Neuronal circuit modulation by myelination in the mammalian visual cortex

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PROJECT SUMMARY In the past decade, the field of myelination has undergone a conceptual revolution. Long considered a static structure, recent studies have revealed that myelination is continuously shaped by external experiences and plays essential roles in supporting learning and memory. A key question that emerges from these studies is how oligodendrocytes, and the myelin sheaths they produce, influence neuronal circuits to impact behavior. My long-term research goal is to determine how oligodendrocytes and myelin shape neuronal circuit function and plasticity during development, learning, and memory. This work will crucially advance our knowledge of the cellular processes underlying neural circuit maturation and lifelong plasticity, particularly considering the numerous recent studies identifying myelination deficits as a common pathological hallmark of neurodevelopmental and neurodegenerative disorders with cognitive symptoms, including autism spectrum disorders, schizophrenia, and Alzheimer’s disease. Given its well-characterized developmental windows for experience-induced neuronal plasticity and accessibility for in vivo readouts of neuronal activity, the mouse visual cortex presents an ideal model for studying the interaction between external experience, myelination, and neuronal plasticity. I will use novel genetic tools in combination with in vivo longitudinal two-photon imaging and in vivo/slice electrophysiology to 1) test the effects of disrupting developmental myelination on the maturation of functional neuronal properties and experience-induced plasticity, 2) determine the synaptic basis for circuit modulation by myelination, and 3) investigate the cell type-specific roles of myelination in circuit function by inhibiting myelination in specific populations of neurons. Results from these experiments will define the specific neuron-myelin interactions underlying neuronal circuit maturation and plasticity with unprecedented rigor and cell specificity, and provide a foundation for studying how these processes are perturbed in pathological contexts. Furthermore, completion of these aims will provide me with rigorous training in in vivo electrophysiology and analysis of large-scale electrophysiology data, which will be critical in the establishment of my independent research program focused on the role of myelination in neuronal circuit maturation and function, as well as how disruptions in myelination can lead to circuit dysfunction in neurodevelopmental and psychiatric disorders.