Lab-Grown Human Cells May Help ‘Rewire’ The Brain Against Depression

Scientists have successfully created a specific type of neuron in the laboratory linked to pleasure, motivation, and emotions, cells that often fail in diseases such as depression, schizophrenia, and addiction. When transplanted into mice, these neurons rebuilt brain circuits and reduced symptoms similar to those of depression. This discovery paves the way for new ways to understand and perhaps treat psychiatric disorders in the future.

Dopaminergic neurons are brain cells responsible for transmitting dopamine, a chemical messenger essential for various functions of our body and mind. They are involved in controlling movement, the sensation of pleasure and reward, motivation, and even our emotions.

These neurons are located in a region called the midbrain and are organized into groups, the most important being A9 and A10. The A9 group is responsible for controlling voluntary movement, and its degeneration is directly linked to Parkinson's, a disease that causes rigidity and tremors.

The A10 group, on the other hand, acts in areas of the brain that regulate pleasure, motivation, and cognition, being fundamental for reward-based behaviors, such as when we feel satisfaction upon achieving a goal. Alterations in this A10 system are associated with disorders such as depression, schizophrenia, and drug addiction.

In recent years, science has made significant progress in the ability to create human cells in the laboratory from stem cells. These cells are special because they can transform into any type of cell in the body, including neurons.

Protocols already existed that allowed the transformation of stem cells into A9 neurons, used in Parkinson's research, but until now, there had been no efficient method for generating A10 neurons, precisely those linked to psychiatric problems. Solving this challenge was important because it would allow us to better understand diseases such as depression and even pave the way for new therapies.

This is exactly what this study achieved. The researchers developed a specific protocol to guide human stem cells to transform into A10 neurons. To achieve this, they used a combination of substances, including a factor called GDNF, vitamin C (ascorbic acid), and a molecule that blocks a signaling pathway called Notch.

These compounds were applied at a very precise moment in cell differentiation, almost as if the scientists had "taught" the stem cells to follow the correct path to become A10 subtype neurons.

This figure shows how scientists managed to transform human stem cells into neurons similar to those that control pleasure, motivation, and emotions (called A10 dopaminergic neurons). In the image, each color represents a different marker: cell nuclei appear in blue (Hoechst), stem cell-derived neurons in red (tdTomato), and neurons activated by the special treatment in green (EGFP). On the left, we see the "control" group, without treatment, in which neurons are present, but in smaller numbers and less connected. On the right, in the group treated with the "GBCATD" cocktail of molecules, there are many more neurons formed, with extensive branching and connections. This demonstrates that the chemical treatment helps direct the stem cells to become specifically A10 dopaminergic neurons, increasing their potential for use in research on depression and other psychiatric disorders.

The laboratory-produced neurons were analyzed and showed that they behave similarly to the original A10 neurons in the human brain. They exhibited the same gene patterns and also responded electrically as expected.

The most impressive step, however, was the transplantation into mice. When implanted, these neurons connected to the correct brain regions, rebuilding the mesolimbic circuit, the main dopamine pathway related to pleasure and motivation.

Behavioral tests yield encouraging results. In mice with depression-like symptoms, activating these transplanted neurons led to clear behavioral changes, as if they had an antidepressant effect. This means that, in the future, this technique could help not only understand the mechanisms of treatment-resistant depression but also serves as the basis for cell therapy that rebuilds brain circuits damaged in psychiatric disorders.

Immunostaining of grafted neurons 6 months after transplantation into the striatum of control or cocktail-treated human mDA precursors (GAD) in mice.

This study is considered a milestone because it shows that it is possible to create a specific type of human neuron in the laboratory, previously very difficult to obtain, and use it to rebuild brain connections in animals.

In addition to pointing to new treatment possibilities for depression, it offers a powerful research tool for understanding how the reward system works in the brain and how it becomes dysregulated in mental illness.

In the future, this approach could open doors to innovative therapies that treat not only the symptoms, but the root cause of disorders such as depression, schizophrenia, and drug addiction.

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Human stem cell-derived A10 dopaminergic neurons specifically integrate into mouse circuits and improve depression-like behaviors

Wei Yan, Qinqin Gao, Yingying Zhou, Peibo Xu, Ziyan Wu, Tingli Yuan, Lianshun Xie, Zhiwen You, Xinyue Zhang, Ban Feng, Shanzheng Yang, Yuejun Chen, and Man Xiong 

Cell Stem Cell. 2025 Aug 5:S1934-5909(25)00264-4. Available online 11 August 2025

https://doi.org/10.1016/j.stem.2025.07.007

Abstract: 

A10 dopaminergic neurons located in the ventral tegmental area play central roles in reward-related and goal-directed behaviors and are proposed to be target cells for treatment of various psychiatric disorders, including depression. Here, we report an efficient differentiation method to generate A10-like midbrain dopaminergic (mDA) neurons from human pluripotent stem cells (hPSCs) and found that post-mitotic patterning by Notch inhibitor, glial cell line-derived neurotrophic factor (GDNF), and ascorbic acid (AA) induced A10 subtype specification. These hPSC-derived mDA neurons exhibited characteristics of the A10 subtype, including gene expression profiles and electrophysiological properties. Moreover, grafted A10-like mDA neurons specifically project to their endogenous target brain regions and induce the anxiolytic phenotype in normal mice or antidepressant-like phenotypes in depression model mice. These results indicate that grafted A10-like mDA neurons can reconstruct specific circuits and functionally restore impaired circuits, highlighting the promising application of hPSC-derived neuron subtypes in the treatment of neuropsychiatric disorders.