Dopamine’s stronghold is the striatum, not the cortex, brain imaging study suggests

A new study published in Diagnostics provides evidence that the striatum, rather than the cerebral cortex, receives the highest concentration of dopamine input in the brain. Advanced confocal imaging in mice revealed that dopamine signals are densely packed in the striatum but appear faint and sparse in the cortex—even when both areas are examined using the same imaging settings. These findings could improve our understanding of movement disorders like Parkinson’s disease and psychiatric conditions such as schizophrenia.

Dopamine is a chemical messenger that helps regulate movement, motivation, and thinking. In Parkinson’s disease, the death of dopamine-producing neurons in the midbrain leads to tremors, stiffness, and slower movement. Antipsychotic medications used to treat schizophrenia work by blocking dopamine receptors in the brain. Although scientists have long studied dopamine activity across different brain regions, research on its role in the cortex has often produced mixed and conflicting results.

Study author Fu-Ming Zhou said the research was driven by a need to create a clearer and more complete picture of where dopamine actually acts in the brain. Earlier research often focused on the cortex because of its role in higher-level thinking and decision-making.

But many of those studies examined cortical tissue in isolation and used imaging techniques that were adjusted to detect dopamine in that specific area. This kind of targeted approach can give a misleading impression of how dopamine is distributed across the brain—especially when results aren’t compared directly to regions like the striatum, where dopamine is much more concentrated.

“Human cognition is highly developed and dependent on the function of the cerebral cortex,” said Zhou, a professor of pharmacology at the University of Tennessee College of Medicine. “Human cognition can go awry as manifested in symptoms of schizophrenic patients. Schizophrenic symptoms can be significantly alleviated by antipsychotic drugs. The key pharmacological mechanism for these drugs is antagonism or inhibition of dopamine D2 type receptors. Because of the central role of the cerebral cortex in human cognition, it is often thought that the cortical dopamine system is the key target for antipsychotic drugs.”

Zhou sought to avoid the limitations of previous research by creating full-slice, high-resolution images of the mouse brain that included both the striatum and cortex in the same image. This allowed them to measure dopamine levels in each region under exactly the same conditions and reveal their relative densities without technical bias.

The researcher used advanced laser-scanning confocal microscopy to capture detailed images of sagittal brain sections from two-month-old male mice. These sections included the midbrain, striatum, thalamus, motor and sensory cortices, and other key regions.

To visualize the brain’s architecture, Zhou used genetically engineered mice in which subsets of neurons were fluorescently labeled: pyramidal neurons glowed yellow, and certain inhibitory neurons glowed green. The researcher also immunostained the tissue for tyrosine hydroxylase, an enzyme that marks dopamine-producing axons, and used a red fluorescent dye to visualize these structures.

A key strength of the study was that all brain regions in each slice were photographed using the same microscope settings. This avoided the common problem of artificially boosting weak signals in low-innervation areas like the cortex or saturating intense signals in dopamine-rich regions like the striatum. The resulting images gave a side-by-side comparison of dopamine activity throughout the brain, providing a global view of the nigro-forebrain dopamine system.

The results showed an overwhelming concentration of dopamine innervation in the striatum. Red fluorescence indicating tyrosine hydroxylase was intensely bright in this area, marking dense networks of dopamine axons. In contrast, signal levels in the cerebral cortex were faint and sparse, almost disappearing in some regions. This pattern was clear in both raw images and zoomed-in views, which also revealed bundled corticofugal axons—the long pathways that carry signals from the cortex to other brain regions—passing through the striatum.

Quantitative neurochemical studies in both rodents and humans have found that dopamine tissue content is about 70 times higher in the striatum than in the frontal cortex. The current imaging data reinforce that estimate, offering a visual confirmation of these measurements. Zhou emphasized that because the same imaging parameters were used for the whole brain slice, the difference in signal intensity reflects true differences in dopamine concentration—not artifacts of the staining or microscopy process.

One practical implication of these findings is that isolated studies of cortical dopamine activity could be misleading if they fail to consider the striatum’s dominant role. Past research on cortical dopamine has yielded mixed results—some studies reported that dopamine excites cortical neurons, while others found it inhibits them. These inconsistent effects may be due in part to the very low levels of dopamine in the cortex, which could make its influence on neuronal activity too small to detect reliably.

The study also has broader relevance for understanding the effects of drugs that target dopamine systems. “Our robust data show clearly that the dopamine system in the striatum is the main brain dopamine system and therefore is the main target of antipsychotic drugs, anti-Parkinson’s drugs, Ritalin (used to treat ADHD) and cocaine,” Zhou told PsyPost. “So our results are clinically very important.”

The study focused on mice, but Zhou notes that dopamine systems are highly conserved across mammals. This means that the patterns seen in mice likely apply to humans as well. Although the images did not cover the absolute entirety of the brain, the sagittal sections included all major dopamine-related structures, providing what the researcher describes as a reasonably complete view of the system.

Zhou said there were no major surprises in the results, as he had suspected this pattern for years. Still, the ability to capture such a detailed and context-rich image of the dopamine system in one view is rare and valuable for both research and teaching. The clarity of the images and the rigor of the approach help resolve longstanding confusion in the literature about where dopamine is most active in the brain.

Looking ahead, Zhou’s goal is to continue mapping the anatomy, physiology, and pharmacology of the striatal dopamine system. By building a more reliable and comprehensive understanding of how dopamine functions in this area, he hopes to support the development of better treatments for brain diseases such as Parkinson’s disease and schizophrenia.

The study, “Whole-Brain Confocal Imaging Provides an Accurate Global View of the Nigral Dopamine System,” was published June 5, 2025.