Dopamine, the brain’s messenger molecule associated with anticipating reward and experiencing pleasure is widely studied in the context of cognitive health and neurological disorders such as Parkinson’s disease where its synthesis is reduced. Although much is known about external signals that control the release of this “feel-good”molecule, less is understood about the spontaneous impulses of dopamine release.

A new study from scientists at the University of California San Diego (UCSD) shows mice can volitionally control random dopamine pulses. These findings that open a new dimension in the study of dopamine’s role in modulating neural activity is reported in the article, “Reinforcement learning links spontaneous cortical dopamine impulses to reward,” published in the journal Current Biology. Financial support for the study came from the National Institutes of Health.

David Kleinfeld, PhD, is Professor at the Department of Physics and Section of Neurobiology, and senior co-author on the current study

David Kleinfeld, PhD, professor in the Department of Physics and Section of Neurobiology, and senior co-author on the paper says, “This started as a serendipitous finding by a talented, and curious, graduate student with intellectual support from a wonderful group of colleagues. As an unanticipated result, we spent many long days expanding on the original study and of course performing control experiments to verify the claims. These led to the current conclusions.”

Conrad Foo, a graduate student at UC San Diego and first author on the paper found that the neocortex in mice is flooded with spontaneous and unpredictable impulses of dopamine that occur approximately once per minute, instead of solely upon encountering pleasure or expecting a reward.

Working with a team of collaborating scientists at the Department of Physics and Section of Neurobiology at UCSD and the Icahn School of Medicine at Mount Sinai in New York, Foo investigated whether mice are aware of these impulses. In the lab these spontaneous releases of dopamine can be documented through molecular and optical imaging protocols.

“We built a cell-based sensor that achieved the same sensitivity to detect dopamine as found with physiological receptors in the brain. This sensor had a unique combination of nanoMolar sensitivity, one-second reporting speed, and hour-long temporal stability that was needed for our studies,” says Kleinfeld.

Adopting a feedback behavioral paradigm where mice on a treadmill received a reward if they indicated they were able to control the impromptu dopamine signals, the scientists uncovered that not only were mice aware of these dopamine impulses, but they learned to anticipate and volitionally act upon at least a fraction of these impulses. The researchers further clarify that dopamine appears to invigorate rather than initiate motor behavior. The team pooled together real-time behavioral, imaging, and analytical techniques from across contemporary experimental neuroscience to arrive at these findings.

“Critically, mice learned to reliably elicit dopamine impulses prior to receiving a reward,” the authors note. “These effects reversed when the reward was removed. We posit that spontaneous dopamine impulses may serve as a salient cognitive event in behavioral planning.”

UC graduate student Conrad Foo and his colleagues found that spontaneous impulses of dopamine occur in the cortex of mice at a rate of approximately 0.01 per second. Using a reinforcement learning paradigm based on rewards, mice learned to volitionally modulate their spontaneous impulses [Julia Kuhl]
When asked to comment on the translational significance of these findings, Kleinfeld says, “There is no direct clinical, significance at this point. Ours is basic research, which in the best of worlds includes studies on the magnetic properties of material that gave rise to MRI and, most recently and famously, work on mRNA expression that facilitated rapid construction of the COVID vaccines. We hope that our research program will, in time, define a role for dopamine in the optimization of internal brain dynamics. Then, just maybe, this and other work will yield a quantitative handle of the logic of neuromodulators in facilitating learning, and mental health.”

In future studies, the authors intend to extend this research to explore the role of spontaneous dopamine signals as animals forage in novel and dangerous environments, search for a mate and modulate social behavior to colonizing new home bases. “An animal’s sense of spontaneous dopamine impulses may motivate it to search and forage in the absence of known reward-predictive stimuli,” the researchers note.

On a more reductionist note, the researchers seek to establish the origin of the spontaneous release of dopamine in the cortex. “We know that the neurons that drive the observed spontaneous impulses of dopamine lie in a part of the midbrain called substantia nigra pars compacta. Are these cells the source of random activity? If so, why? If not, we will drill down further,” says Kleinfeld.

Kleinfeld says he and his team are guided by ideas on the potential molecular basis of curiosity.

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