Activity-dependent Myelination Research Articles

Adaptive myelination causes slow oscillations in recurrent neural loops.

The brain is known to be plastic, i.e., capable of changing and reorganizing as it develops and accumulates experience. Recently, a novel form of brain plasticity was described which is activity-dependent myelination of nerve fibers. Since the speed of propagation of action potentials along axons depends significantly on their degree of myelination, this process leads to adaptive change of axonal delays depending on the neural activity. To understand the possible influence of the adaptive delays on the behavior of neural networks, we consider a simple setup, a neuronal oscillator with delayed feedback. We show that introducing the delay plasticity into this circuit can lead to the occurrence of slow oscillations which are impossible with a constant delay.

Transient demyelination causes long-term cognitive impairment, myelin alteration and network synchrony defects.

In the adult brain, activity-dependent myelin plasticity is required for proper learning and memory consolidation. Myelin loss, alteration, or even subtle structural modifications can therefore compromise the network activity, leading to functional impairment. In multiple sclerosis, spontaneous myelin repair process is possible, but it is heterogeneous among patients, sometimes leading to functional recovery, often more visible at the motor level than at the cognitive level. In cuprizone-treated mouse model, massive brain demyelination is followed by spontaneous and robust remyelination. However, reformed myelin, although functional, may not exhibit the same morphological characteristics as developmental myelin, which can have an impact on the activity of neural networks. In this context, we used the cuprizone-treated mouse model to analyze the structural, functional, and cognitive long-term effects of transient demyelination. Our results show that an episode of demyelination induces despite remyelination long-term cognitive impairment, such as deficits in spatial working memory, social memory, cognitive flexibility, and hyperactivity. These deficits were associated with a reduction in myelin content in the medial prefrontal cortex (mPFC) and hippocampus (HPC), as well as structural myelin modifications, suggesting that the remyelination process may be imperfect in these structures. In vivo electrophysiological recordings showed that the demyelination episode altered the synchronization of HPC-mPFC activity, which is crucial for memory processes. Altogether, our data indicate that the myelin repair process following transient demyelination does not allow the complete recovery of the initial myelin properties in cortical structures. These subtle modifications alter network features, leading to prolonged cognitive deficits in mice.

Activity-dependent oligodendrocyte calcium dynamics and their changes in Alzheimer's disease.

Oligodendrocytes (OCs) form myelin around axons, which is dependent on neuronal activity. This activity-dependent myelination plays a crucial role in training and learning. Previous studies have suggested that neuronal activity regulates proliferation and differentiation of oligodendrocyte precursor cells (OPCs) and myelination. In addition, deficient activity-dependent myelination results in impaired motor learning. However, the functional response of OC responsible for neuronal activity and their pathological changes is not fully elucidated. In this research, we aimed to understand the activity-dependent OC responses and their different properties by observing OCs using in vivo two-photon microscopy. We clarified that the Ca2+ activity in OCs is neuronal activity dependent and differentially regulated by neurotransmitters such as glutamate or adenosine triphosphate (ATP). Furthermore, in 5-month-old mice models of Alzheimer's disease, a period before the appearance of behavioral abnormalities, the elevated Ca2+ responses in OCs are ATP dependent, suggesting that OCs receive ATP from damaged tissue. We anticipate that our research will help in determining the correct therapeutic strategy for neurodegenerative diseases beyond the synapse.

Quantitative MRI reveals widespread, network-specific myelination change during generalized epilepsy progression

Activity-dependent myelination is a fundamental mode of brain plasticity which significantly influences network function. We recently discovered that absence seizures, which occur in multiple forms of generalized epilepsy, can induce activity-dependent myelination, which in turn promotes further progression of epilepsy. Structural alterations of myelin are likely to be widespread, given that absence seizures arise from an extensive thalamocortical network involving frontoparietal regions of the bilateral hemispheres. However, the temporal course and spatial extent of myelin plasticity is unknown, due to limitations of gold-standard histological methods such as electron microscopy (EM). In this study, we leveraged magnetization transfer and diffusion MRI for estimation of g-ratios across major white matter tracts in a mouse model of generalized epilepsy with progressive absence seizures. EM was performed on the same brains after MRI. After seizure progression, we found increased myelination (decreased g-ratios) throughout the anterior portion (genu-to-body) of the corpus callosum but not in the posterior portion (body-splenium) nor in the fornix or the internal capsule. Curves obtained from averaging g-ratio values at every longitudinal point of the corpus callosum were statistically different with p<0.001. Seizure-associated myelin differences found in the corpus callosum body with MRI were statistically significant (p = 0.0027) and were concordant with EM in the same region (p = 0.01). Notably, these differences were not detected by diffusion tensor imaging. This study reveals widespread myelin structural change that is specific to the absence seizure network. Furthermore, our findings demonstrate the potential utility and importance of MRI-based g-ratio estimation to non-invasively detect myelin plasticity.

