Myelin Plasticity and Nervous System Function.

Structural plasticity in the myelinated infrastructure of the nervous system has come to light. Although an innate program of myelin development proceeds independent of nervous system activity, a second mode of myelination exists in which activity-dependent, plastic changes in myelin-forming cells influence myelin structure and neurological function. These complementary and possibly temporally overlapping activity-independent and activity-dependent modes of myelination crystallize in a model of experience-modulated myelin development and plasticity with broad implications for neurological function. In this article, I consider the contributions of myelin to neural circuit function, the dynamic influences of experience on myelin microstructure, and the role that plasticity of myelin may play in cognition.

Reorganization of dopamine circuitry in the anterior corpus callosum between early adolescence and adulthood in the mouse.

The maturation of forebrain dopamine circuitry occurs over multiple developmental periods, extending from early postnatal life until adulthood, with the precise timing of maturation defined by the target region. We recently demonstrated in the adult mouse brain that axon terminals arising from midbrain dopamine neurons innervate the anterior corpus callosum and that oligodendrocyte lineage cells in this white matter tract express dopamine receptor transcripts. Whether corpus callosal dopamine circuitry undergoes maturational changes between early adolescence and adulthood is unknown but may be relevant to understanding the dramatic micro- and macro-anatomical changes that occur in the corpus callosum of multiple species during early adolescence, including in the degree of myelination. Using quantitative neuroanatomy, we show that dopamine innervation in the forceps minor, but not the rostral genu, of the corpus callosum, is greater during early adolescence (P21) compared to adulthood (>P90) in wild-type mice. We further demonstrate with RNAscope that, as in the adult, Drd1 and Drd2 transcripts are expressed at higher levels in oligodendrocyte precursor cells (OPCs) and decline as these cells differentiate into oligodendrocytes. In addition, the number of OPCs that express Drd1 transcripts during early adolescence is double the number of those expressing the transcript during early adulthood. These data further implicate dopamine in axon myelination and myelin regulation. Moreover, because developmental (activity-independent) myelination peaks during early adolescence, with experience-dependent (activity-dependent) myelination greatest during early adulthood, our data suggest that potential roles of dopamine on callosal myelination shift between early adolescence and adulthood, from a developmental role to an experience-dependent role.

Coherent, time-shifted patterns of microstructural plasticity during motor-skill learning.

Motor skill learning relies on neural plasticity in the motor and limbic systems. However, the spatial and temporal characteristics of these changes-and their microstructural underpinnings-remain unclear. Eighteen healthy males received 1 h of training in a computer-based motion game, 4 times a week, for 4 consecutive weeks, while 14 untrained participants underwent scanning only. Performance improvements were observed in all trained participants. Serial myelin- and iron-sensitive multiparametric mapping at 3T during this period of intensive motor skill acquisition revealed temporally and spatially distributed, performance-related microstructural changes in the grey and white matter across a corticospinal-cerebellar-hippocampal circuit. Analysis of the trajectory of these transient changes suggested time-shifted cascades of plasticity from the dominant sensorimotor system to the contralateral hippocampus. In the cranial corticospinal tracts, changes in myelin-sensitive metrics during training in the posterior limb of the internal capsule were of greater magnitude in those who trained their upper limbs vs. lower limb trainees. Motor skill learning is associated with waves of grey and white matter plasticity, across a broad sensorimotor network.

Influenza A virus infection disrupts oligodendrocyte homeostasis and alters the myelin lipidome in the adult mouse.

