March 17, 2020
Written by: Claudia Lopez-Lloreda
Your every thought, movement, and reflex are the outcome of one or multiple neurons communicating with each other. An electrical message is sent, which may travel from one brain region to the other to tell the brain to move your hand towards a coffee cup or to raise your hand to ask a question in class. Neurons send this signal through connections called axons, nerve fibers that arise from one cell and extend towards the others to maintain constant communication.
The brain works hard to maintain these connections in tip-top shape, so the communication can continue uninterrupted. One of the ways this happens is by insulating the axons with a fatty substance called myelin. The myelin sheath wraps around the axons the same way insulating material wraps around wires to help the spread of electrical signals (like the cover image). The insulation allows current to go through the axon more easily. This crucial process of myelination is carried out by cells called oligodendrocytes. Oligodendrocyte precursor cells (OPCs) divide and later turn into to the mature oligodendrocytes that generate the myelin sheath.
Sometimes myelin fails to wrap around neurons, or it is stripped away in response to damaging brain injury. Researchers have studied the implications of this loss of myelin in the context of diseases such as multiple sclerosis. However, the role of myelin goes beyond just diseases. Myelin is particularly important for learning. For example, motor skill learning (like learning juggling) requires production of oligodendrocytes and active myelination1. Additionally, there is enhanced myelin production in response to experiences such as sensory enrichment2. However, whether myelin is needed for other types of learning, since different types use different brain circuits, or what specific abnormalities underlie the deficits in learning when myelin is inhibited, is not entirely clear.
Now, a new study from the University of California, San Francisco untangles the relationship between myelin and memories. The new study, a collaboration between Mazen Kheirbek’s and Jonah Chan’s labs, wanted to see if myelin was important for fear learning, a type of learning in which a stable memory is generated by reorganization of neuronal circuits3. This type of learning happens when a cue, in this case a sound, is presented to a mouse and paired with a foot shock. In response to the shock, mice tend to freeze, indicating that they are in a “fear” state. Eventually, because mice learn to associate the sound and the foot shock, they freeze in response to the sound even without the shock.
First, the researchers wanted to see how fear learning affected oligodendrocyte production. They injected a dye that allows scientists to see which cells are going through cell division in the medial prefrontal cortex, an area that plays a key role in the acquisition, consolidation, and retrieval of fear memory. After the mice formed a fear memory from the pairing of a sound with a foot shock, the researchers looked at the amount of OPCs, the oligodendrocyte precursor cells, that were dividing. They observed that after 24 hours, the number of dividing OPCs increased dramatically. Additionally, these dividing cells went on to mature into myelin-forming oligodendrocytes. 30 days later, mice that were subjected to fear learning had increased mature oligodendrocytes and increased density of myelinated axons when compared to mice that were not subjected to fear learning.
Then the scientists asked how fear learning would be affected in mice that were not able to create new myelin. The researchers got rid of an important protein that the OPCs use to become mature oligodendrocytes. When they get rid of this protein in mice, they are able to inhibit new myelin formation. The scientists found that mice that do not generate new myelin spend equal amounts of time freezing during the learning process or after 24 hours of creating the fear memory. However, 30 days after learning the memory, mice that do not generate myelin spent less time freezing in response to the sound, meaning they had impaired recall of the fear memory.
So how was loss of myelin affecting fear learning? To answer this question, the researchers looked at what could be the main consequence of decreased myelin: impaired neuronal activity. To do this, they looked at neuron activation by measuring the number of neurons that expressed a gene that turns on when neurons are active. They saw that the number of neurons that were activated in the medial prefrontal cortex and in the hippocampus were significantly dampened in mice that were not able to generate myelin. The scientists also looked at neuronal dynamics, the activation waves that come and go through circuits. They saw that 30 days after fear learning control mice that produced myelin had elevated activity in the medial prefrontal cortex when they recall the memory and freeze. However, the medial prefrontal cortex activity was suppressed in mice that were not able to produce new myelin, indicating that myelin is important for the process that underlie memory consolidation.
Finally, the researchers wanted to know if rescuing the capacity to myelinate would rescue the deficits in fear learning. To quick-start myelination, they injected mice with a compound that has been previously shown to promote myelination4. Treating mice that could not generate myelin with the compound increased the number of mature oligodendrocytes, rescued the number of active neurons and the fear learning impairments. These findings suggest that myelin formation during the recall of a memory is important in controlling neuronal activation and consequently memory formation and learning. Further studies need to explore just exactly how oligodendrocytes and myelin affect these neuronal circuits.
- Mckenzie, I. A., Ohayon, D., Li, H., Faria, J. P. D., Emery, B., Tohyama, K., & Richardson, W. D. (2014). Motor skill learning requires active central myelination. Science, 346(6207), 318–322. doi: 10.1126/science.1254960
- Hughes, E. G., Orthmann-Murphy, J. L., Langseth, A. J., & Bergles, D. E. (2018). Myelin remodeling through experience-dependent oligodendrogenesis in the adult somatosensory cortex. Nature Neuroscience, 21(5), 696–706. doi: 10.1038/s41593-018-0121-5
- Pan, S., Mayoral, S. R., Choi, H. S., Chan, J. R., & Kheirbek, M. A. (2020). Preservation of a remote fear memory requires new myelin formation. Nature Neuroscience. doi: 10.1038/s41593-019-0582-1
- Mei, F., Lehmann-Horn, K., Shen, Y.-A. A., Rankin, K. A., Stebbins, K. J., Lorrain, D. S., … Chan, J. R. (2016). Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery. ELife, 5. doi: 10.7554/elife.18246
Cover image from Wikipedia, CC BY 4.0.