Experience-dependent myelination following stress is mediated by the neuropeptide dynorphin

• Published in: Neuron (Cambridge, Mass.) Vol. 109; no. 22; pp. 3619 - 3632.e5
• Main Authors: Osso, Lindsay A., Rankin, Kelsey A., Chan, Jonah R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.11.2021
• Subjects: axon selection; development; dynorphin; experience-dependent myelination; myelin; neuropeptide; oligodendrocyte; oligodendrocyte precursor cell differentiation; stress; striatum; myelin; stress; dynorphin; development; experience-dependent myelination; striatum; axon selection; neuropeptide; oligodendrocyte; oligodendrocyte precursor cell differentiation
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2021.08.015

Emerging evidence implicates experience-dependent myelination in learning and memory. However, the specific signals underlying this process remain unresolved. We demonstrate that the neuropeptide dynorphin, which is released from neurons upon high levels of activity, promotes experience-dependent myelination. Following forced swim stress, an experience that induces striatal dynorphin release, we observe increased striatal oligodendrocyte precursor cell (OPC) differentiation and myelination, which is abolished by deleting dynorphin or blocking its endogenous receptor, kappa opioid receptor (KOR). We find that dynorphin also promotes developmental OPC differentiation and myelination and demonstrate that this effect requires KOR expression specifically in OPCs. We characterize dynorphin-expressing neurons and use genetic sparse labeling to trace their axonal projections. Surprisingly, we find that they are unmyelinated normally and following forced swim stress. We propose a new model whereby experience-dependent and developmental myelination is mediated by unmyelinated, neuropeptide-expressing neurons that promote OPC differentiation for the myelination of neighboring axons. •Forced swim stress promotes experience-dependent OPC differentiation•Stress-induced OPC differentiation is mediated by the neuropeptide dynorphin•Dynorphin promotes developmental OPC differentiation•The axons of dynorphin-expressing neurons are unmyelinated Recent studies have implicated experience-dependent myelination in learning and memory, but the mechanisms regulating this process are unknown. Osso et al. identify the neuropeptide dynorphin as a novel regulator of experience-dependent myelination following stress.