Mechanism that underlies local dopamine release in the brain

Date:
March 24, 2022
Source:
Harvard Medical School
Summary:
When we initiate an action in our everyday lives--chasing after
a runaway napkin or getting out of the car--the brain releases a
chemical messenger called dopamine that helps regulate the brain
area that controls this action.



FULL STORY ==========================================================================
When we initiate an action in our everyday lives--chasing after a runaway napkin or getting out of the car--the brain releases a chemical messenger called dopamine that helps regulate the brain area that controls this
action.


========================================================================== Dopamine signaling is a highly 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 at Harvard Medical School has identified a new mechanism that underlies dopamine release in the brain. The research, conducted in mice
and published March 24 in Science,shows that another chemical messenger
called acetylcholine can trigger the firing of dopamine neurons by binding
to a part of these neurons not previously known to initiate firing.

The findings reveal more about how the acetylcholine and dopamine
systems in the brain interact, and challenge the existing dogma that
signals are initiated at one end of neurons and flow to the other end,
where they prompt the release of chemical messengers. More specifically,
the research suggests that the axon of a neuron, which has traditionally
been considered an output structure, can also initiate signaling.

If confirmed in further animal studies and then in humans, the discovery
could inform new strategies for treating diseases such as 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 in the Blavatnik Institute at Harvard Medical School.



========================================================================== Sending Signals Neurons are specialized nerve cells that send and
receive signals throughout the body. The signal transmission starts with
a neuron receiving a chemical signal in its branched tentacles called
dendrites at one end. Next, the nearby cell body--the cell's command center--integrates the signal to induce firing, sending an electrical
impulse, or action potential, along a long, thin projection called an
axon to the far end of the cell. There, the action potential prompts the release of neurotransmitters, chemical messengers that flow to nearby
neurons, carrying 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
many others.

Kaeser and his team study the striatum, a centralized cluster of neurons
in the brain that integrates input from other brain areas to regulate
everyday actions. The researchers are interested in how dopamine neurons,
which sit in another region of the brain, 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 dopamine release that modulates everyday
actions. However, previous research established that this isn't always
the case. Sometimes, acetylcholine initiates dopamine release directly in
the striatum, seemingly skipping several steps of the signaling process.

"We were fascinated by this because it's a really strong 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.



========================================================================== Looking Local To investigate 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 sparks of dopamine
in the tissue, even though the dendrites and cell bodies of dopamine
neurons in the midbrain were cut off from their axons in the striatum.

"This was really striking because it happens without cell bodies, so
the neurons don't have their command center, and it happens without stimulation; it just happens on its own," Kaeser said. "This is
spontaneous local triggering of dopamine release." The team then
established that there are fewer dopamine signals than acetylcholine
signals in the striatum, but each dopamine signal is more powerful and
spreads over a larger area of the brain--indicating that there is a
propagating signal when acetylcholine triggers local dopamine release.

In another set of experiments, the researchers explored the machinery
involved.

Previous studies revealed 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 those same sites are responsible for local dopamine release prompted by acetylcholine.

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

"This is really the heart of the mechanism: It tells you that providing acetylcholine is sufficient to trigger an action potential out of the
axon, so you don't need the dendrites of the neuron," Kaeser said.

In a final set of experiments, the team investigated 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 moved, and the onset of acetylcholine signals occurred just before that of the dopamine signals. When the
researchers interfered with acetylcholine receptors on dopamine neurons
to disrupt signaling, dopamine levels in the mouse striatum dropped.

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

The Big Picture Although this localized mechanism is only one of three
types of dopamine neuron firing in the brain, Kaeser considers it an
important one--not least of all because it challenges conventional
thinking on how neurons send and receive signals.

"I think the most important insight that comes from this work is that
a local signaling system can initiate an action potential in the axon,
which is an output structure," Kaeser said. "This goes at a very old,
core principle of how neurons work." It's possible, Kaeser added,
that the same mechanism may be used by other axons throughout the brain, especially those with acetylcholine receptors. "We have no direct evidence
for that yet, but I do think that we may have to rethink how neurons
integrate signals based on this work." "Now that we have clear evidence
that this is happening, we can ask further questions about whether this
type of signaling actually happens more commonly than we thought. We
may be seeing just the tip of the iceberg," added lead author Changliang
Liu, a research fellow in neurobiology at HMS. Liu wants to understand
why this localized mechanism of dopamine release is needed, and what
advantages it offers over dopamine release initiated by the cell body.

Kaeser is also interested in exploring whether it's possible to completely reverse the directionality of dopamine neurons by sending a signal back
up the axon to the cell body and dendrites. If such a reversal can occur,
it would further upend the classic view of how neurons function.

Although the study was done in mice, Kaeser noted that the components
of the mechanism are conserved across species and are present in humans, suggesting that the mechanism may be present as well.

If the mechanism is confirmed in humans, the findings could eventually
inform the development of new treatments for neurodegenerative disorders
that affect movement, such as Parkinson's disease. In Parkinson's
disease, dopamine neurons start to break down and dopamine levels drop,
causing difficulty with walking, balance, and coordination, among other symptoms. Researchers may be able to figure out, for example, how to
use acetylcholine neurons as a source of dopamine in the striatum,
a strategy that could be used to restore falling dopamine levels.

"If we can define how the dopamine and acetylcholine systems interact,
we will definitely better understand what happens when you take out
dopamine neurons," Kaeser said--a step that "is really important for understanding and treating Parkinson's disease." Additional authors
include Xintong Cai, a visiting graduate student in neurobiology at HMS; Andreas Ritzau-Jost and Stefan Hallermann of Leipzig University; Paul
Kramer and Zayd Khaliq of the National Institutes of Health; and Yulong
Li of Peking University.

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


========================================================================== Story Source: Materials provided by Harvard_Medical_School. Original
written by Catherine Caruso. Note: Content may be edited for style
and length.


========================================================================== 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220324143742.htm

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