In 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. Now, by deploying a novel pattern-based approach to the stimulation of neurons, University of Toronto researchers have gathered previously unknown insights into brain function.“We used to call certain parts of our DNA ‘junk,’ dismissing specific arrangements as noise, when, really, they were important all along,” said researcher Lyla El-Fayomi, of the Toronto team. “I think a similar oversight has been happening with patterns of neural firing in the brain.” Researchers El-Fayomi and van der Kooy in the van der Kooy lab. Courtesy of the University of Toronto. Previous research had a contradiction: There was a group of cells in the brain known to be crucial drivers of reward behavior, but the optogenetic stimulation of those cells was not pleasurable. The researchers aimed to find the reason for this contradiction, specifically in response to activating a primary reward pathway known as the ventral tegmental area (VTA), which sees activity during rewarding experiences. Researchers must choose a pattern of light stimulation when activating neurons. In previous studies, continuous stimulation of inhibitory gamma-aminobutyric acid (GABA) neurons in the VTA caused mouse models to have an aversive response; it was not pleasurable. With the tonic stimulation (akin to a controlled pulse) 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 had established a role for VTA GABA neurons as drivers of reward behaviors. 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. Like 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. “What we're suggesting is that there's a pattern — there's information in the temporal code,” said Derek van der Kooy, a professor of molecular genetics and 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, the researchers recorded their natural firing patterns. They successfully recreated the pleasurable response in a drug-naive mouse, but only by mimicking the observed firing pattern. In further testing, they rearranged the distances between the spikes in the timing and found it to be aversive, concluding that the sequencing of the pattern drives the behavioral responses: the specific firing code is what matters most. “In order to decode the brain, we're going to have to learn to speak the brain's language,” said El-Fayomi. “Until we observe and listen to what the brain is doing, we're not going to have the full picture.” The research team hopes the select few optogenetics studies implementing biomimicry will be the start of a turning point in the field. This research was published in iScience (www.doi.org/10.17632/ysbgx5y95d.1)