“We can’t possibly try and treat a memory disorder unless we know how memories are normally formed and stored in the brain,” explains Dr. Sheena Josselyn, a Brain Canada-funded researcher based at The Hospital for Sick Children (SickKids) and the University of Toronto who studies these questions.

“We haven’t figured it all out yet, but we are making some major strides,” she explains. Two major strides, in fact, were recently made possible by Dr. Josselyn’s Brain Canada-funded platform. The first focuses on memory development and the second on memory recall.

A molecular cause for memory change in early childhood

Between four and six years old, a child’s memories change from general or “gist-like” to episodic or event-based. In other words, the content of memories start being more specific. Dr. Josselyn, along with lead authors Dr. Paul Frankland, Brain Canada-funded PhD student Adam Ramsaran and their research teams, conducted one of the first studies to examine this change in memory development in juvenile mice. They identified a potential molecular cause for the change and published their work in the high impact journal Science.

“Dr. Josselyn’s research brings us one step closer to understanding exactly how information is encoded and stored and used, and what happens when it’s not encoded, stored or used correctly.”

The molecular cause they identified is a dense matrix, known as the perineuronal net, that develops around specialized cells called parvalbumin-expressing (PV) interneurons in the hippocampus. These interneurons are responsible for constraining the size of the memory trace in the brain and enabling memory specificity. The team found that as the perineuronal net develops around them, the interneurons mature, resulting in memory traces in the brain becoming more sparse and memories changing from general to more specific.

Building on this discovery, the team was able to speed up the growth of the perineuronal net in the juvenile mice and allow specific, rather than general, memories to form. These results are informing child development research at SickKids and the University of Toronto.

“Outside of memory development, similar maturation-type mechanisms are involved in different sensory systems of the brain,” says Dr. Frankland, who is a Senior Scientist at SickKids and a team member on the Brain Canada-funded platform grant. “The same brain mechanism may be used by several different brain regions for several different purposes, which presents exciting new opportunities for research and collaboration.”

Using new tools to test an old hypothesis

Dr. Josselyn and her team also recently proved for the first time that a decades old hypothesis to explain memory recall – and lack of recall – holds at the level of neurons. They published the proof in the high impact journal Neuron in June 2023.

The encoding specificity hypothesis explaining memory recall was developed by Canadian research pioneer Dr. Endel Tulving back in the 1960s and 1970s. It states that we recall memories best when the retrieval conditions match the training conditions.

This idea has been validated through many behavioural studies. One of Dr. Josselyn’s favourites is a 1975 experiment where researchers engaged two groups of trained scuba divers in a test; one group received a word list to remember on land and the second group received a word list to remember underwater. The divers could recall the word lists best when conditions on encoding and retrieval matched. In other words, even if the divers learned underwater – and you assume they would recall better on land – they would recall the list best underwater.

Dr. Josselyn and her team sought to build on these behavioural studies to explore the encoding specificity hypothesis at a deeper level – the level of individual neurons.

Memories for experiences are thought to be stored in ensembles of neurons that are co-active at the time of experience. Called memory traces, or engrams, these ensembles are active when we experience something, and are also active when we recall something. Using a series of sophisticated tools funded by her Brain Canada-funded Platform Support Grant, Dr. Josselyn and her team studied how engrams in the mouse brain are reactivated under these different conditions. The custom microscope they’ve built, for example, basically allows them to watch the mouse brain at work.

“We have all these advanced tools to test hypotheses that have been proven behaviourally – in everything from worms and ants to mice and humans – at the level of individual neurons. We were never able to do this before. It’s something that I never thought I would see in my scientific lifetime,” Dr. Josselyn explains. “It’s a very cool time to be a neuroscientist.”

By watching mice think, Dr. Josselyn and her team showed time that optimum neuron reactivation – and the memory recall that comes with it – does indeed occur when retrieval conditions closely match training conditions.

What’s next

The next step for the first project on how a child’s memories change is to use the imaging capability they’ve developed to study their finding in even greater detail and build their understanding of the molecular mechanism.

“The Brain Canada platform grant made all this cutting-edge research possible,” Dr. Josselyn explains.

Through the platform, Dr. Josselyn and the team are also developing analysis pipelines, which allow other researchers to explore these sorts of questions without having advanced computational expertise on their teams – and without having to buy and set up their own custom microscope.

Dr. Josselyn’s research brings us one step closer to understanding exactly how information is encoded and stored and used, and what happens when it’s not encoded, stored or used correctly. This understanding is crucial for addressing conditions that affect the brain, such as autism spectrum disorder, which is a deficit in how we store and use information.

“The platform infrastructure allows us to test these very fundamental questions in the brain and actually come up with real answers that can be translated into help for people who need it, which is the goal,” she explains.

Dr. Sheena Josselyn is the lead investigator of a Brain Canada Platform Support Grant entitled SLAP-CAN In vivo Imaging Facility and is a member of Brain Canada’s Research Committee. She is a Senior Scientist in the Neurosciences & Mental Health program at The Hospital for Sick Children in Toronto and a Professor in the Departments of Psychology and Physiology at the University of Toronto.

Learn more at braincanada.ca