Long-Lasting Memory Needs New Myelin Formation

Post by D. Chloe Chung

What's the science?

Our experiences can be recorded in the brain and persist as long-lasting or “remote” memory, through a process called memory consolidation, in which neuronal networks are reorganized over time to structurally represent certain memories. While several neural circuits have been suggested to be potentially responsible for memory consolidation, we still do not fully understand what is happening at the cellular level when particular experiences become solidified as a remote memory. One hint we can find from past studies is that memory functions can be mediated by oligodendrocytes, glial cells that form an insulating fatty tissue called myelin that wraps around axons of the neurons to help efficient neuronal transmission. This week in Nature Neuroscience, Pan and colleagues show that freshly generated oligodendrocytes and their new myelin formation are highly important in consolidating fearful experiences as remote fear memory.

How did they do it?

To make mice in the study learn certain experiences and remember them, the authors used fear conditioning. Fear conditioning trains mice to associate a fearful stimulus like an electric foot shock to neutral cues such as a particular smell or noise. If the mice later freeze (out of fear) after simply being placed in the same chamber even without experiencing a foot shock, this indicates that the mice correctly learned to remember a fearful experience. In this study, right before the fear conditioning, mice were injected with a chemical that incorporates into DNA of dividing cells, so that cells that are newly formed after the injection can be readily identified. 

Brains of these mice were examined either a day or a month after fear learning to evaluate various changes in the brain at different timepoints. To further explore how important new myelin-forming oligodendrocytes are in storing fear memory, the authors used a genetically engineered mouse model that can be induced to stop the production of new oligodendrocytes at any desired timepoint. These transgenic mice underwent the same memory test to determine the effects of new myelin formation on memory consolidation. As another approach, the authors also used a drug called clemastine that can induce new myelin formation and tested how it can change the ability of fear-conditioned mice in recalling remote fear memory.

What did they find?

The authors first observed that mice that successfully learned a fearful experience produced cells with the potential to become oligodendrocytes in the medial prefrontal cortex (mPFC), one of the brain regions important in storing long-term memory. Over the course of several weeks, these cells further matured and became oligodendrocytes that can actively myelinate axons. Interestingly, the authors found that mice that were genetically inhibited to produce new oligodendrocytes, failed to effectively recall a fearful experience from a month ago, as they did not show freezing behaviors like normal mice. Since these transgenic mice were able to remember a fear experience that happened a day before, the authors speculated that new myelin formation is important specifically for the long-term storage of fear memory. Upon closely examining the cells in the genetically inhibited mice that cannot form new myelin, the authors found that neurons in the memory consolidation brain regions were not efficiently activated, as shown by greatly reduced expressions of immediate early genes that are normally activated with external stimuli. Mice injected with myelination-promoting clemastine showed remote fear memory that was significantly more persistent and stabilized than the control group. This observation, accompanied by increased expression of immediate early genes, suggests that new myelin formation can substantially preserve remote fear memory.

What’s the impact?

This study presents the first evidence that effective storage of fear memories over a long period of time requires newly generated oligodendrocytes that can provide fresh myelin for neurons. This study is particularly interesting as it showed that myelination, which has been thought to mostly occur during the early development of the brain, is, in fact, a very dynamic process that can critically help to preserve long-lasting memories in the adult brain. Findings from this study may ultimately provide useful insights in developing effective treatment options for neurological diseases like post-traumatic stress disorder (PTSD), a disorder associated with the abnormal, intense recall of fear memories.

Pan et al. Preservation of a remote fear memory requires new myelin formation. Nature Neuroscience (2020). Access the original scientific publication here.