Researchers led by a team at NYU Grossman School of Medicine have applied Botox to individual neurons, to help demonstrate how neurons control their own release of dopamine (DA), a chemical messenger involved in motivation, memory, and movement. Through their studies, the team showed that feedback from individual nerve cells controls the release of dopamine. The findings indicate that dopamine-releasing brain cells respond to their own signals to regulate their output of the hormone. This self-regulation through autoinhibition, the researchers suggest, stands in contrast to the widely held view that mechanisms for controlling the release of dopamine—the “feel good” hormone—by any individual cell rely on feedback from nearby cells effectively recognizing how much is being released.

The results could provide new insight into why dopamine-releasing brain cells die in Parkinson’s disease. “Our findings provide the first evidence that dopamine neurons regulate themselves in the brain,” said Takuya Hikima, PhD, an instructor in the department of neurosurgery at NYU Langone Health. “Now that we better understand how these cells behave when they are healthy, we can start to unravel why they break down in neurodegenerative disorders like Parkinson’s disease.” Hikima is lead author of the team’s published paper in Cell Reports, titled, “Activity-dependent somatodendritic dopamine release in the substantia nigra autoinhibits the releasing neuron.”

Dopamine is involved in regulating movement and motivation, and a change in the transmission of DA is implicated in certain neuropsychiatric disorders, the authors explained. In Parkinson’s disease, they stated, “… loss of midbrain DA neurons in the substantia nigra pars compacta (SNc) leads to motor deficits, including decreased movement speed and amplitude.”

The study carried out by Hikima and colleagues was prompted by what the team saw as potential flaws in the traditional way of thinking about how dopamine is regulated, which would indicate that in order for one cell to control its neighbour with dopamine, a large number of synapses—the junctions where two cells meet and exchange messages—would be required. Yet researchers noted that there were not enough synapses to account for this. “This interpretation, however, neglects important anatomical differences between DA neurons in the SNc and in the VTA. Dendro-dendritic synapses between DA neurons are rare in the SNc and are absent between neighboring DA dendrites in the SNr [substnaia nigra pars reticulate],” they pointed out. In effect, they noted, “ … the source of autoregulatory DA remains controversial.” In addition, many types of hormone-producing cells in the body use a streamlined system that self-regulates further release, so it seemed odd that dopamine neurons would use a more roundabout process.

To investigate the control of dopamine regulation more closely, the research team first collected dopamine neurons from dozens of mice, and set up a series of studies that allowed the team to study the neurons individually. “Here, we tested the hypothesis that a given SNc DA neuron is regulated primarily by its own DA release, rather than by synaptically released DA from neighboring neurons,” they wrote. Through their experiments, the team applied antibodies and other agents to test this hypothesis. One of the strategies involved injecting individual brain cells with Botox (BoNT/A)—the toxin produced by the bacterium Clostridium botulinum—which blocks nerve cells from sending chemical messages to neurons and other cells. The chemical’s nerve-blocking action accounts for its ability to relax muscles in migraine and wrinkle treatments.

By injecting Botox into single neurons, the researchers hoped to show whether any signal to continue or stop dopamine release could only come from outside the “paralyzed” cell. If the neurons were controlled by neighboring dopamine cells, then dopamine release would remain unaffected, because the cells would still receive dopamine signals from the untreated cells nearby.

But what they found instead was that Botox administration led to a 75% drop in dopamine output, suggesting that dopamine neurons largely rely on their own dopamine release to control ongoing release rate of the hormone. “We report that a SNc DA neuron is regulated primarily by its own DA release, rather than by synaptic DA release from its neighbors,” the team concluded. “ … somatodendritic DA release in the SNc autoinhibits the neuron that releases it … Our data thus indicate that somatodendritic DA release in SNc is a true autoregulatory signal.”

The team plans to use the technique to continue to study communication between cells in the brain. “Since our Botox technique helped us solve the problem of how dopamine neurons regulate their communication, it should also enable us to uncover how other nerve cells interact with each other in the mammalian brain,” said study senior author Margaret Rice, PhD, a professor in the departments of neurosurgery and neuroscience and physiology at NYU Langone.

The researchers also aim to study other areas of dopamine neuron activity that remain poorly understood, such as the dependence of dopamine release on calcium from outside the brain cells, and to examine how self-regulation of dopamine might contribute to cell death in Parkinson’s disease.

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