BACKGROUND: Recent data suggest that myelin may be altered by physiological events occurring outside of the central nervous system, which may cause changes to cognition and behavior. Similarly, peripheral infection by non-neurotropic viruses is also known to evoke changes to cognition and behavior. METHODS: Mice were inoculated with saline or influenza A virus. Bulk RNA-seq, lipidomics, RT-qPCR, flow cytometry, immunostaining, and western blots were used to determine the effect of infection on OL viability, protein expression and changes to the lipidome. To determine if microglia mediated infection-induced changes to OL homeostasis, mice were treated with GW2580, an inhibitor of microglia activation. Additionally, conditioned medium experiments using primary glial cell cultures were also used to test whether secreted factors from microglia could suppress OL gene expression. RESULTS: Transcriptomic and RT-qPCR analyses revealed temporal downregulation of OL-specific transcripts with concurrent upregulation of markers characteristic of cellular stress. OLs isolated from infected mice had reduced cellular expression of myelin proteins compared with those from saline-inoculated controls. In contrast, the expression of these proteins within myelin was not different between groups. Similarly, histological and immunoblotting analysis performed on various brain regions indicated that infection did not alter OL viability, but increased expression of a cellular stress marker. Shot-gun lipidomic analysis revealed that infection altered the lipid profile within the prefrontal cortex as well as in purified brain myelin and that these changes persisted after recovery from infection. Treatment with GW2580 during infection suppressed the expression of genes associated with glial activation and partially restored OL-specific transcripts to baseline levels. Finally, conditioned medium from activated microglia reduced OL-gene expression in primary OLs without altering their viability. CONCLUSIONS: These findings show that peripheral respiratory viral infection with IAV is capable of altering OL homeostasis and indicate that microglia activation is likely involved in the process.

miR-124 regulates early isolation-induced social abnormalities via inhibiting myelinogenesis in the medial prefrontal cortex.

Patients with autism spectrum disorder (ASD) typically experience substantial social isolation, which may cause secondary adverse effects on their brain development. miR-124 is the most abundant miRNA in the human brain, acting as a pivotal molecule regulating neuronal fate determination. Alterations of miR-124 maturation or expression are observed in various neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. In the present study, we analyzed a panel of brain-enriched microRNAs in serums from 2 to 6 year old boys diagnosed with ASD. The hsa-miR-124 level was found significantly elevated in ASD boys than in age and sex-matched healthy controls. In an isolation-reared weanling mouse model, we evidenced elevated mmu-miR-124 level in the serum and the medial prefrontal cortex (mPFC). These mice displayed significant sociability deficits, as well as myelin abnormality in the mPFC, which was partially rescued by expressing the miR-124 sponge in the bilateral mPFC, ubiquitously or specifically in oligodendroglia. In cultured mouse oligodendrocyte precursor cells, introducing a synthetic mmu-miR-124 inhibited the differentiation process through suppressing expression of nuclear receptor subfamily 4 group A member 1 (Nr4a1). Overexpressing Nr4a1 in the bilateral mPFC also corrected the social behavioral deficits and myelin impairments in the isolation-reared mice. This study revealed an unanticipated role of the miR-124/Nr4a1 signaling in regulating early social experience-dependent mPFC myelination, which may serve as a potential therapy target for social neglect or social isolation-related neuropsychiatric disorders.

Remodelling of myelinated axons and oligodendrocyte differentiation is stimulated by environmental enrichment in the young adult brain.

Oligodendrocyte production and myelination continues lifelong in the central nervous system (CNS), and all stages of this process can be adaptively regulated by neuronal activity. While artificial exogenous stimulation of neuronal circuits greatly enhances oligodendrocyte progenitor cell (OPC) production and increases myelination during development, the extent to which physiological stimuli replicates this is unclear, particularly in the adult CNS when the rate of new myelin addition slows. Here, we used environmental enrichment (EE) to physiologically stimulate neuronal activity for 6 weeks in 9-week-old C57BL/six male and female mice and found no increase in compact myelin in the corpus callosum or somatosensory cortex. Instead, we observed a global increase in callosal axon diameter with thicker myelin sheaths, elongated paranodes and shortened nodes of Ranvier. These findings indicate that EE induced the dynamic structural remodelling of myelinated axons. Additionally, we observed a global increase in the differentiation of OPCs and pre-myelinating oligodendroglia in the corpus callosum and somatosensory cortex. Our findings of structural remodelling of myelinated axons in response to physiological neural stimuli during young adulthood provide important insights in understanding experience-dependent myelin plasticity throughout the lifespan and provide a platform to investigate axon-myelin interactions in a physiologically relevant context.

Trigeminal neuropathy causes hypomyelination in the anterior cingulate cortex, disrupts the synchrony of neural circuitry, and impairs decision-making in male rats.

