antidepressants, and scientists believe it encourages new neural connections that can help overwrite unhealthy, depressive thought patterns. 


The active ingredient in ‘magic mushrooms,’ psilocybin is a powerful hallucinogen.  

It, too, acts far more quickly than traditional drugs and is being analyzed for use in patients with both depression and PTSD. 

Psyilocybin helps encourage neurplasticity and is thought to quiet down the ‘default mode network’ in the brain, and activate the ‘salience network’ that is involved in medication. 

In August, the FDA cleared the largest clinical trial for psilocybin to-date. 


The club drug MDMA – sometimes called ‘Molly’ – is currently in trials to treat PTSD. 

MDMA appears to quiet activity in the amygdala and hippocampus, regions of the brain involved in emotional processing and fear responses, which are over-active in those with PTSD. 

Patients participating in MDMA trials take a dose of the drug, and remain in an eight-hour session with two therapists who guide their experience. 


The psychedelic compound LSD has a similar structure to the brain chemical, serotonin. 

LSD’s discovery played a role in our discovery of how serotonin works in the brain and why imbalances of the neurochemical are involved in depression and anxiety. 

Trials using LSD-assisted therapy to treat anxiety are ongoing and have shown early promise.   

In scientific terms, when an animal loses a fight, it’s called a ‘social defeat’ and is considered comparable to the human experience of losing an interpersonal conflict or confrontation.

Between each conflict, the winning and losing mice lived in neighboring enclosure, where they could see, hear and smell one another, but couldn’t have physical contact.

Unsurprisingly, this stressed out the losing mice.

The scientists compared their behavior to that of the control mice, which were just handled by researchers, weighed and kept in enclosures next to mice they had no conflicts with. They were considered (relatively) un-stressed.

Then, they watched how the mice behaved when they were placed in enclosures with other mice, including the bullies.

Mice that were vulnerable to depression – marked in both the animals and humans by social avoidance – tended to spend their time in the corners of the enclosure, while resilient ones were more active in the social areas of the enclosure.

‘Just like humans, depression is very individual,’ Dr Tak Pak Wong, lead study author and a psychiatrist at McGill, told DailyMail.com. 

‘Not everyone who responds to stress develops depression.’ 


Finally, the researchers put the mice into single cages, not adjacent to other animals, and then triggered bad memories once more in some of the stressed mice by subjecting them to one more round of aggression from the bully mice.

When the McGill scientists looked at the brains of each group of mice, they saw, that the bullied mice that were susceptible to depression had more engrams, or units, of negative memory cells.

And when those negative memories were re-triggered by one more bullying session, far more engrams in the brains of depression-susceptible mice were activated again. 

Fewer engrams turned back on in the brains of the resilient mice.  

The difference in negative memory engrams between susceptible and resilient mice have important implications for depression,’ the scientists wrote in the Journal of Neuroscience.

It may be that what they saw in the mice’s brains explains why we, too, tend not only to recall more bad memories with a darker cast when we’re depressed, but why the new memories we form while depressed are often made in such a similarly negative light.

And all of that brain space being taken up by negative memories seemed, in the mice, to be linked to social withdrawal, too.


The McGill scientists think that if these negative memory units in the hippocampus could somehow be insulated from triggers that would reactivate them, that perhaps this could help treat the ‘cognitive symptoms’ of depression, like negative thinking, difficultly remembering or paying attention, and indecision.  

One way that might be possible is through an Eternal Sunshine of the Spotless Mind-type treatment – or something similar but less extreme and permanent. 

‘Others have been able to use methods to activate or inactivate those engrams,’ said Dr Wong. 

‘They can cause the formation and erasure of memory.’ 

Or, in a less creepy attempt: ‘You could think about why some have a higher sensitivity to the formation of engrams, and target that,’ says Dr Wong. 

‘Then we can think about people who are susceptible to depression and trying to reduce their recall of that negative memory.’ 

Some scientists and psychiatrists are already experimenting with ketamine, which targets a receptor involved in recall of negative memories, to treat PTSD. 

If the negative memories that loom large in depressed minds could be similarly targeted, doctors might be able to alleviate the cognitive symptoms of depression, too.  

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