Dr. Gül Dölen
Professor University of California, Berkeley
Postdoctoral fellow Stanford University
MD/PhD Brown University & MIT
To young Gül Dölen, the ocean was a frightening place. Having grown up in inland Texas, her first experience with the sea was during a visit with her zoologist grandmother in Turkey. Here, her grandmother shared her wonder of the natural world with Gül. She learned to overcome her fear by examining the spiny sea urchins — discovering that there was in fact nothing to be afraid of, and instead, many things to be curious about. This spark of scientific curiosity has propelled her throughout her career, leading her to become a Professor and Endowed Chair at the University of California, Berkeley. Dr. Gül Dölen now runs her own laboratory, exploring how psychedelics influence social development and neuroplasticity in both earth-bound and ocean-dwelling organisms.
Gül is a creative and independent thinker. In college at Duke University, her interest in consciousness led her to design her own major on “comparative perspectives on the mind”, which combined coursework in philosophy, neuroscience, linguistics, and religion. She learned that it was challenging to derive satisfying answers to the “big questions” — what is consciousness, what is mind, what is qualia? Seeking tangible answers to some of these big questions, Gül found herself drawn to studying the brain. In a Drugs, Brain, and Behavior class in college, Gül was taken by the structural similarities between the endogenous neurotransmitter serotonin and the psychedelic drug LSD. She wondered if this similarity might one day reveal something important about consciousness. She pocketed this idea, returning to it many years later after developing her expertise in neuroscience.
Having finished her bachelor’s degree, Gül wasn’t certain she wanted to attend graduate school. In the back of her mind she had dreams of becoming a National Geographic explorer. Amazingly, Gül found a job as an underwater photographer for the excavation of a shipwreck off the coast of Turkey. During this adventure, she passionately discussed topics in neuroscience with the team’s archeologists. This is when she realized that, despite the adventurous lifestyle that archeology could provide, she felt an undeniable pull toward neuroscience. This ultimately led her to graduate school where she could venture through uncharted territory of the brain.
Gül enrolled in an MD-PhD program at Brown University, where she worked in the lab of Dr. Mark Bear (who later moved to MIT). There, she studied critical periods: windows of time during development when the brain is particularly sensitive to and permanently altered by certain stimuli. For example, if one eye is damaged or covered during a specific visual critical period during early development, the strength of connections from each eye to the visual cortex will be altered to favor the intact eye. In the Bear lab, Gül studied this phenomenon, called “ocular dominance plasticity”, in a mouse model of Fragile X syndrome, which is the most common inherited single-gene disorder and the leading known genetic cause of autism spectrum disorder. Previously, the Bear lab had found that the activity of a metabotropic glutamate receptor (mGluR) was increased in this model, leading to elevated neuroplasticity. Gül discovered that removing mGluR decreased plasticity and recovered much of the Fragile X mouse’s behavioral deficits. This was evidence that not all plasticity is good plasticity, and that this particular type of autism might be due to a failure to properly close a critical period. A number of human clinical trials targeting mGluR were started based on Gül’s PhD findings, but sadly these trials failed. Gül was heartbroken and confused, but curious to find out why the therapeutics had not worked as expected. Based on the trials, she suspected that this type of autism is a manifestation of disrupted synaptic plasticity across the brain, and thus targeting one receptor would be insufficient to address this wide-reaching dysfunction.
Gül decided to pursue a postdoc in the lab of Dr. Robert Malenka at Stanford, where she set out to study the fundamentals of social reward learning in mice. For her experiments, Gül used a socially conditioned place preference (sCPP) behavioral assay. In this paradigm, a mouse was first habituated to a 2-chamber behavioral arena. Following this, they were conditioned to associate the bedding in one chamber with social partners, and the bedding in the other chamber with isolation. Finally, the mouse roamed free in the entire arena again. Gül found that mice have a strong preference for spending time in the chamber containing bedding with the learned association of their social group members. Using sCPP in combination with neurophysiology and pharmacology, Gül discovered that serotonin acts as a social reward signal, a finding that brought her back to the world of psychedelics.
When Gül started her own lab at Johns Hopkins about a decade ago, she and her postdoc Dr. Romain Nardou discovered that there is indeed a critical period for social reward learning — a finding that challenged prior notions of critical periods, which were previously understood to occur only in the context of sensory and motor processes. They found that while juvenile mice could learn from their social environments, adult mice could not. However, 48 hours after treatment with a psychedelic (either MDMA, ketamine, psilocybin, or ibogaine), social reward learning in adult mice was restored. Something about psychedelics seemed to be reopening this critical period.
Finding the mechanism behind this critical period reopening was puzzling. Psychedelic drugs bind to a diverse array of receptors and have differences in their acute subjective properties (i.e., their trips feel different). Through much trial and error, Gül and her lab discovered that genes encoding for components or regulators of the extracellular matrix (ECM) — a network of proteins and molecules that surround, support, and provide structure to cells — were altered after any type of psychedelic treatment. They excitedly landed on the commonality they were searching for: psychedelics trigger ECM remodeling and metaplasticity, which allows for the reopening of the critical period. Like her finding about the social reward learning critical period, this notion again challenges a dogma. Contrary to how scientists thought psychedelics worked in the brain, the mechanistic explanation that Gül’s lab discovered is not specific to a singular region or even receptor. Instead, these changes occur at the level of molecules that are shared across species and across brain regions. Because of this, psychedelics may uniquely serve as a master key to unlock other types of critical periods as well.
Gül was curious to see if she could use psychedelics’ effects on social critical periods and apply this to an aggressively asocial creature: the octopus. Since octopuses suspend their social aggression for a short period of time in order to mate, Gül hypothesized that octopuses must have neural circuitry for a type of prosociality that is suppressed outside of that small reproductive window. Fascinatingly, after treating octopuses with MDMA, Gül found that these once asocial creatures spent more time in a chamber containing a social partner. Her lab is currently expanding upon this exciting finding.
As a PI, Gül has faced many hurdles. Her research is controversial, not just because she studies psychedelics, but because her findings have significantly challenged the classical understanding of how the brain functions. It took her 17 tries to receive her first two R01 grants from the NIH. She considered quitting — not wanting to spend her life convincing people that her ideas were worth funding. However, her supportive network of scientist colleagues, especially female mentors, made her feel like she could do it. “They believed in me,” she said.
Now that she has received tenure and has moved her lab to UC Berkeley, Gül feels like she has the liberty to be the best mentor that she can be. Gül brings people into her lab that share her scientific curiosity, creativity, independence of thought, and tendency to push boundaries. She loves to engage in dialogue and meaningful scientific debates with her trainees.
Throughout her career, and now as a mentor, Gül taps into the same feelings of apprehension and excitement that she felt when her grandmother first showed her the sea urchin back on the beachside in Turkey. Science, much like the sea, can be daunting, but in pursuit of curiosity and wonder, Gül dives right in.
Find out more Gül about and her lab’s research here.
Listen to Meenakshi’s full interview with Gül on March 26, 2024 below!