Infraorbital nerve-chronic constriction injury (ION-CCI) has become the most popular chronic trigeminal neuropathic pain (TNP) injury animal model which causes prolonged mechanical allodynia. Accumulative evidence suggests that TNP interferes with cognitive functions, however the underlying mechanisms are not known. The aim of this study was to investigate decision-making performance as well as synaptic and large-scale neural synchronized alterations in the spinal trigeminal nucleus (SpV) circuitry and anterior cingulate cortex (ACC) neural circuitry in male rats with TNP. Rat gambling task showed that ION-CCI led to decrease the proportion of good decision makers and increase the proportion of poor decision makers. Electrophysiological recordings showed long-lasting synaptic potentiation of local field potential in the trigeminal ganglia-SpV caudalis (SpVc) synapses in TNP rats. In this study, TNP led to disruption of ACC spike timing and basolateral amygdala (BLA) theta oscillation associated with suppressed synchronization of theta oscillation between the BLA and ACC, indicating reduced neuronal communications. Myelination is critical for information flow between brain regions, and myelin plasticity is an important feature for learning. Neural activity in the cortical regions impacts myelination by regulating oligodendrocyte (OL) proliferation, differentiation, and myelin formation. We characterized newly formed oligodendrocyte progenitor cells, and mature OLs are reduced in TNP and are associated with reduced myelin strength in the ACC region. The functional disturbances in the BLA-ACC neural circuitry is pathologically associated with the myelin defects in the ACC region which may be relevant causes for the deficits in decision-making in chronic TNP state.

Regulation of myelin structure and conduction velocity by perinodal astrocytes.

The speed of impulse transmission is critical for optimal neural circuit function, but it is unclear how the appropriate conduction velocity is established in individual axons. The velocity of impulse transmission is influenced by the thickness of the myelin sheath and the morphology of electrogenic nodes of Ranvier along axons. Here we show that myelin thickness and nodal gap length are reversibly altered by astrocytes, glial cells that contact nodes of Ranvier. Thrombin-dependent proteolysis of a cell adhesion molecule that attaches myelin to the axon (neurofascin 155) is inhibited by vesicular release of thrombin protease inhibitors from perinodal astrocytes. Transgenic mice expressing a dominant-negative fragment of VAMP2 in astrocytes, to reduce exocytosis by 50%, exhibited detachment of adjacent paranodal loops of myelin from the axon, increased nodal gap length, and thinning of the myelin sheath in the optic nerve. These morphological changes alter the passive cable properties of axons to reduce conduction velocity and spike-time arrival in the CNS in parallel with a decrease in visual acuity. All effects were reversed by the thrombin inhibitor Fondaparinux. Similar results were obtained by viral transfection of tetanus toxin into astrocytes of rat corpus callosum. Previously, it was unknown how the myelin sheath could be thinned and the functions of perinodal astrocytes were not well understood. These findings describe a form of nervous system plasticity in which myelin structure and conduction velocity are adjusted by astrocytes. The thrombin-dependent cleavage of neurofascin 155 may also have relevance to myelin disruption and repair.

Schema-like learning and memory consolidation acting through myelination.

Memory is a dynamic brain function that is continually processed after encoding. Although psychologic concepts of mental schema are now well established, they have rarely been considered in animal studies. We used a behavior paradigm of multiple flavor-place paired associates (PAs) and showed that memory schema facilitates fast acquisition of new PAs in a single trial. The hippocampus is necessary for the encoding of new PAs and for memory retrieval within a certain time window-24 h following new PA consolidation. Whereas the anterior cingulate cortex (ACC) plays a critical role for dynamic PA learning and consolidation during training sessions, ACC is essential in schema representation and activation. New myelin generation is essential for learning. Neural activity in the cortical regions impacts myelination by regulating oligodendrocyte (OL) proliferation, differentiation, and myelin formation. Here, we show that newly formed OL progenitor cells and mature OLs are increased following repeated PA learning and that establishment of the memory schema is associated with enhanced myelin strength in the ACC region. Furthermore, to ensure that myelination is necessary for the acquisition of paired-associate learning, ACC lysolecithin-induced demyelination revealed impaired PA learning associated with decrease in ACC θ band power and reduced spike-field coherence and phase-locking in ACC.-Hasan, M., Kanna, M. S., Jun, W., Ramkrishnan, A. S., Iqbal, Z., Lee, Y., Li, Y. Schema-like learning and memory consolidation acting through myelination.

Axoglial interactions in myelin plasticity: Evaluating the relationship between neuronal activity and oligodendrocyte dynamics.