Adaptive and maladaptive myelination in health and disease.

Within the past decade, multiple lines of evidence have converged to identify a critical role for activity-regulated myelination in tuning the function of neural networks. In this Review, we provide an overview of accumulating evidence that activity-regulated myelination is required for brain adaptation and learning across multiple domains. We then discuss dysregulation of activity-dependent myelination in the context of neurological disease, a novel frontier with the potential to uncover new mechanisms of disease pathogenesis and to develop new therapeutic strategies. Alterations in myelination and neural network function can result from deficient myelin plasticity that impairs neurological function or from maladaptive myelination, in which intact activity-dependent myelination contributes to the disease process by promoting pathological patterns of neuronal activity. These emerging mechanisms suggest new avenues for therapeutic intervention that could more fully address the complex interactions between neurons and oligodendroglia.

Effects of Visual Deprivation on Remodeling of Nodes of Ranvier in Optic Nerve.

Oligodendrocytes, the myelinating cells of the CNS, promote rapid action potential conduction along axons. Changes in the geometry of gaps between myelin segments, known as nodes of Ranvier, affect the conduction speed of neuronal impulses and can ultimately alter neural synchronization and circuit function. In contrast to synaptic plasticity, much less is known about how neural activity may affect node of Ranvier structure. Recently, perinodal astrocytes have been shown to remodel nodes of Ranvier by regulating thrombin proteolysis, but it is not known whether neural activity influences this process. To test this hypothesis, we used transgenic mice with astrocytic expression of a dominant-negative vesicle-associated membrane protein 2 ([gfap]dnVAMP2) to reduce exocytosis of thrombin inhibitors, modulating astrocytic regulation of paranodal loop attachment to induce nodal remodeling, under normal conditions and in adult mice maintained in darkness from postnatal day 40 (P40) to P70. This mechanism of nodal lengthening proceeded normally following binocular visual deprivation (BVD). The effect of BVD on nodal plasticity in animals with unimpaired astrocyte function has not been previously investigated. We find that when exocytosis from astrocytes was unimpaired, nodal gap length was not altered by BVD in adult mice. We conclude that if perinodal astrocytes participate in activity-dependent myelin remodeling through exocytosis, then, as with synaptic plasticity in the visual system, the process must be driven by alterations in neuronal firing other than those produced by BVD.

Homeostatic coordination and up-regulation of neural activity by activity-dependent myelination.

Activity-dependent myelination (ADM) is a fundamental dimension of brain plasticity through which myelin changes as a function of neural activity. Mediated by structural changes in glia, ADM notably regulates axonal conduction velocity. Yet, it remains unclear how neural activity impacts myelination to orchestrate the timing of neural signalling, and how ADM shapes neural activity. We developed a model of spiking neurons enhanced with neuron-oligodendrocyte feedback and examined the relationship between ADM and neural activity. We found that ADM implements a homeostatic gain control mechanism that enhances neural firing rates and correlations through the temporal coordination of action potentials as axon lengths increase. Stimuli engage ADM plasticity to trigger bidirectional and reversible changes in conduction delays, as may occur during learning. Furthermore, ADM was found to enhance information transmission under various types of time-varying stimuli. These results highlight the role of ADM in shaping neural activity and communication.

Homeostatic coordination and up-regulation of neural activity by activity-dependent myelination

Homeostatic coordination and up-regulation of neural activity by activity-dependent myelination

Maladaptive myelination promotes generalized epilepsy progression.

Activity-dependent myelination can fine-tune neural network dynamics. Conversely, aberrant neuronal activity, as occurs in disorders of recurrent seizures (epilepsy), could promote maladaptive myelination, contributing to pathogenesis. In this study, we tested the hypothesis that activity-dependent myelination resulting from absence seizures, which manifest as frequent behavioral arrests with generalized electroencephalography (EEG) spike-wave discharges, promote thalamocortical network hypersynchrony and contribute to epilepsy progression. We found increased oligodendrogenesis and myelination specifically within the seizure network in two models of generalized epilepsy with absence seizures (Wag/Rij rats and Scn8a+/mut mice), evident only after epilepsy onset. Aberrant myelination was prevented by pharmacological seizure inhibition in Wag/Rij rats. Blocking activity-dependent myelination decreased seizure burden over time and reduced ictal synchrony as assessed by EEG coherence. These findings indicate that activity-dependent myelination driven by absence seizures contributes to epilepsy progression; maladaptive myelination may be pathogenic in some forms of epilepsy and other neurological diseases.

