Sheena Josselyn - Making fear memories

Kat - This month I'm reporting back from the Genetics Society autumn meeting, held at the Royal Society at the end of November, which focused on the genetics and neurobiology of learning and memory. Several of the talks focused on the hunt for something called the 'engram' - the exact part of the brain where memories are stored. Opening the meeting was Sheena Josselyn, from the Hospital for Sick Children in Toronto, who told me about the search.

Sheena -  So, it really starts with, how do we store and use information? Everyone knows the brain is involved, but exactly, where in the brain?  People have been looking where in the brain a memory has been stored for centuries.  I think we're starting to corner where exactly a memory traces in the brain.

Kat -  In your talk, you used the wonderful word 'engram'.  What's the search for the 'engram'?

Sheena -  So, engram is a really old word, first proposed by Richard Semon who was a German scientist.  He thought engram was those bits in the brain that store a particular memory.  So engraphy was the process of writing down a memory in the brain.

Kat -  So say, I was to go somewhere, it would be written into a little particular bit of my brain.

Sheena -  Absolutely.  I mean, it's not exactly a snapshot, but you can sort of think of it as a little snapshot in your brain.

Kat -  Like a photo album.

Sheena -  Exactly.  Just that our memory is not like a photo album, but for this sort of analogy, that's fair enough.

Kat -  So, in the intervening time, where have we come in understanding this and how are you trying to figure out where in the brain our memories are made.

Sheena -  Well, it turns out that the sort of history of looking for the engram or the memory traces is pretty colourful has a wonderful past and a lot of people have looked.  It's very elusive.  People can't seem to find exactly where in the brain a memory is stored and it's been sort of frustrating scientists for generations.  But now, with some more modern techniques, we can sort of look at turning on and off populations of cells in the brain to really try and corner the engram.  I don't know if we've caught it, but it's certainly cornered.

Kat -  What do we know so far about, I guess, what a memory is, what does it look like in the brain?

Sheena -  So, it's sort of like describing what an elephant is by grabbing little parts of it.  We know parts about the memory, but we can't describe the entire thing.  We know memories are stored in collections of brain cells or neurons in the brain.  We know that they can become tightly bound together so that they become an ensemble or group of neurons.  We know that these neurons are pretty sparse.  So, very few of them across the brain can hold the memory.  Other than that, we're still trying to find out more about the memory.  We haven't exactly figured out what it is yet and how exactly it's formed.

Kat -  So, tell me a bit about your work and you're working on the response to fear.  How are you trying to dissect that and figure out where these fear memories are stored?

Sheena -  We're really interested in how a fear memory is encoded in the brain.  We know that it's encoded primarily in one particular area of the brain called the amygdala.  It's been known for a while that that area is really important in fear.  What we're trying to do is turn on and turn off populations of cells in the amygdala to try and turn on a memory or turn off a memory.  In that way, really get how the memory is formed in the brain.

Kat -  So, how are you actually experimentally doing this?  How do you test for fear and fear memories?

Sheena -  So, it's really easy in people.  You can ask them, you can look at them, "Are you afraid?"

Kat -  Aargh!

Sheena -  Exactly!  Just looking at their face, it's amazing.  But we use experimental rodents and it's really hard when you ask them, "Are you afraid?"  They just sort of look at you blankly.  So, what we do is try and tap into their responses, what they normally do when they're afraid.  It turns out if you're a small rodent like a mouse, when you're afraid you display freezing.  So, if you're being predated by a cat, you sort of stop and you pretend like you're not moving and then hopefully, the cat will walk on past you.  So, we use this response called freezing to find out when a mouse is afraid.

Kat -  And by understanding this, what have you found out so far about how this freezing response to fear works?

Sheena -  Well, it's really interesting.  We've been sort of playing around with how freezing works and how we can turn it on and turn it off by just playing around with a very, very small population of cells in the amygdala.  What we found is that a memory is very sparsely encoded.  So, very few cells in the brain can hold a memory and they can hold multiple memories.  So now, what we're trying to do is figure out how different memories interact in the brain, how they can be linked in the brain, just by looking at how we can manipulate cells.

Kat -  And in your talk, you presented some really nifty techniques that are finally enabling researchers to really manipulate at the genetic level, turn genes on and off, turn cells on and off really specifically?  How are you employing some of those new techniques?

Sheena -  The research world has really been opened up with techniques.  That's sort of the decade of techniques in neuroscience and in genetics.  We're trying to take advantage of the different tools that are available.  So, we use viral vectors to express normal genes or overexpress genes.  We can also express optogenetics that make a cell responsive to light.  We can use chemical genetics to make a cell responsive to different chemicals.  By using, really taking advantage and pulling in from all different areas, we can try and use different techniques to manipulate our system.

Kat -  And so, using all these things together, can you paint me a picture I guess of how you think a fear memory gets written into the brain from what we know so far?

Sheena -  So, what we do is we pair a specific tone with a mild electric shock.  Not enough to injure an animal, but certainly enough to make them afraid.  So, we think that when these two stimuli come together that neurons that express either the tone memory or express the fear memory are co-activated.  This co-activation binds these neurons together so that any time these neurons are active together in a group, an animal will display fear.

Kat -  So, they hear the sound, you give them a little electric shock, these two groups of cells that switch on and then forever more, they're entwined.

Sheena -  Exactly.  So, any time you excite any part of this trace, presumably, the entire trace becomes active and the animal becomes afraid.  It's like, one little thing can trigger your memory and then bring the whole memory to life.  We think this is how that happens.

Kat -  So, when they hear the sound again, they'll freeze and feel afraid.

Sheena -  Absolutely.

Kat -  And so, on a kind of a genetic or molecular level, are we getting to close to understanding where the engram is, where the fear is encoded in the brain?

Sheena -  Absolutely.  We're really getting close.  I think this is not only important to understanding how a fear memory is made, but understanding how memories are made, how we can restore memories in patients that have too much memory like posttraumatic stress disorder, or patients that have too little memory like in Alzheimer's disease and really understanding the fundamentals will help us translate these findings into helping people.

Kat -  The work that you do is in mouse.  Where is the field coming to in trying to understand these processes in humans?

Sheena -  The mouse work in the basic research work, I think it's critical to informing what we do with people.  I work in a children's hospital and I don't see us doing any of these techniques in people right away.  But it tells us how we should approach the problem, how can we make drugs, target a specific area of the brain rather than systemically treating a person.  I think that these sort of basic research findings will really inform how we go forward with people.

Kat - That was Sheena Josselyn, from the Hospital for Sick Children in Toronto.