Mechanism underlying local dopamine release in the brain (2023)

Dopamine signaling is a highly complex process that scientists are keen to understand, particularly given its role in movement disorders such as Parkinson's disease.

Now a team from Harvard Medical School has identified a new mechanism underlying the release of dopamine in the brain. The performed on mice and on 24Science,shows that another chemical messenger called acetylcholine can trigger dopamine neurons to fire by binding to a part of those neurons that was not previously known to trigger firing.

The findings reveal more about how the brain's acetylcholine and dopamine systems interact, challenging the existing dogma that signals are initiated at one end by neurons and flow to the other end, where they trigger the release of chemical messengers. More specifically, the research suggests that a neuron's axon, traditionally thought of as the output structure, can also initiate signaling.

If the discovery is confirmed in more animal studies, and then in humans, the discovery could inform new strategies for treating diseases like Parkinson's, in which dopamine signaling is disrupted.

"Defining the interactions of dopamine and acetylcholine is fundamental to understanding how the actions we perform in our daily lives are generated and modulated," said senior author Pascal Kaeser, professor of neurobiology at Harvard Medical's Blavatnik Institute School.

send signals

Neurons are specialized nerve cells that send and receive signals throughout the body. Signaling begins when a neuron receives a chemical signal in its branching tentacles called dendrites at one end. Next, the nearby cell body — the cell's command center — integrates the signal to induce firing by sending an electrical impulse, or action potential, down a long, thin projection called the axon to the other end of the cell . There, the action potential triggers the release of neurotransmitters, chemical messengers that flow to nearby neurons and carry the message from one cell to the next. Dopamine and acetylcholine are among the most important neurotransmitters in the body. They are involved in the regulation of vital functions, including voluntary and involuntary movement, pain processing, pleasure, mood, smooth muscle contraction, and blood vessel dilation, among others.

Kaeser and his team study the striatum, a centralized collection of neurons in the brain that integrates input from other brain areas to regulate everyday actions. Researchers are interested in how dopamine neurons, which are located in a different region of the brain called the midbrain but have axons that project into the striatum, communicate with the striatum to modulate its function.

The classic model of this process, Kaeser explained, is that dopamine neurons receive chemical signals in their dendrites in the midbrain and their cell bodies send action potentials down their axons into the striatum, triggering the release of dopamine that modulates everyday actions. However, previous research has shown that this is not always the case. Sometimes acetylcholine initiates dopamine release directly in the striatum, seemingly skipping several steps in the signaling process.

"We were intrigued by it because it's a really powerful mechanism, but how it actually works - how acetylcholine triggers the release of dopamine, this very important modulator that regulates commands in the striatum, was unknown," Kaeser said.

search locally

To study this phenomenon in mice, Kaeser and his team used a microscope to analyze brain tissue in which the striatum had been separated from the other regions. They saw dopamine sparks in the tissue even though the dendrites and cell bodies of the dopamine neurons in the midbrain were severed from their axons in the striatum.

"That was really remarkable because it happens without a cell body, so the neurons don't have a command center, and it happens without stimulation, it just happens by itself," Kaeser said. "This is a spontaneous local triggering of dopamine release."

The team then found that there are fewer dopamine signals in the striatum than acetylcholine signals, but each dopamine signal is stronger and spreads over a larger area of ​​the brain - indicating that there is a spreading signal when acetylcholine triggers local dopamine release.

In another series of experiments, the researchers examined the machines involved. Previous studies have shown that axons on dopamine neurons have few sites for dopamine release, which are used when the cell body initiates an action potential. Kaeser and his team showed that the same sites are responsible for the local release of dopamine triggered by acetylcholine.

Next, the researchers conducted experiments in which they either activated acetylcholine neurons or puffed a drug that acts like acetylcholine directly onto dopamine axons. When they did, the acetylcholine induced action potentials in dopamine neurons, which relayed the signal and triggered the release of dopamine. Acetylcholine triggered these action potentials by binding to acetylcholine receptors on the axons of dopamine neurons.

"That's really at the heart of the mechanism: it tells you that providing acetylcholine is enough to trigger an action potential out of the axon, so you don't need the neuron's dendrites," Kaeser said.

In a final set of experiments, the team examined dopamine and acetylcholine signals in the brain as mice moved around in the environment. The researchers found that both signals correlated with the direction in which the mouse's head was moving, and that the acetylcholine signals started just before the dopamine signals. When the researchers interfered with acetylcholine receptors on dopamine neurons to disrupt signaling, dopamine levels in the mouse striatum dropped.

"This is evidence that this mechanism also plays in vivo, although more research is needed to understand how it affects mouse striatal function and behavior," said Kaeser.

The big picture

Although this localized mechanism is just one of three types of dopamine neurons that fire in the brain, Kaeser thinks it's important — not least because it challenges conventional thinking about how neurons send and receive signals.

"I think the most important finding from this work is that a local signaling system can trigger an action potential in the axon, which is an output structure," Kaeser said. "It goes back to a very old core principle of how neurons work."

It's possible, Kaeser added, that the same mechanism is used by other axons throughout the brain, particularly those with acetylcholine receptors. "We don't have direct evidence of that yet, but I think based on this work, we may need to rethink how neurons integrate signals."

“Now that we have clear evidence that this is happening, we can ask more questions about whether this type of signaling is actually more common than we thought. We may only be seeing the tip of the iceberg," added lead author Changliang Liu, a research associate in neurobiology at HMS. Liu wants to understand why this localized mechanism of dopamine release is needed and what advantages it offers over cell body-initiated dopamine release.

Kaeser is also interested in exploring whether it is possible to completely reverse the direction of dopamine neurons by sending a signal up the axon to the cell body and dendrites. If such a reversal could occur, it would further upend the classical view of how neurons work.

Although the study was conducted in mice, Kaeser noted that the mechanism's components are conserved across species and are present in humans, suggesting that the mechanism may also be present.

Eventually, if the mechanism is confirmed in humans, the results could help develop new treatments for neurodegenerative diseases that impair movement, such as: B. Parkinson's disease. In Parkinson's disease, dopamine neurons begin to degrade and dopamine levels drop, leading to difficulty with walking, balance, and coordination, among other symptoms. For example, researchers could figure out how to use acetylcholine neurons as a source of dopamine in the striatum, a strategy that could restore declining dopamine levels.

"If we can define how the dopamine and acetylcholine systems interact, we'll definitely have a better understanding of what happens when you remove dopamine neurons," Kaeser said -- a step that's "really important to understanding Parkinson's disease." and treat.”

Additional authors include Xintong Cai, a visiting student in neurobiology at HMS; Andreas Ritzau-Jost and Stefan Hallermann from the University of Leipzig; Paul Kramer and Zayd Khaliq from the National Institutes of Health; and Yulong Li from Peking University.

The study was funded by the NIH (R01NS103484; R01NS083898; NINDS Intramural 330 Research Program Grant NS003135), the European Research Council, the Deutsche Forschungsgemeinschaft, the HMS Dean's Initiative Award for Innovation, a Harvard/MIT Joint Research Grant, and a Gordon Family grant and a PhD Mobility National Grants scholarship from Xi'an Jiaotong University/China Scholarship Council.