How does myelin plasticity influence neural circuit dynamics required for long-term memories?

The National Institute of Mental Health (NIMH) awarded a Project Grant of $150,104 to The Regents of the University of California, San Francisco under the Mental Health Research Grants program (CFDA 93.242) to conduct basic neuroscience research investigating the relationship between myelin plasticity and long-term memory formation. The research project, active from March 1, 2026 through October 31, 2028, will employ an active avoidance learning paradigm in mice to identify which neurons become newly myelinated in the medial prefrontal cortex following avoidance learning and to determine how oligodendrogenesis (the formation of new myelinating cells) influences neural synchronization across the cortical-hippocampal-amygdala network during memory recall. Using two-photon microscopy and behavioral analysis, the principal investigator will generate empirical evidence clarifying the cellular mechanisms by which myelin plasticity regulates neural circuit dynamics essential for long-term memory storage and retrieval.

This research addresses a fundamental gap in neuroscience knowledge by investigating how myelin—previously understood as a static substance—dynamically changes in response to learning and contributes to memory consolidation. The findings are expected to advance understanding of the neurobiological mechanisms underlying memory formation and may have downstream implications for memory-related disorders and therapeutic intervention development.

Abstract

To retain new memories over long periods of time, the brain must be able to change in response to learning and then stabilize those changes to store long-term memories. However, the cellular mechanisms that enable long-term memory recall remain incompletely understood. Intriguingly, recent evidence suggests that myelin, the lipid-rich substance produced by glial cells known as oligodendrocytes, is critical for long- term memory recall. Myelin, previously thought to be static and stable after development, is critical for nervous system function; its primary role is to increase the conduction velocity of electrical signaling by neurons. In the adult brain, learning can induce the formation of new myelinating oligodendrocytes, known as oligodendrogenesis. The new myelin sheaths created by oligodendrogenesis are critical for the recall of long-term memories. However, how myelin is precisely modulated to regulate the neural activity underlying long- term memory storage remains an open question. To address this, i use an active avoidance paradigm in which mice learn to associate a light CUE with a mild footshock and escape by shuttling to avoid footshock. The trial-based structure, the ability to compare correct and incorrect trials, and the greater diversity of behavioral readouts enable precise correlation between neural features and behavior. Furthermore, the specificity of these readouts can help uncover the precise circuits that are impacted by new myelin formation. Using the active avoidance, i will 1) identify which neurons become myelinated in the medial prefrontal cortex after avoidance learning using two-photon microscopy and 2) determine how oligodendrogenesis influences synchronization in the cortical-hippocampal-amygdala network during avoidance memory recall. Together, i will uncover how learning shapes myelination and how this myelin plasticity influences neural dynamics during long-term memory. These studies will shed light on underexplored, non-neuronal plasticity mechanisms that shape neural dynamics and have broad implications for our understanding of how the brain changes after learning. I will be conducting these experiments in DR. Mazen kheirbek's laboratory, where all the techniques necessary for my project have been set up. The kheirbek laboratory is located at the university of california, SAN francisco, a world-renowned biomedical research facility. With the support of DR. Kheirbek, CO-sponsor DR. Vikaas sohal, and additional support from DR. Jonah chan, i am perfectly positioned to complete the described project. My postdoctoral work will enable me to achieve my ultimate career goal of running an independent academic laboratory studying how neuron-glia interactions influence neural circuit dynamics and behavior.