UBC researchers are revealing how the brain creates, stores and retrieves memories, opening the door to new treatments for PTSD, Alzheimer’s disease and autism spectrum disorder.
Imagine, for a moment, that you’re walking to work or school on a crisp autumn day. You reach a busy intersection and, looking both ways, step into the street. From out of nowhere, a car roars through the red light and you’re forced to jump out of the way. A near-miss. You’re shaken, but as you continue your commute the shock of the experience soon gives way to relief, and the incident fades from your mind. Chances are, though, that the next time you find yourself at that intersection — and many times after that — you will remember the car, the fear, the rush of adrenaline. From now on you’ll take a little extra care to watch for speeding vehicles, even when the pedestrian signal says ‘walk.’ For most people, this is a perfectly ordinary reaction to an out-of-the-ordinary situation, and hardly something to wonder about.
“What is a memory, physically speaking? This is one of the holy grails of neuroscience.”
– Dr. Mark Cembrowski
But for the Faculty of Medicine’s Dr. Mark Cembrowski, the experience of fear offers a clue to one of the fundamental mysteries of the brain: how it creates, stores and retrieves memories.
“Physically speaking, what is a memory? This is one of the holy grails of neuroscience,” Dr. Cembrowksi, an associate professor in the Department of Cellular and Physiological Sciences, says.
“Fear is a powerful emotion. It’s also extremely useful for studying how memory works because it shapes the behaviour of humans and other animals in ways that can be readily observed in a lab setting.”
With this in mind, Dr. Cembrowski and a team of graduate students and postdoctoral researchers with expertise in neuroscience, mathematics and other disciplines created a deceptively simple and effective experiment.
The team used a single-photon miniature fluorescence microscope to observe the ovoid cells’ behaviour as mice interacted with unfamiliar objects (right).
Lab mice were released into an enclosure where the floor was rigged to deliver a single, very mild jolt — just enough to generate a fear response. Then, at intervals of a few days, weeks and months, the animals were released into the space again, but without ever receiving another jolt.
“Mice will momentarily freeze when they encounter a frightening situation,” he explains. “And that’s what they do each time after the initial jolt — they are remembering the first unpleasant experience.”
Before, during and after each ‘fear memory,’ the researchers took a small tissue sample and, using a technique called single-cell spatial transcriptomics, created data-rich snapshots of the mouse brains.
“It’s an exceptionally challenging experimental technique involving machine learning that allows us to collect and analyze enormous amounts of information about the cellular and molecular environment,” Dr. Cembrowski says.
The team compared the snapshots and mapped the changes happening inside the hippocampus and amygdala, regions of the brain that mediate the experience of fear in both mice and humans.
What emerged was a high-resolution portrait of fear memory in action. The study has already yielded a number of critical insights that open up the possibility of novel treatments for post-traumatic stress disorder (PTSD).
“Once we have a picture of causal neurobiological components involved in the formation of fear memories, we can begin to test molecular pathways that can be targeted to reduce the intensity of those memories,” he says.
Dr. Cembrowski imagines a future treatment that could be administered to patients soon after a traumatic experience — for example, by paramedics at the scene of a motor vehicle accident — to prevent the experience from becoming a debilitating, chronic trauma, which is what happens in PTSD.
“This is our ultimate goal: to reduce the severity and burden of traumatic experiences in a safe and effective way so people can heal more fully.”
But the team’s discovery of a previously undocumented subtype of neuron, present in both mice and human brains with the same gene expression, could have even farther-reaching implications for how we understand and treat memory-related disorders and diseases.
“It’s wild. A lot of the features that we’ve discovered in these cells are totally unprecedented in neuroscience literature,” Dr. Cembrowski says.
From PTSD to new insights into Alzheimer’s disease, epilepsy and autism spectrum disorder
The neurons, which the team dubbed ‘ovoid cells,’ are found in the hippocampus of mice and humans in relatively small numbers and appear to play a key role in recognition memory, the fundamental process by which the brain registers the difference between new and familiar things and forms long-term memories.
“The anatomy of these cells is quite unusual. What’s exciting is that they perform a highly specialized function in recognition memory that corresponds to the behaviour we see in mice,” says Adrienne Kinman, a PhD student in neuroscience and member of Dr. Cembrowski’s team.
In a spin-off study, Kinman devised a way to manipulate the ovoid cells in mice so they fluoresce when they are active inside the brain. The team then used a single-photon miniature fluorescence microscope to observe the cells’ behaviour as the mice interacted with unfamiliar objects.
Ovoid cells play a key role in recognition memory. The high-resolution video footage (second image) shows their unique structure and morphology within the brain (above).
What the researchers discovered was that the ovoid cells lit up when the mice encountered something new, but as they grew used to it, the cells stopped responding. In other words, the new had become familiar: the mice now remembered the objects. The cells had done their job.
This was especially true in younger animals: “Once the mice locked onto a new object, the ovoid cells remembered it. They recognized it a day, a week, even a month later,” says Dr. Cembrowski.
In older mice, however, the ovoid cells were much less active when the animals encountered new objects.
“What’s remarkable is that the drop we saw in cellular activity appears to parallel the change in behaviour and decline in cognitive ability that we observed behaviourally in these older animals. They struggled to differentiate between the new and the familiar,” he says.
When the cells become dysregulated they could be driving some of the cognitive symptoms found in autism spectrum disorder, Alzheimer’s disease and epilepsy.
The next phase of the research will investigate the role that ovoid cells play in neurodegenerative diseases and other brain disorders. The team’s working hypothesis is that when the cells become dysregulated, either too active or not active enough, they are driving some of the cognitive symptoms found in autism spectrum disorder (ASD), Alzheimer’s disease and epilepsy.
“Object-recognition issues are common to ASD and Alzheimer’s in different ways. People with ASD might fixate on a new object or, on the other hand, find it unbearable. Whereas Alzheimer’s disrupts the ability to recognize familiar objects and environments,” Kinman explains.
Dr. Cembrowski also points to the link between Alzheimer’s disease and epilepsy. There is a well-documented but not-well-understood connection between the two, in that people with epilepsy have a much higher risk of developing Alzheimer’s, and vice versa.
“Dysregulated ovoid cells are a feature we see in Alzheimer’s and epilepsy. We think ovoid cells could unlock potential treatments for both.”
As they continue the painstaking work of investigating these connections and mapping the underlying molecular and cellular mechanisms, the team is optimistic.
“We’re getting much, much better at finding needles in the proverbial haystack. Once you have the transcriptomics and can put all of this research into a coherent, holistic framework, you’re really opening the door to new personalized therapeutic approaches that will change lives,” says Dr. Cembrowski.
A version of this story was originally posted in UBC Medicine’s Pathways magazine.
