Stem cell-derived dopamine neurons improve depression-like behaviors in mice

The Institute of Neuroscience, Chinese Academy of Sciences, reports that human stem cell-derived A10-like midbrain dopaminergic neurons integrate into mouse mesocorticolimbic circuits and suppress anxiety and depression behaviors upon activation.

Midbrain dopaminergic neurons regulate voluntary movement, reward, motivation, cognition, and emotions. A10 ventral tegmental area neurons connect with nucleus accumbens, amygdala, olfactory tubercle, and medial prefrontal cortex. Dysfunction of the A10 system is implicated in drug addiction, schizophrenia, and depression.

Human pluripotent stem cells enable fresh production of disorder-relevant neurons, with previous success in enriching A9 neurons for Parkinson’s disease therapy. Efficient differentiation of human A10 dopaminergic neurons remains elusive.

Depression is the most prevalent neuropsychiatric disorder and is projected to be the third leading cause of global disease burden by 2030.

In the study, “Human stem cell-derived A10 dopaminergic neurons specifically integrate into mouse circuits and improve depression-like behaviors,” published in Cell Stem Cell, researchers developed a differentiation method to generate A10-like midbrain dopaminergic neurons from human pluripotent stem cells to reconstruct mesocorticolimbic pathways and alleviate depression-like behavior in mice.

Researchers used human stem cells to grow early-stage dopamine neurons and then transplanted those precursors into mouse brain regions involved in reward and mood, including nucleus accumbens and ventral tegmental area.

Some grafted cells carried light or drug-responsive switches so that scientists could adjust activity. Behavior tests for anxiety and depression signs followed, alongside brain chemistry sampling in the nucleus accumbens to track dopamine.

Treatment with a three-molecule mix produced the largest share of A10-like dopamine neurons, reaching 69.93% ± 2.34% of TH⁺ cells and 30.39% ± 1.66% of all cells. Single-cell RNA sequencing determined that the A10 protocol produced 62% A10-like neurons and 16% A9-like neurons.

Grafted A10-like neurons showed higher membrane resistance and lower capacitance than A9-like neurons, smaller sag responses and longer rebound delays, and faster firing during current steps.

Axons from grafted A10-like neurons reached the amygdala and lateral hypothalamus, and ectopic ventral striatum grafts also sent fibers to the medial prefrontal cortex and amygdala.

The authors conclude that grafted A10-like midbrain dopaminergic neurons reconstruct specific circuits and functionally restore impaired mesocorticolimbic pathways, with antidepressant-like and anxiolytic-like effects after activation.

The findings indicate the potential for A10-mDA-neuron-based therapy for major depression and support a rationale for human pluripotent stem cell-derived neuron subtypes in a wide range of neuropsychiatric disorders.

© 2025 Science X Network

The Institute of Neuroscience, Chinese Academy of Sciences, reports that human stem cell-derived A10-like midbrain dopaminergic neurons integrate into mouse mesocorticolimbic circuits and suppress anxiety and depression behaviors upon activation.

Midbrain dopaminergic neurons regulate voluntary movement, reward, motivation, cognition, and emotions. A10 ventral tegmental area neurons connect with nucleus accumbens, amygdala, olfactory tubercle, and medial prefrontal cortex. Dysfunction of the A10 system is implicated in drug addiction, schizophrenia, and depression.

Human pluripotent stem cells enable fresh production of disorder-relevant neurons, with previous success in enriching A9 neurons for Parkinson’s disease therapy. Efficient differentiation of human A10 dopaminergic neurons remains elusive.

Depression is the most prevalent neuropsychiatric disorder and is projected to be the third leading cause of global disease burden by 2030.

In the study, “Human stem cell-derived A10 dopaminergic neurons specifically integrate into mouse circuits and improve depression-like behaviors,” published in Cell Stem Cell, researchers developed a differentiation method to generate A10-like midbrain dopaminergic neurons from human pluripotent stem cells to reconstruct mesocorticolimbic pathways and alleviate depression-like behavior in mice.

Researchers used human stem cells to grow early-stage dopamine neurons and then transplanted those precursors into mouse brain regions involved in reward and mood, including nucleus accumbens and ventral tegmental area.

Some grafted cells carried light or drug-responsive switches so that scientists could adjust activity. Behavior tests for anxiety and depression signs followed, alongside brain chemistry sampling in the nucleus accumbens to track dopamine.

Treatment with a three-molecule mix produced the largest share of A10-like dopamine neurons, reaching 69.93% ± 2.34% of TH⁺ cells and 30.39% ± 1.66% of all cells. Single-cell RNA sequencing determined that the A10 protocol produced 62% A10-like neurons and 16% A9-like neurons.

Grafted A10-like neurons showed higher membrane resistance and lower capacitance than A9-like neurons, smaller sag responses and longer rebound delays, and faster firing during current steps.

Axons from grafted A10-like neurons reached the amygdala and lateral hypothalamus, and ectopic ventral striatum grafts also sent fibers to the medial prefrontal cortex and amygdala.

The authors conclude that grafted A10-like midbrain dopaminergic neurons reconstruct specific circuits and functionally restore impaired mesocorticolimbic pathways, with antidepressant-like and anxiolytic-like effects after activation.

The findings indicate the potential for A10-mDA-neuron-based therapy for major depression and support a rationale for human pluripotent stem cell-derived neuron subtypes in a wide range of neuropsychiatric disorders.

© 2025 Science X Network