Myelin is a critical component of the vertebrate nervous system, both increasing the conduction velocity of myelinated axons and allowing for metabolic coupling between the myelinating cells and axons. An increasing number of studies demonstrate that myelination is not simply a developmentally hardwired program, but rather that new myelinating oligodendrocytes can be generated throughout life. The generation of these oligodendrocytes and the formation of myelin are influenced both during development and adulthood by experience and levels of neuronal activity. This led to the concept of adaptive myelination, where ongoing activity-dependent changes to myelin represent a form of neural plasticity, refining neuronal functioning, and circuitry. Although human neuroimaging experiments support the concept of dynamic changes within specific white matter tracts relevant to individual tasks, animal studies have only just begun to probe the extent to which neuronal activity may alter myelination at the level of individual circuits and axons. Uncovering the role of adaptive myelination requires a detailed understanding of the localized interactions that occur between active axons and myelinating cells. In this review, we focus on recent animal studies that have begun to investigate the interactions between active axons and myelinating cells and review the evidence for-and against-the ability of neuronal activity to alter myelination at an axon-specific level.

ERK1/2 Activation in Preexisting Oligodendrocytes of Adult Mice Drives New Myelin Synthesis and Enhanced CNS Function.

UNLABELLED: Growing evidence shows that mechanisms controlling CNS plasticity extend beyond the synapse and that alterations in myelin can modify conduction velocity, leading to changes in neural circuitry. Although it is widely accepted that newly generated oligodendrocytes (OLs) produce myelin in the adult CNS, the contribution of preexisting OLs to functional myelin remodeling is not known. Here, we show that sustained activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in preexisting OLs of adult mice is sufficient to drive increased myelin thickness, faster conduction speeds, and enhanced hippocampal-dependent emotional learning. Although preexisting OLs do not normally contribute to remyelination, we show that sustained activation of ERK1/2 renders them able to do so. These data suggest that strategies designed to push mature OLs to reinitiate myelination may be beneficial both for enhancing remyelination in demyelinating diseases and for increasing neural plasticity in the adult CNS. SIGNIFICANCE STATEMENT: Myelin is a crucial regulator of CNS plasticity, function, and repair. Although it is generally accepted that new myelin production in the adult CNS is initiated by newly generated oligodendrocytes (OLs), great interest remains in additionally driving mature preexisting OLs to make myelin. The ability to induce myelination by the larger population of preexisting OLs carries the potential for enhanced remyelination in demyelinating diseases and increased neural plasticity in the adult CNS. Here, we show that sustained activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway is sufficient to drive mature OLs in the adult mouse CNS to reinitiate myelination, leading to new myelin wraps and functional changes.

Differential conduction velocity regulation in ipsilateral and contralateral collaterals innervating brainstem coincidence detector neurons.

Information processing in the brain relies on precise timing of signal propagation. The highly conserved neuronal network for computing spatial representations of acoustic signals resolves microsecond timing of sounds processed by the two ears. As such, it provides an excellent model for understanding how precise temporal regulation of neuronal signals is achieved and maintained. The well described avian and mammalian brainstem circuit for computation of interaural time differences is composed of monaural cells in the cochlear nucleus (CN; nucleus magnocellularis in birds) projecting to binaurally innervated coincidence detection neurons in the medial superior olivary nucleus (MSO) in mammals or nucleus laminaris (NL) in birds. Individual axons from CN neurons issue a single axon that bifurcates into an ipsilateral branch and a contralateral branch that innervate segregated dendritic regions of the MSO/NL coincidence detector neurons. We measured conduction velocities of the ipsilateral and contralateral branches of these bifurcating axon collaterals in the chicken by antidromic stimulation of two sites along each branch and whole-cell recordings in the parent neurons. At the end of each experiment, the individual CN neuron and its axon collaterals were filled with dye. We show that the two collaterals of a single axon adjust the conduction velocities individually to achieve the specific conduction velocities essential for precise temporal integration of information from the two ears, as required for sound localization. More generally, these results suggest that individual axonal segments in the CNS interact locally with surrounding neural structures to determine conduction velocity.

Central myelin dysfunction bridges obesity and neurological diseases.

The central nervous system (CNS) relies on myelin for proper functioning. Myelin remodeling is a risk factor for neurometabolic and endocrine malfunction, resulting in cognitive decline and heightened susceptibility to neurological diseases. The plasticity of myelin upon nutrient shifts may lead to dietary and hormonal interventions for preventing and treating neural complications.

