The human brain remains adaptable even into adulthood alternately strengthening and weakening various neural pathways. And now, new research from Stanford Medicine scientists suggests that this quality of the brain may help explain how opioid addiction develops. Details are published in a Nature paper titled, “Myelin plasticity in ventral tegmental area is required for opioid reward.”
The paper draws a possible link between opioid addiction and a type of neuroplasticity called adaptive myelination—the process by which active brain circuits gain more myelin. The new Stanford study done in mice suggests that this type of myelination, which typically occurs when people learn new skills or practice existing ones, might also be at work in the process of addiction. Specifically, they found that a single morphine dose triggered the steps leading to the myelination of dopaminergic neurons, and a greater desire for more of the drug in mice. They also found that blocking a pathway involved in myelin formation prevented the craving in test subjects.
“Myelin development does not complete until we’re in our late 20s or early 30s, which is kind of fascinating,” said Michelle Monje, MD, PhD, a professor of pediatric neuro-oncology at Stanford University and senior author of the study. “What we’ve come to understand over the last decade or so is that myelin, in some parts of the nervous system, is actually plastic and adaptable to experience. The activity of a neuron can regulate the extent to which its axon is myelinated.”
Neuroplasticity and reward learning
Monje’s lab is responsible for much of the foundational knowledge about adaptive myelination. In previous studies, her lab reported that stimulating the premotor cortex of mice increased myelination there and improved limb movement. They’ve also shown that adaptive myelination could explain worsening epileptic seizures in some patients and linked reduced myelin plasticity to the cognitive impairment in patients receiving chemotherapy treatments.
For this study, Monje’s team was interested in the role of adaptive myelination in reward learning. They generated rewarding experiences in mice by either giving them an addictive substance like cocaine or morphine or by using optogenetics techniques to stimulate dopamine-producing neurons.
Within three hours of a single drug dose or 30 minutes of stimulation, the researchers observed specialized stem cells gathering in the ventral tegmental area of the brain, which is involved in reward learning and addiction. These stem cells were destined to become oligodendrocytes, which produce myelin to wrap the neurons. After a month of repeated dosing and stimulation, the researchers found even more oligodendrocytes and myelinated dopamine-producing cells with thick myelin in the ventral tegmental area.
Next, the researchers wanted to see how the extra layers of myelin changed mouse behavior. To test this, they placed the mice boxes that let them move freely between two chambers. In one chamber, the mice got a daily injection of morphine. After five days, the scientists observed that the mice preferred the chamber where they got their daily dosing. Their preference for morphine was consistent even in the presence of a food reward. Mice that preferred the drug had more myelin around the dopamine-producing neurons in the ventral tegmental area.
The researchers also identified a possible signaling pathway that may influence the myelination process. Specifically, when a pathway known as BDNF-TrkB signaling is blocked, mice did not generate new oligodendrocytes and did not express a preference for the chamber where they were drugged.
Ultimately, a better understanding of adaptive myelination might reveal new strategies to help people recover from opioid addiction. While it’s unclear whether the changes are permanent, “there’s reason to believe that they would not be,” Monje said. “We think that myelin plasticity is bidirectional—you can both increase myelination of a circuit and decrease myelination of a circuit.”
