Mimicking the brain’s natural firing patterns could be the next phase of neural mapping

University of Toronto scientists have added their voices to a growing group of researchers who have gleaned insights into brain function with a novel pattern-based approach to the stimulation of neurons. 

“We used to call certain parts of our DNA ‘junk,’ dismissing specific arrangements as noise, when, really, they were important all along,” says Lyla El-Fayomi, who recently completed a doctorate in the lab of Derek van der Kooy, a professor of molecular genetics at the Donnelly Centre for Cellular and Biomolecular Research. “I think a similar oversight has been happening with patterns of neural firing in the brain.” 

The researchers published their findings in a recent issue of the journal iScience.   

In the field of optogenetics, researchers genetically modify brain cells and cause the expression of a light-responsive protein. When exposed to focused light, these modified neurons will ‘fire,’ generating an electrical impulse and sending that signal to other neurons. Researchers can control this focused light within milliseconds of specificity.  

At the heart of El-Fayomi's PhD work was a conflicting piece of established research: There was a group of cells in the brain known to be crucial drivers of reward behaviour, but the optogenetic stimulation of those cells was not pleasurable. 

Her research aimed to uncover the reasons behind this contradiction, specifically in response to activating a primary reward pathway known as the ventral tegmental area (VTA). As an integral part to the brain’s reward circuitry, the VTA sees activity during rewarding experiences, from eating a slice of chocolate cake to taking morphine.  

Types of Optogenetic Stimulation 

When activating neurons, optogenetics researchers must choose a pattern of light stimulation. These different options can be compared to music.  

Continuous stimulation is like the droning sound of a synthesizer, a continuing note that is either ‘on’ or ‘off.’ In previous studies, continuous stimulation of inhibitory GABA neurons in the VTA caused mouse models to have an aversive response; it was not pleasurable.  

Tonic stimulation, the status quo in optogenetics, is comparable to the regular beat of a drum; it is a controlled pulse in which each spike is the exact same distance relative to one another. With the tonic stimulation of VTA GABA neurons, there was no reaction from the mouse models, neither pleasurable nor aversive. These results were surprising to researchers, as previous work at the van der Kooy lab had established a role for VTA GABA neurons as drivers of reward behaviours.  

“We came in and said, ‘what if we change that stimulation pattern, make it more physiologically relevant, more context specific?’” El-Fayomi says. “What if we unlock a third outcome?”  

While some areas of the brain naturally fire tonically, some areas do not. Biomimetic stimulation, also known as temporally patterned, is the mimicry of the brain’s natural firing patterns in vivo (in living organisms). Similar to tonic stimulation, it is a pulsing pattern, but the intervals between each pulse are unique to the types of activation and the area of the brain. While tonic stimulation might be compared to a regular beat, biomimetic stimulation can be imagined as an irregular but specified rhythm. By recreating the pattern of action potentials, the team essentially recreates the natural ‘music’ of our brains.  

“What we're suggesting is that there's a pattern—there's information in the temporal code,” says van der Kooy, principal investigator on the study. “Why would it be there if you didn't use it? Why would it survive? It's a different view of how the brain works.” 

After exposing drug-naïve mice to morphine, El-Fayomi recorded their natural firing patterns; the ‘song’ of an in vivo mouse brain responding to its first exposure to an opiate. This pattern of activity served as a blueprint for the next stage of her research.  

“It's certainly not tonic or continuous when you look at the actual trace,” El-Fayomi explains. “We played those firing patterns back in brand new mice that had never received any drug, and they really liked the stimulation with the morphine firing pattern." 

El-Fayomi successfully recreated the pleasurable response in a drug-naive mouse, but only by mimicking the observed firing pattern. In further testing, she rearranged the distances between the spikes in the timing and found it to be aversive, concluding that the sequencing of the pattern drives the behavioural responses: the specific firing code is what matters most.  

“The spaces between [electrical impulses/spikes] are critical for producing certain types of effects,” says van der Kooy. “There's a lot of information that can be stored within those temporal and spatial codes.”  

Both El-Fayomi and van der Kooy expect to see researchers revisiting past studies and reworking experiments to include elements of biomimetic stimulation. 

“People have seen great success with tonic stimulation. That was the birth of optogenetics,” says El-Fayomi, who is now a postdoctoral fellow at University Health Network. “But there are, clearly, pronounced exceptions that will be missed. Given the tools and the technology we have at our disposal, now is the time.”  

El-Fayomi hopes the select few optogenetics studies implementing biomimicry will be the start of a turning point in the field. She is thrilled to contribute to that growth.  

“In order to decode the brain, we're going to have to learn to speak the brain's language,” says El-Fayomi. “Until we observe and listen to what the brain is doing, we're not going to have the full picture.”