White Matter Tracts and Diffuse Lower-Grade Gliomas: The Pivotal Role of Myelin Plasticity in the Tumor Pathogenesis, Infiltration Patterns, Functional Consequences and Therapeutic Management.

For many decades, interactions between diffuse lower-grade glioma (LGG) and brain connectome were neglected. However, the neoplasm progression is intimately linked to its environment, especially the white matter (WM) tracts and their myelin status. First, while the etiopathogenesis of LGG is unclear, this tumor seems to appear during the adolescence, and it is mostly located within anterior and associative cerebral areas. Because these structures correspond to those which were myelinated later in the brain maturation process, WM myelination could play a role in the development of LGG. Second, WM fibers and the myelin characteristics also participate in LGG diffusion, since glioma cells migrate along the subcortical pathways, especially when exhibiting a demyelinated phenotype, which may result in a large invasion of the parenchyma. Third, such a migratory pattern can induce functional (neurological, cognitive and behavioral) disturbances, because myelinated WM tracts represent the main limitation of neuroplastic potential. These parameters are critical for tailoring an individualized therapeutic strategy, both (i) regarding the timing of active treatment(s) which must be proposed earlier, before a too wide glioma infiltration along the WM bundles, (ii) and regarding the anatomic extent of surgical resection and irradiation, which should take account of the subcortical connectivity. Therefore, the new science of connectomics must be integrated in LGG management, based upon an improved understanding of the interplay across glioma dissemination within WM and reactional neural networks reconfiguration, in order to optimize long-term oncological and functional outcomes. To this end, mechanisms of activity-dependent myelin plasticity should be better investigated.

Novel Toolboxes for the Investigation of Activity-Dependent Myelination in the Central Nervous System.

Myelination is essential for signal processing within neural networks. Emerging data suggest that neuronal activity positively instructs myelin development and myelin adaptation during adulthood. However, the underlying mechanisms controlling activity-dependent myelination have not been fully elucidated. Myelination is a multi-step process that involves the proliferation and differentiation of oligodendrocyte precursor cells followed by the initial contact and ensheathment of axons by mature oligodendrocytes. Conventional end-point studies rarely capture the dynamic interaction between neurons and oligodendrocyte lineage cells spanning such a long temporal window. Given that such interactions and downstream signaling cascades are likely to occur within fine cellular processes of oligodendrocytes and their precursor cells, overcoming spatial resolution limitations represents another technical hurdle in the field. In this mini-review, we discuss how advanced genetic, cutting-edge imaging, and electrophysiological approaches enable us to investigate neuron-oligodendrocyte lineage cell interaction and myelination with both temporal and spatial precision.

Cognitive Dysfunction in White Matter Disorders: New Perspectives in Treatment and Recovery.

White matter disorders are increasingly appreciated as capable of disrupting cognitive function, and this impairment may be sufficiently severe to produce the syndrome of white matter dementia. Although recognizing this problem is important for diagnostic accuracy, the treatment of cognitive dysfunction and dementia in the white matter disorders has received relatively little attention. Similarly, few data are available regarding the potential for cognitive recovery in these disorders. Recent clinical and laboratory advances, however, indicate that effective treatment and meaningful recovery may be achievable goals for many patients with macrostructural or microstructural white matter pathology. One recent observation is that leukoaraiosis has been observed to regress with treatment of hypertension, often with concomitant improvement in cognition. Equally novel is emerging evidence that white matter exhibits substantial plasticity related to activity-dependent myelination and that this phenomenon may produce clinical benefit. These insights suggest that noninvasive and inexpensive interventions targeting white matter are warranted for a wide range of cognitively impaired patients. Moreover, given the well-established risk that vascular white matter pathology portends for developing dementia-including both vascular dementia and Alzheimer's disease-the application of these principles before dementia onset may also be efficacious for prevention. In view of the increasingly compelling case for early white matter involvement in the etiopathogenesis of late-life dementia and the continuing lack of disease-modifying therapy, progress in treating cognitive disturbances arising from white matter disorders offers the prospect that this approach may enhance the prevention of dementia as well as the treatment of cognitive dysfunction.