Early postnatal whisker deprivation cross-modally modulates prefrontal cortex myelination and leads to social novelty deficit.

Sensory experience affects not only the corresponding primary sensory cortex, but also synaptic and neural circuit functions in other brain regions in a cross-modal manner. However, it remains unclear whether oligodendrocyte (OL) generation and myelination can also undergo cross-modal modulation. Here, we report that while early life short-term whisker deprivation from birth significantly reduces in the number of mature of OLs and the degree of myelination in the primary somatosensory cortex(S1) at postnatal day 14 (P14), it also simultaneously affects the primary visual cortex (V1), but not the medial prefrontal cortex (mPFC) with a similar reduction. Interestingly, when mice were subjected to long-term early whisker deprivation from birth (P0) to P35, they exhibited dramatically impaired myelination and a deduced number of differentiated OLs in regions including the S1, V1, and mPFC, as detected at P60. Meanwhile, the process complexity of OL precursor cells (OPCs) was also rduced, as detected in the mPFC. However, when whisker deprivation occurred during the mid-late postnatal period (P35 to P50), myelination was unaffected in both V1 and mPFC brain regions at P60. In addition to impaired OL and myelin development in the mPFC, long-term early whisker-deprived mice also showed deficits in social novelty, accompanied by abnormal activation of c-Fos in the mPFC. Thus, our results reveal a novel form of cross-modal modulation of myelination by sensory experience that can lead to abnormalities in social behavioral, suggesting a possible similar mechanism underlying brain pathological conditions that suffer from both sensory and social behavioral deficits, such as autism spectrum disorders.

Translating Molecular Approaches to Oligodendrocyte-Mediated Neurological Circuit Modulation.

The central nervous system (CNS) exhibits remarkable adaptability throughout life, enabled by intricate interactions between neurons and glial cells, in particular, oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs). This adaptability is pivotal for learning and memory, with OLs and OPCs playing a crucial role in neural circuit development, synaptic modulation, and myelination dynamics. Myelination by OLs not only supports axonal conduction but also undergoes adaptive modifications in response to neuronal activity, which is vital for cognitive processing and memory functions. This review discusses how these cellular interactions and myelin dynamics are implicated in various neurocircuit diseases and disorders such as epilepsy, gliomas, and psychiatric conditions, focusing on how maladaptive changes contribute to disease pathology and influence clinical outcomes. It also covers the potential for new diagnostics and therapeutic approaches, including pharmacological strategies and emerging biomarkers in oligodendrocyte functions and myelination processes. The evidence supports a fundamental role for myelin plasticity and oligodendrocyte functionality in synchronizing neural activity and high-level cognitive functions, offering promising avenues for targeted interventions in CNS disorders.

Oligodendrocyte-mediated myelin plasticity and its role in neural synchronization.

Temporal synchrony of signals arriving from different neurons or brain regions is essential for proper neural processing. Nevertheless, it is not well understood how such synchrony is achieved and maintained in a complex network of time-delayed neural interactions. Myelin plasticity, accomplished by oligodendrocytes (OLs), has been suggested as an efficient mechanism for controlling timing in brain communications through adaptive changes of axonal conduction velocity and consequently conduction time delays, or latencies; however, local rules and feedback mechanisms that OLs use to achieve synchronization are not known. We propose a mathematical model of oligodendrocyte-mediated myelin plasticity (OMP) in which OLs play an active role in providing such feedback. This is achieved without using arrival times at the synapse or modulatory signaling from astrocytes; instead, it relies on the presence of global and transient OL responses to local action potentials in the axons they myelinate. While inspired by OL morphology, we provide the theoretical underpinnings that motivated the model and explore its performance for a wide range of its parameters. Our results indicate that when the characteristic time of OL's transient intracellular responses to neural spikes is between 10 and 40 ms and the firing rates in individual axons are relatively low (10 Hz), the OMP model efficiently synchronizes correlated and time-locked signals while latencies in axons carrying independent signals are unaffected. This suggests a novel form of selective synchronization in the CNS in which oligodendrocytes play an active role by modulating the conduction delays of correlated spike trains as they traverse to their targets.

Axo-glial interactions between midbrain dopamine neurons and oligodendrocyte lineage cells in the anterior corpus callosum.

