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When we commence an activity in our daily lives, such as chasing a stray napkin or stepping out of the car, the brain produces a chemical messenger called dopamine, which helps govern the brain region that regulates that action.

Dopamine signalling is a tremendously complicated mechanism that scientists are keen to comprehend, particularly given its role in movement disorders such as Parkinson’s disease.
Now, researchers at Harvard Medical School have discovered a novel mechanism behind dopamine release in the brain. The study, which was done in mice and published on March 24 in Science, demonstrates that another chemical messenger known as acetylcholine may stimulate the firing of dopamine neurons by attaching to a region of these neurons that was previously unknown to induce firing.

The results shed new light on how the cholinergic and dopamine systems in the brain interact, and they call into question the long-held belief that impulses start at one end of neurons and travel to the other, where they cause the release of chemical messengers. More particular, the study reveals that a neuron’s axon, which has previously been thought to be an output component, might actually begin signalling.

If verified in more animal research and eventually in people, the discovery might lead to novel treatments for disorders such as Parkinson’s, which are caused by a disruption in dopamine transmission.  “Defining the interactions of dopamine and acetylcholine is critical to understanding how the behaviours we execute in our daily lives are created and controlled,” said senior author Pascal Kaeser, a professor of neuroscience at Harvard Medical School’s Blavatnik Institute.

Sending Signals
Neurons are nerve cells that are specialised in sending and receiving messages throughout the body. The signal transmission process begins with a neuron receiving a chemical signal in one of its branching tentacles known as dendrites. The signal is then integrated by the neighbouring cell body—the cell’s command center—to trigger firing, sending an electrical impulse, or action potential, through a long, thin projection called an axon to the far end of the cell.

The action potential causes the release of neurotransmitters, which are chemical messengers that go to neighbouring neurons, delivering the message from one cell to the next. Dopamine and acetylcholine are two of the body’s most significant neurotransmitters. They regulate important processes such as voluntary and involuntary movement, pain processing, pleasure, mood, smooth muscle contraction, and blood vessel dilatation, to name a few.

Kaeser and his colleagues are researching the striatum, a concentrated cluster of neurons in the brain that integrates input from various brain regions to govern daily behaviours. The researchers want to know how dopamine neurons, which are located in the midbrain but have axons that go into the striatum, connect with the striatum to influence its activity.

The action potential causes the release of neurotransmitters, which are chemical messengers that go to neighbouring neurons, delivering the message from one cell to the next. Dopamine and acetylcholine are two of the body’s most significant neurotransmitters. They regulate important processes such as voluntary and involuntary movement, pain processing, pleasure, mood, smooth muscle contraction, and blood vessel dilatation, to name a few.

Kaeser and his colleagues are researching the striatum, a concentrated cluster of neurons in the brain that integrates input from various brain regions to govern daily behaviours. The researchers want to know how dopamine neurons, which are located in the midbrain but have axons that go into the striatum, connect with the striatum to influence its activity.

Looking Local

Kaeser and his colleagues utilised a microscope to examine brain tissue in which the striatum has been isolated from the other areas to research this occurrence in mice. Even though the dendrites and cell bodies of dopamine neurons in the midbrain were severed from their axons in the striatum, they detected dopamine sparks in the tissue.

“This was particularly surprising because it happens without cell bodies, so the neurons don’t have their command centre, and it happens without stimulus; it simply happens,” Kaeser added. “This is a case of spontaneous local dopamine release.”

The researchers looked at the equipment involved in another series of trials. Previous research found that dopamine neurons’ axons had few dopamine release sites, which are employed when the cell body starts an action potential. Kaeser and his colleagues demonstrated that the same locations are responsible for acetylcholine-induced local dopamine release.

The researchers next performed trials in which they either stimulated cholinergic neurons or blew a chemical that functions similarly to acetylcholine straight onto dopamine axons. Acetylcholine produced action potentials in dopamine neurons, which transmitted the signal and caused dopamine release. Acetylcholine triggered these action potentials by attaching to acetylcholine receptors on dopamine neurons’ axons.

“This is really the essence of the mechanism: It tells you that supplying acetylcholine is enough to activate an action potential out of the axon, so you don’t require the neuron’s dendrites,” Kaeser explained.

In the third series of studies, the researchers looked at dopamine and acetylcholine signals in the brain while mice walked about the surroundings. The researchers discovered that both signals corresponded with the direction the mouse’s head moved, and that the commencement of cholinergic signals happened shortly before the onset of dopamine signals. Dopamine levels in the mouse striatum fell after the researchers interfered with acetylcholine receptors on dopamine neurons to disrupt signalling.

“This gives evidence that this system operates in vivo as well,” Kaeser said. “However, additional study is needed to understand how it impacts striatal function and mouse behaviour.”

The Entire Picture

Although this localised process is only one of three forms of dopamine neuron firing in the brain, Kaeser regards it as significant, not least because it defies traditional wisdom about how neurons transmit and receive messages.

“I believe the most important finding from our study is that a local signalling system may generate an action potential in the axon, which is an output structure,” Kaeser said. “This is a really ancient, fundamental notion of how neurons operate.”

It’s probable that additional axons throughout the brain, particularly those with acetylcholine receptors, employ the same method, according to Kaeser. “We don’t have concrete proof for it yet, but based on this research, I believe we may need to reconsider how neurons integrate messages.”

“Now that we have unambiguous proof that this is happening, we may wonder whether this form of signalling occurs more frequently than we previously assumed.” “We may only be witnessing the top of the iceberg,” said lead author Changliang Liu, an HMS research fellow in neurobiology. Liu is curious about why this localised method of dopamine release is required and what advantages it has over dopamine release triggered by the cell body.

Kaeser also wants to see if it’s feasible to entirely reverse the directionality of dopamine neurons by delivering a signal up the axon to the cell body and dendrites. If such a reversal is possible, it will further challenge the conventional understanding of how neurons work.

Although the study was conducted on mice, Kaeser observed that the process’s components are conserved across species and are present in humans, implying that the mechanism is present in people as well.

If the process is verified in people, the discoveries may potentially help to guide the development of novel therapies for neurodegenerative illnesses that impact mobility, such as Parkinson’s disease. Dopamine neurons begin to degrade and dopamine levels fall in Parkinson’s disease, causing problems walking, balance, and coordination, among other symptoms. Researchers may be able to find out how to employ cholinergic neurons as a source of dopamine in the striatum, for example, an approach that may be used to restore declining dopamine levels.

“If we can describe how the dopamine and acetylcholine systems interact, we will absolutely better understand what occurs when dopamine neurons are removed,” Kaeser said, adding that this step is “very crucial for understanding and treating Parkinson’s disease.”

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 are among the other writers.

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 supported the study.