Auxiliary Subunits Control Function and Subcellular Distribution of AMPA Receptor Complexes in NG2 Glia of the Developing Hippocampus.

Synaptic and axonal glutamatergic signaling to NG2 glia in white matter is critical for the cells’ differentiation and activity dependent myelination. However, in gray matter the impact of neuron-to-NG2 glia signaling is still elusive, because most of these cells keep their non-myelinating phenotype throughout live. Early in postnatal development, hippocampal NG2 glia express AMPA receptors with a significant Ca2+ permeability allowing for plasticity of the neuron-glia synapses, but whether this property changes by adulthood is not known. Moreover, it is unclear whether NG2 glia express auxiliary transmembrane AMPA receptor related proteins (TARPs), which modify AMPA receptor properties, including their Ca2+ permeability. Through combined molecular and functional analyses, here we show that hippocampal NG2 glia abundantly express TARPs γ4, γ7, and γ8 as well as cornichon (CNIH)-2. TARP γ8 undergoes profound downregulation during development. Receptors of adult NG2 glia showed an increased sensitivity to blockers of Ca2+ permeable AMPA receptors, but this increase mainly concerned receptors located close to the soma. Evoked synaptic currents of NG2 glia were also sensitive to blockers of Ca2+ permeable AMPA receptors. The presence of AMPA receptors with varying Ca2+ permeability during postnatal maturation may be important for the cells’ ability to sense and respond to local glutamatergic activity and for regulating process motility, differentiation, and proliferation.

A morphological analysis of activity-dependent myelination and myelin injury in transitional oligodendrocytes

Neuronal activity is established as a driver of oligodendrocyte (OL) differentiation and myelination. The concept of activity-dependent myelin plasticity, and its role in cognition and disease, is gaining support. Methods capable of resolving changes in the morphology of individual myelinating OL would advance our understanding of myelin plasticity and injury, thus we adapted a labelling approach involving Semliki Forest Virus (SFV) vectors to resolve and quantify the 3-D structure of OL processes and internodes in cerebellar slice cultures. We first demonstrate the utility of the approach by studying changes in OL morphology after complement-mediated injury. SFV vectors injected into cerebellar white matter labelled transitional OL (TOL), whose characteristic mixture of myelinating and non-myelinating processes exhibited significant degeneration after complement injury. The method was also capable of resolving finer changes in morphology related to neuronal activity. Prolonged suppression of neuronal activity, which reduced myelination, selectively decreased the length of putative internodes, and the proportion of process branches that supported them, while leaving other features of process morphology unaltered. Overall this work provides novel information on the morphology of TOL, and their response to conditions that alter circuit function or induce demyelination.

Oligodendroglial Epigenetics, from Lineage Specification to Activity-Dependent Myelination.

Oligodendroglial cells are the myelinating cells of the central nervous system. While myelination is crucial to axonal activity and conduction, oligodendrocyte progenitor cells and oligodendrocytes have also been shown to be essential for neuronal support and metabolism. Thus, a tight regulation of oligodendroglial cell specification, proliferation, and myelination is required for correct neuronal connectivity and function. Here, we review the role of epigenetic modifications in oligodendroglial lineage cells. First, we briefly describe the epigenetic modalities of gene regulation, which are known to have a role in oligodendroglial cells. We then address how epigenetic enzymes and/or marks have been associated with oligodendrocyte progenitor specification, survival and proliferation, differentiation, and finally, myelination. We finally mention how environmental cues, in particular, neuronal signals, are translated into epigenetic modifications, which can directly influence oligodendroglial biology.

Neuronal activity-dependent myelin repair promotes motor function recovery after contusion spinal cord injury

An increasing number of studies connect neuronal activity with developmental myelination but how neuronal activity regulates remyelination has not been clarified. In this study, we induced the demyelination of the dorsal corticospinal tract (dCST) by a mild contusion spinal cord injury (SCI) on the T10 segment, and manipulated the neuronal activity of the primary motor cortex (M1) using chemogenetic viruses to induce activity and to suppress it. We found that oligodendrocyte precursor cell (OPC) proliferation and oligodendrocyte maturity following remyelination was strengthened after 4-week of neuronal activity stimulation. Furthermore, hindlimb motor function was also found to be improved. Vice versa, suppression of neuronal activity attenuated these effects. These results indicate that bidirectional regulation of neuronal activity can effectively modulate the development of oligodendrocyte lineage cells and the remyelination process. Neuronal activity supports the proliferation of OPCs, improves oligodendrocyte maturation and amplifies the axonal remyelination process, even though leads to better motor function recovery. Manipulation of neuronal activity in a non-invasive manner is therefore a promising avenue for exploration towards the treatment of central nervous system (CNS) demyelination diseases.