Oligodendrocyte progenitor cells (OPCs) receive synaptic innervation from glutamatergic and GABAergic axons and can be dynamically regulated by neural activity, resulting in activity-dependent changes in patterns of axon myelination. However, it remains unclear to what extent other types of neurons may innervate OPCs. Here, we provide evidence implicating midbrain dopamine neurons in the innervation of oligodendrocyte lineage cells in the anterior corpus callosum and nearby white matter tracts of male and female adult mice. Dopaminergic axon terminals were identified in the corpus callosum of DAT-Cre mice after injection of an eYFP reporter virus into the midbrain. Furthermore, fast-scan cyclic voltammetry revealed monoaminergic transients in the anterior corpus callosum, consistent with the anatomical findings. Using RNAscope, we further demonstrate that ~ 40% of Olig2 + /Pdfgra + cells and ~ 20% of Olig2 + /Pdgfra- cells in the anterior corpus callosum express Drd1 and Drd2 transcripts. These results suggest that oligodendrocyte lineage cells may respond to dopamine released from midbrain dopamine axons, which could affect myelination. Together, this work broadens our understanding of neuron-glia interactions with important implications for myelin plasticity by identifying midbrain dopamine axons as a potential regulator of corpus callosal oligodendrocyte lineage cells.

Hebbian activity-dependent plasticity in white matter.

Synaptic plasticity is required for learning and follows Hebb's rule, the computational principle underpinning associative learning. In recent years, a complementary type of brain plasticity has been identified in myelinated axons, which make up the majority of brain's white matter. Like synaptic plasticity, myelin plasticity is required for learning, but it is unclear whether it is Hebbian or whether it follows different rules. Here, we provide evidence that white matter plasticity operates following Hebb's rule in humans. Across two experiments, we find that co-stimulating cortical areas to induce Hebbian plasticity leads to relative increases in cortical excitability and associated increases in a myelin marker within the stimulated fiber bundle. We conclude that Hebbian plasticity extends beyond synaptic changes and can be observed in human white matter fibers.

Evolutionary Origins of the Oligodendrocyte Cell Type and Adaptive Myelination.

Oligodendrocytes are multifunctional central nervous system (CNS) glia that are essential for neural function in gnathostomes. The evolutionary origins and specializations of the oligodendrocyte cell type are among the many remaining mysteries in glial biology and neuroscience. The role of oligodendrocytes as CNS myelinating glia is well established, but recent studies demonstrate that oligodendrocytes also participate in several myelin-independent aspects of CNS development, function, and maintenance. Furthermore, many recent studies have collectively advanced our understanding of myelin plasticity, and it is now clear that experience-dependent adaptations to myelination are an additional form of neural plasticity. These observations beg the questions of when and for which functions the ancestral oligodendrocyte cell type emerged, when primitive oligodendrocytes evolved new functionalities, and the genetic changes responsible for these evolutionary innovations. Here, I review recent findings and propose working models addressing the origins and evolution of the oligodendrocyte cell type and adaptive myelination. The core gene regulatory network (GRN) specifying the oligodendrocyte cell type is also reviewed as a means to probe the existence of oligodendrocytes in basal vertebrates and chordate invertebrates.

Myelin plasticity modulates neural circuitry required for learning and behavior.

Oligodendrocytes, which form the myelin sheaths that insulate axons, regulate conduction velocity. Myelinated axons make up the brain's white matter and contribute to the efficiency of information processing by regulating the timing of neural activity. Traditionally, it has been thought that myelin is a static, inactive insulator around the axon. However, recent studies in humans using magnetic resonance imaging have shown that structural changes in the white matter occur during learning and training, suggesting that 1) white matter change depends on neural activity and 2) activity-dependent changes in white matter are essential for learning and behavior. Furthermore, suppression of oligodendrocytes and their progenitor cells leads to deficits in motor learning and remote fear memory consolidation, suggesting a causal relationship between glial function and the learning process. However, for technical reasons, it remains unclear how myelin-generating glia modulate neural circuitry and what underlying mechanisms they employ to affect learning and behavior. Recent advances in optical and genetic techniques have helped elucidate this mechanism. In this review, we highlight evidence that neural activities regulated by myelin plasticity play a pivotal role in learning and behavior and provide further insight into possible therapeutic targets for treating diseases accompanied by myelin impairment.