Science: Mechanisms of local dopamine release in the brain

Dopamine signaling is a very complex process and one that scientists are eager to understand -- especially given its role in movement disorders such as Parkinson's disease

Now, a team of researchers at Harvard Medical School has discovered a new mechanism that underlies the brain's release of dopamine

The findings reveal more about how the acetylcholine and dopamine systems in the brain interact and challenge existing beliefs that signals start at one end of a neuron and travel to the other, where they facilitate the activation of chemical messengers.

If confirmed in further animal studies and human studies, the finding could lead to new strategies for treating diseases such as Parkinson's, in which dopamine signaling is disrupted

"Defining the interaction of dopamine and acetylcholine is fundamental to understanding how behavior is generated and regulated in our everyday lives," said senior author Pascal Kaeser, professor of neurobiology at the Blavatnik Institute at Harvard Medical School

send a signal

Neurons are specialized nerve cells that send and receive signals throughout the body

Kaeser and his team studied the striatum, a concentrated cluster of neurons in the brain that integrates input from other brain regions to regulate daily activities

The classic model for this process, Kaeser explained, is that dopamine neurons receive chemical signals in dendrites in the midbrain, and their cell bodies send action potentials through the axon to the striatum, triggering the release of dopamine that regulates daily behavior

"We were interested in this because it's a very powerful mechanism, but how does it actually work -- how acetylcholine triggers the release of dopamine, a very important regulator of striatal instructions Regulators, we don't know yet," Kaiser said

find local

To study this phenomenon in mice, Kaeser and his team used a microscope to analyze brain tissue in which the striatum is separated from other regions

"It's really amazing because it happens without the cell body, so the neurons don't have their command center, it happens without the stimulus; it just happens so naturally," Kessel said

The team then confirmed that there are fewer dopamine signals in the striatum than acetylcholine signals, but each dopamine signal is stronger and spreads over larger areas of the brain -- suggesting that when acetylcholine triggers local dopamine release, there is a propagate the signal

In another set of experiments, the researchers explored the mechanism

Next, the researchers conducted experiments in which they either activated the acetylcholine neurons or sprayed an acetylcholine-like drug directly onto the dopamine axons

"This is the heart of the mechanism: It tells you that providing acetylcholine is enough to trigger action potentials outside the axon, so you don't need the dendrites of the neuron," Kaeser said

In a final set of experiments, the team looked at dopamine and acetylcholine signaling in the brains of mice while they were active in the environment

"Although more research is needed to understand how it affects striatal function and mouse behavior, this finding provides evidence that this mechanism also works in vivo," Kaeser said
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Overall situation

Although this local mechanism is only one of three types of dopamine neuron firing in the brain, Kaiser believes it is an important mechanism—especially because it challenges conventional thinking about how neurons send and receive signals
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"I think the most important finding in this work is that the local signaling system can initiate action potentials in the axon, which is an output structure," Kaeser said
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"This has to do with a very old core principle of how neurons work
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"

Kaeser added that the mechanism may also apply to other axons throughout the brain, especially those with acetylcholine receptors
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"We don't have direct evidence for this yet, but I do think that we may need to rethink how neurons integrate signals based on this work
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"

"Now that we have clear evidence that this is happening, we can ask further questions about whether this type of signaling is really more common than we thought
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We may be seeing just the tip of the iceberg," the study said.
Added lead author Changliang Liu, a neurobiology researcher at HMS,
who wanted to understand why this localized mechanism of dopamine release is necessary and what advantages it has over cell body-initiated dopamine release
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Kaeser was also interested in whether it might be possible to completely reverse the orientation of dopamine neurons by transmitting signals from the axon back to the cell body and dendrites
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If such a reversal could occur, it would further upend the classic view of how neurons work
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Although the study was performed in mice, Kaeser noted that components of the mechanism are conserved across species and also in humans, suggesting that the mechanism may also exist
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If this mechanism is confirmed in humans, the discovery may eventually inform the development of new treatments for neurodegenerative diseases that affect movement, such as Parkinson's disease
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In Parkinson's, dopamine neurons begin to break down and dopamine levels drop, leading to symptoms such as difficulty walking, balance and coordination
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For example, researchers may be able to figure out how to use acetylcholine neurons as sources of dopamine in the striatum, a strategy that could be used to restore declining dopamine levels
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"If we can determine how the dopamine and acetylcholine systems interact, we can definitely better understand what happens when you take out a dopamine neuron," Kaeser said -- a step "very important for understanding and treating Parkinson's disease.
"
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Journal Reference :

1. Changliang Liu, Xintong Cai, Andreas Ritzau-Jost, Paul F.
   Kramer, Yulong Li, Zayd M.
   Khaliq, Stefan Hallermann and Pascal S.
   Kaeser.
   An action potential initiation mechanism in distal axons for the control of dopamine release .
   Science , 2022 DOI: 10.
   1126/science.
   abn0532