Daniel Cardozo Pinto, soon to be appointed a Harvard Junior Fellow, represents a compelling new voice in systems neuroscience. His research, grounded in a profound curiosity about the neural mechanisms underlying learning, focuses on the intricate interplay between dopamine and serotonin signals in reward processing. Cardozo Pinto’s work, which spans doctoral studies at Stanford University and current postdoctoral research with MCB’s Naoshige Uchida, holds significant promise for elucidating the fundamental principles of reinforcement and their dysfunction in neuropsychiatric conditions characterized by disordered reward processing, like addiction.
Cardozo Pinto’s initial engagement with science stemmed from a strong desire to understand the world around him. “Thinking back, I fell in love with science at libraries and museums as a kid,” he reflects. “I didn’t have scientist role models in my life, but I knew that I was really curious and that I loved learning. And even though I didn’t know what a career in science looked like or what it could entail, I always had this feeling that learning about the world around me felt like magic – but better, because in science, things get more interesting when you understand how they work, not less.” This early fascination solidified during his undergraduate studies at the University of California, Berkeley, where he pursued a dual major in psychology and molecular and cell biology, ultimately finding his intellectual home in the intricacies of the brain.
His nascent research career took shape at UC Berkeley in the laboratory of Stephan Lammel, who studies the dopamine system and how different branches of that system work similarly or differently from one another. This period was marked by Cardozo Pinto’s first discoveries. He was one of the first people to publish that the different cell types – dopamine, serotonin, glutamate, and GABA – in a part of the brain called the Dorsal Raphe nucleus are arranged in a stereotyped pattern. The work was published in Nature Communications. “It was just amazing to see something under the microscope that I’d never seen in any papers before,” he recalls. “That was the first time that I felt the rush of knowing something new about the world that nobody else knew.”
Cardozo Pinto then pursued his doctoral studies in Neuroscience at Stanford University under the mentorship of Robert Malenka and in collaboration with Neir Eshel, a decision driven by Malenka’s pioneering science and distinguished record in shaping the careers of leading neuroscientists. In Malenka’s lab, Cardozo Pinto’s doctoral research focused on how the dopamine and serotonin neurons work together to coordinate optimal reward learning behavior—a topic that had been the subject of controversy in the field for years. Cardozo Pinto took an innovative approach to this old problem, devising a double transgenic approach to achieve simultaneous manipulation or observation of both of these neuromodulatory cell populations in the same animal for the first time. This methodological advance revealed an inverse relationship between dopamine and serotonin signaling during the processing of natural rewards. “I showed that when animals consume a reward, the dopamine signaling goes up, the serotonin signaling goes down, and both of these signals are necessary for a stimulus to be maximally rewarding and drive optimal learning.”
This work, published in Nature, provided the first direct demonstration of a long-hypothesized opponent relationship between dopamine and serotonin, suggesting that the two signals work roughly like the gas and brake systems of a car to control reward learning. The discovery earned Cardozo Pinto national and international recognition, winning a Best Poster award at the 2022 meeting of the Dopamine Society and the Weintraub Award for outstanding achievement in graduate studies from the Fred Hutch Cancer Center.
It also earned Uchida’s attention. “His discovery that serotonin acts as a gating mechanism for dopamine-dependent reinforcement learning represents a fundamental advance in our understanding of neuromodulation, and establishes Daniel as an emerging leader in the field,” adds Uchida. “Naturally, I was thrilled to offer him a position for his postdoctoral training.”
As a Harvard Junior Fellow, Cardozo Pinto is now poised to extend his research into the maladaptive neural circuit changes underlying substance abuse disorder. Working in collaboration with the Uchida lab, he will benefit from the lab’s resources and intellectual environment while spearheading a project investigating the disruption of dopamine-serotonin dynamics in the context of drug rewards.
“I am very glad that his excellence was recognized as a Harvard Junior Fellow,” says Uchida. This is special also because Daniel was trained by Neir Eshel—my former graduate student and now an assistant professor at Stanford. I have known Daniel since his undergraduate years. He is not only generous and collegial but also ambitious and bold in his scientific pursuits, and I have been consistently impressed by his exceptional scientific achievements and deep knowledge in the field.”
Now, in the Uchida laboratory—which works at the intersection of experimental and theoretical approaches in systems neuroscience—Cardozo Pinto is spearheading an exciting new research direction that investigates the neural mechanisms underlying addiction. While addiction has not been a primary focus for the Uchida lab, Daniel’s experience and initiative are expanding the lab’s research scope in a novel and innovative way. “Daniel’s research direction on addiction mechanisms aligns with my lab’s focus on reinforcement learning while forging a novel and independent path,” Uchida says. “Addiction is an area I have long been interested in exploring, and given our foundational work on dopamine signaling and technical developments such as genetically encoded sensors for dopamine and serotonin, the timing is ideal.”
In fact, recent theoretical work by the lab suggests a potential mechanism for addiction-related learning deficits. “We proposed a theory that tonic baseline dopamine levels modulate the efficacy of learning from positive and negative dopamine transients,” Uchida explains. “This theory indicates that elevated baseline dopamine levels blunt learning from negative outcomes, potentially explaining why addiction overrides negative consequences. One of Daniel’s key aims is to test this hypothesis in the context of addiction, bridging theoretical and experimental approaches.”
Cardozo Pinto’s proposed research will utilize sophisticated in vivo techniques to simultaneously record and manipulate the activity of dopamine and serotonin neurons while administering controlled doses of drugs of abuse, such as cocaine. This approach aims to directly compare the neural responses to natural rewards with those elicited by drugs, seeking to identify specific alterations in the opponent relationship between dopamine and serotonin that may contribute to the pathological reward learning characteristic of addiction. “I’m hoping that we can test some hypotheses about how dopamine and serotonin opponency is disrupted in addiction and perhaps identify the specific components of dopamine or serotonin signaling that change during the transition to compulsive drug use,” he elaborates.
Building on a foundation of rigorous discovery, theoretical insight, and innovative methodology, Cardozo Pinto is charting an exciting path toward a deeper understanding of the neural mechanisms underlying addiction and the broader principles governing reward learning.
