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

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. Project Number: 1F32MH142114-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Manasi Iyer | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $75,052 | Activity Code: F32 | Study Section: Special Emphasis Panel[ZRG1 F01B-X (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11243018