A role of oligodendrocytes in information processing

Myelinating oligodendrocytes enable fast propagation of action potentials along the ensheathed axons. In addition, oligodendrocytes play diverse non-canonical roles including axonal metabolic support and activity-dependent myelination. An open question remains whether myelination also contributes to information processing in addition to speeding up conduction velocity. Here, we analyze the role of myelin in auditory information processing using paradigms that are also good predictors of speech understanding in humans. We compare mice with different degrees of dysmyelination using acute multiunit recordings in the auditory cortex, in combination with behavioral readouts. We find complex alterations of neuronal responses that reflect fatigue and temporal acuity deficits. We observe partially discriminable but similar deficits in well myelinated mice in which glial cells cannot fully support axons metabolically. We suggest a model in which myelination contributes to sustained stimulus perception in temporally complex paradigms, with a role of metabolically active oligodendrocytes in cortical information processing.

Maladaptive Myelination Promotes Epileptogenesis in Absence Epilepsy

Neuronal activity can influence the generation of new oligodendrocytes (oligodendrogenesis) and myelination. In health, this is an adaptive process that can increase synchrony within distributed neuronal networks and contribute to cognitive function. Absence epilepsy is a disease defined by increasingly frequent behavioral arrest seizures over time, thought to be due to thalamocortical network hypersynchrony. We tested the hypothesis that activity-dependent myelination resulting from absence seizures promotes epileptogenesis. Using two distinct models of absence epilepsy, Wag/Rij rats and Scn8a+/mut mice, we found increased oligodendrogenesis and myelination specifically within the absence seizure network. These changes are evident only after seizure onset in both models and are prevented with pharmacological inhibition of seizures. Genetic blockade of activity-dependent myelination during epileptogenesis markedly decreased seizure frequency in the Scn8a+/mut mouse model of absence epilepsy. Taken together, these findings indicate that activity-dependent myelination driven by absence seizures contributes to seizure kindling during epileptogenesis.

Synchronization and resilience in the Kuramoto white matter network model with adaptive state-dependent delays

White matter pathways form a complex network of myelinated axons that regulate signal transmission in the nervous system and play a key role in behaviour and cognition. Recent evidence reveals that white matter networks are adaptive and that myelin remodels itself in an activity-dependent way, during both developmental stages and later on through behaviour and learning. As a result, axonal conduction delays continuously adjust in order to regulate the timing of neural signals propagating between different brain areas. This delay plasticity mechanism has yet to be integrated in computational neural models, where conduction delays are oftentimes constant or simply ignored. As a first approach to adaptive white matter remodeling, we modified the canonical Kuramoto model by enabling all connections with adaptive, phase-dependent delays. We analyzed the equilibria and stability of this system, and applied our results to two-oscillator and large-dimensional networks. Our joint mathematical and numerical analysis demonstrates that plastic delays act as a stabilizing mechanism promoting the network’s ability to maintain synchronous activity. Our work also shows that global synchronization is more resilient to perturbations and injury towards network architecture. Our results provide key insights about the analysis and potential significance of activity-dependent myelination in large-scale brain synchrony.

Therapeutic potential of neuromodulation for demyelinating diseases

Neuromodulation represents a cutting edge class of both invasive and non-invasive therapeutic methods which alter the activity of neurons. Currently, several different techniques have been developed - or are currently being investigated – to treat a wide variety of neurological and neuropsychiatric disorders. Recently, in vivo and in vitro studies have revealed that neuromodulation can also induce myelination, meaning that it could hold potential as a therapy for various demyelinating diseases including multiple sclerosis and progressive multifocal leukencepalopathy. These findings come on the heels of a paradigm shift in the view of myelin’s role within the nervous system from a static structure to an active co-regulator of central nervous system plasticity and participant in neuron-mediated modulation. In the present review, we highlight several of the recent findings regarding the role of neural activity in altering myelination including several soluble and contact-dependent factors that seem to mediate neural activity-dependent myelination. We also highlight several considerations for neuromodulatory techniques, including the need for further research into spatiotemporal precision, dosage, and the safety and efficacy of transcranial focused ultrasound stimulation, an emerging neuromodulation technology. As the field of neuromodulation continues to evolve, it could potentially bring forth methods for the treatment of demyelinating diseases, and as such, further investigation into the mechanisms of neuron-dependent myelination as well as neuro-imaging modalities that can monitor myelination activity is warranted.