ECNP Congress programme spotlight
Making and breaking memories

Professor Sheena Josselyn is a senior scientist at the Hospital for Sick Children (SickKids) and a professor in the Departments of Psychology and Physiology at the University of Toronto in Canada. She holds a Canada Research Chair in brain mechanisms underlying memory and is a fellow of the Royal Society of Canada.

She will present the Keynote lecture, ‘Making and breaking memories’ at the 36th ECNP Congress in Barcelona, on Saturday 7 October. She recently spoke to ECNP Press Officer Tom Parkhill.

* * *

“All that detail just from memory, Sir?” “Memory, Agent Starling, is what I have instead of a view.”

Dr Hannibal Lecter replying to Clarice Starling, describing how he was able to render accurate depictions of Florence from his prison cell (Silence of the Lambs, 1991).

TP: I see that you have connections with both the Canada and the USA? So are you Canadian or American?
SJ: I was born in the US. My father was a naval architect, which took the family to various places around the world. He went to the University of Glasgow. The family moved around a lot from Hamburg to Bordeaux to Cleveland. I was born in Cleveland, way back when they still built ships there. We lived there after my dad died, up until I was in middle school. Then my mother – who is Canadian – brought the family back to Canada. I definitely have roots here now.

I see that you have a couple of awards from neuropsychopharmacology organisations. Do you have any direct connect to the ECNP?
Yes, I’m an active member of the ACNP (the American College) and CCNP (the Canadian College). I am honoured to have received awards from both of these organisations. I don’t have any direct connections to ECNP, but I’ve had the pleasure of attending a few ECNP meetings. The ECNP meetings were really great; I learned a lot and had the opportunity to connect with researchers and clinicians from all over the world.

I work in various different fields, and sometimes I have difficulty in explaining to outsiders the breadth of topics covered by the neuropsychopharmacology discipline – neuroscience, memory, sleep, psychiatry, and so on. It looks to me that you have been attracted to organisations which embody this multi-disciplinary approach. Is that how you see yourself?
Absolutely. I study how the brain encodes and uses information, and to me that is one of the most fundamental things the brain does. There are many, many things that can go wrong with this basic brain process and some could contribute to a psychiatric disorder. For instance, one could imagine that remembering bad experiences over and over again could contribute to conditions such as depression. Or a disruption in the way the brain organises information could result in different things that are not normally associated being associated, which could contribute to conditions such as schizophrenia. I think that understanding the processes underlying memory is important not just for developing treatments for frank memory disorders (such as PTSD or Alzheimer’s disease) but also for various other psychiatric conditions. Because of this, I think it is vital that my lab interacts with all different types of researchers and clinicians. It brings a broad background of knowledge to our work and really inspires us. So, yes, our lab studies memory, but we define memory incredibly broadly.

How did you get interested in the field?
I liked trying to solve puzzles and try to figure things out. To me, the human brain is the most intriguing puzzle ever. When I started out, I wanted to be a clinical psychologist for a while. So I got a master’s degree in clinical psychology and – for better or for worse – I was very influenced by the movie Silence of the Lambs. Matching wits with the Anthony Hopkins character, the quintessential psychopathic genius, seemed like an amazingly hard puzzle to try to solve. I’d always done basic rodent work for my PhD thesis, but I also had this side-line in clinical psychology. After my PhD was completed, I decided to try the clinical psychology path 100% and worked with sex offenders in prison for a time. I never met the Anthony Hopkins character in this prison and it certainly didn’t feel like I was solving any problems. In fact, it was just deadly boring. This experience renewed my joy in conducting research in the lab and allowed me to be as creative as I dared to understand how the brain works in terms of fundamental mechanisms. I have never looked back! And it emphasises to me that the career paths of many scientists I admire are often not straight lines.

I think everyone can make a contribution to the scientific process, it’s not that I’m in some way more special than anyone else. In fact, I believe it is important that people apply their unique background and knowledge and follow their own ideas to understand the brain. The brain is the most complex thing out there, and I think it will take a huge village of unique scientists asking their own question to understand this incredible puzzle.

You seem to be interested in the history of what memory means to people. In talks you speak of Richard Semon, the engram, and so on.
Yes, Richard Semon is a scientific hero of mine. His goal was to study memory using scientific rather than vernacular words. He came up with the term “engram” to describe a memory trace in the brain. I love learning more about the history of science. As scientists we often think we are coming up with an original idea, and then you find out that someone thought of a similar concept many years ago but may have expressed this idea using slightly different words. I think that as scientists we need to acknowledge that we all stand on the shoulders of those who came before us. Our generation of scientists is lucky to build on a rich base of those who have gone before us. Our goal should be to add novel insights onto this base. Neuroscience is in a wonderful time right now. We have an amazing array of tools that allow us to do things that would have seemed impossible even 20 years ago. So now we can do these things, it’s a good time to revisit some theories about how things could work and test these age-old theories using modern tools.

You talk is on making and breaking memories. A lot of your work is animal work. How do you go investigating memory?
When you think about it, just about any kind of animal, even single-celled animals, can learn and remember things. Memory is incredibly important for survival. In my lab, we study memory in mice using various techniques. For instance, we do Pavlovian threat conditioning where we pair an innocuous tone with a slightly aversive shock. This shock is similar to the type of static electricity shock we get when we shuffle our feet on a carpet and then touch a door handle. So it is startling, but not really painful or noxious. We can then ask the mice if they remember this event by replaying the tone. If a mouse remembers this association, they will display a typical defensive response known as freezing. It is a quick and easy way of assessing memory in the lab. Sometimes these seemingly simple behaviours can yield important insights into how the brain works.

So how do you tie down this induced memory to a particular brain area, to particular neurons?
That’s the huge challenge! Pioneering researchers from the 80s and 90s showed us where to look in the brain for an engram supporting this particular type of conditioned threat memory. These scientists showed us that the lateral nucleus of the amygdala was a key brain region. But we also knew from previous work that not every cell or neuron in the lateral amygdala would be involved in a particular engram – that is, that the engram would be sparsely encoded. Our contribution was to start to ask how individual neurons are recruited or allocated to a sparse engram. We showed that neurons with increased excitability at the time of an event are somehow “primed” and therefore more likely to be allocated to an engram.

How can you manipulate these memories?
Many labs have contributed to this area. Together, we discovered that neurons that are active during an experience are likely to be allocated to an engram supporting that experience. Moreover, we developed ways to allow researchers to subsequently manipulate the activity of just cells to increase or silence particular memories. These findings feel like real-life science fiction. Of course, all of these studies are conducted in rodents, but they provide the proof-of-principle of how memory works. This builds a foundation of our knowledge of how memory works. Our goal is that we and other researchers and clinicians will build on this foundation of knowledge to open up new areas of therapeutic potential.

What’s the most important thing to take this field forward?
I think our knowledge has scratched the surface of understanding how the brain encodes memories. The next step is to investigate precisely how this process is happening. To do this, I believe we need more people interested in the overall concept, so that we can crowdsource ideas. I have my ideas, but I’d love it if a bunch of new people joined us and said, “This is what I think, this is what I’m going to try”. If we have a whole load of individual voices addressing this hugely complex problem, I think we will make progress. And for me, progress is not just to figure out how mice encode memories, it’s to figure it out and to apply it to people, so fundamental processes go wrong, for example in PTSD, in Alzheimer’s Disease, these uniquely human disorders, we can get to an underlying cause, and target manipulations. The best thing is to not only solve a puzzle but also have the solution do some good in the world.

Sheena Josselyn, Canada, will speak on Saturday 7 October 2023.
KL01 — Making and breaking memories

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