Myelin formation and remodeling.

Myelin is a multilayer wrapping of insulation formed by glial cells around axons that is essential for rapid impulse transmission, but how glial cells accomplish this cellular choreography has long intrigued researchers. In this issue of Cell, Snaidero et al., provide new insights into how myelin forms and is remodeled.

Autophagy in Myelinating Glia.

Autophagy is the cellular process involved in transportation and degradation of membrane, proteins, pathogens, and organelles. This fundamental cellular process is vital in development, plasticity, and response to disease and injury. Compared with neurons, little information is available on autophagy in glia, but it is paramount for glia to perform their critical responses to nervous system disease and injury, including active tissue remodeling and phagocytosis. In myelinating glia, autophagy has expanded roles, particularly in phagocytosis of mature myelin and in generating the vast amounts of membrane proteins and lipids that must be transported to form new myelin. Notably, autophagy plays important roles in removing excess cytoplasm to promote myelin compaction and development of oligodendrocytes, as well as in remyelination by Schwann cells after nerve trauma. This review summarizes the cell biology of autophagy, detailing the major pathways and proteins involved, as well as the roles of autophagy in Schwann cells and oligodendrocytes in development, plasticity, and diseases in which myelin is affected. This includes traumatic brain injury, Alexander's disease, Alzheimer's disease, hypoxia, multiple sclerosis, hereditary spastic paraplegia, and others. Promising areas for future research are highlighted.

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.

Motor learning requires myelination to reduce asynchrony and spontaneity in neural activity.

Myelination increases the conduction velocity in long-range axons and is prerequisite for many brain functions. Impaired myelin regulation or impairment of myelin itself is frequently associated with deficits in learning and cognition in neurological and psychiatric disorders. However, it has not been revealed what perturbation of neural activity induced by myelin impairment causes learning deficits. Here, we measured neural activity in the motor cortex during motor learning in transgenic mice with a subtle impairment of their myelin. This deficit in myelin impaired motor learning, and was accompanied by a decrease in the amplitude of movement-related activity and an increase in the frequency of spontaneous activity. Thalamocortical axons showed variability in axonal conduction with a large spread in the timing of postsynaptic cortical responses. Repetitive pairing of forelimb movements with optogenetic stimulation of thalamocortical axon terminals restored motor learning. Thus, myelin regulation helps to maintain the synchrony of cortical spike-time arrivals through long-range axons, facilitating the propagation of the information required for learning. Our results revealed the pathological neuronal circuit activity with impaired myelin and suggest the possibility that pairing of noninvasive brain stimulation with relevant behaviors may ameliorate cognitive and behavioral abnormalities in diseases with impaired myelination.

A new mechanism of nervous system plasticity: activity-dependent myelination.

The synapse is the focus of experimental research and theory on the cellular mechanisms of nervous system plasticity and learning, but recent research is expanding the consideration of plasticity into new mechanisms beyond the synapse, notably including the possibility that conduction velocity could be modifiable through changes in myelin to optimize the timing of information transmission through neural circuits. This concept emerges from a confluence of brain imaging that reveals changes in white matter in the human brain during learning, together with cellular studies showing that the process of myelination can be influenced by action potential firing in axons. This Opinion article summarizes the new research on activity-dependent myelination, explores the possible implications of these studies and outlines the potential for new research.

The Brain Learns in Unexpected Ways: Neuroscientists have discovered a set of unfamiliar cellular mechanisms for making fresh memories.

The connecting points between neurons, called synapses, are where learning is thought to occur. Yet the synapses alone store recollections of only the most elementary reflexes. Learning and memory require the coupling of information from many different brain regions. This activity alters the physical structure of myelin, the insulating material surrounding the wiring that connects neurons. Myelin, it turns out, plays a key role in learning by adjusting the speed of information transmission through neural networks.

The First Annual Meeting of the Society for Neuroscience, 1971: Reflections Approaching the 50th Anniversary of the Society's Formation.

The formation of the Society for Neuroscience in 1969 was a scientific landmark, remarkable for the conceptual transformation it represented by uniting all fields touching on the nervous system. The scientific program of the first annual meeting of the Society for Neuroscience, held in Washington, DC in 1971, is summarized here. By reviewing the scientific program from the vantage point of the 50th anniversary of the Society for Neuroscience, the trajectory of research now and into the future can be tracked to its origins, and the impact that the founding of the Society has had on basic and biomedical science is evident. The broad foundation of the Society was firmly cast at this first meeting, which embraced the full spectrum of science related to the nervous system, emphasized the importance of public education, and attracted the most renowned scientists of the day who were drawn together by a common purpose and eagerness to share research and ideas. Some intriguing areas of investigation discussed at this first meeting blossomed into new branches of research that flourish today, but others dwindled and have been largely forgotten. Technological developments and advances in understanding of brain function have been profound since 1971, but the success of the first meeting demonstrates how uniting scientists across diversity fueled prosperity of the Society and propelled the vigorous advancement of science.

THE ROOTS OF HUMAN AGGRESSION: Experiments in humans and animals have started to identify how violent behaviors begin in the brain.

From his sniper's perch on the 32nd floor of the mandalay bay hotel in las vegas, a lone gunman fired 1,000 bullets from high-powered rifles into a crowd of concertgoers in 2017, murdering 58 innocent people and injuring 869 others. After he committed suicide at the crime scene, the mass murderer's brain was shipped to Stanford University to seek a possible biological explanation for this depraved incident. What could the scientists possibly find during such an inspection? Quite a lot, in fact. No genetic test for homicidal behavior is in the offing. But this type of investigation can add insight into how violence is controlled by the brain. Using the same experimental methods that have enabled the tracing of brain circuits responsible for other complex human activities-including walking, speech and reading-neuroscientists now can pinpoint pathways that underlie aggressive behaviors. These new findings help to expose the underlying mechanisms at work in acts of extreme violence, such as the Las Vegas atrocity, but they also help to explain the more commonplace road rage and even a mother's instantaneous response to any threat to her child.

Cholinergic signaling in myelination.

There is a long history of research on acetylcholine (ACh) function in myelinating glia, but a resurgence of interest recently as a result of the therapeutic potential of manipulating ACh signaling to promote remyelination, and the broader interest in neurotransmitter signaling in activity-dependent myelination. Myelinating glia express all the major types of muscarinic and nicotinic ACh receptors at different stages of development, and acetylcholinesterase and butyrylcholinesterase are highly expressed in white matter. This review traces the history of research on ACh signaling in Schwann cells, oligodendrocytes, and in the myelin sheath, and summarizes current knowledge on the intracellular signaling and functional consequences of ACh signaling in myelinating glia. Implications of ACh in diseases, such as Alzheimer's disease, multiple sclerosis, and white matter toxicity caused by pesticides are considered, together with an outline of major questions for future research. GLIA 2017;65:687-698.

White matter and cognition: making the connection.

Whereas the cerebral cortex has long been regarded by neuroscientists as the major locus of cognitive function, the white matter of the brain is increasingly recognized as equally critical for cognition. White matter comprises half of the brain, has expanded more than gray matter in evolution, and forms an indispensable component of distributed neural networks that subserve neurobehavioral operations. White matter tracts mediate the essential connectivity by which human behavior is organized, working in concert with gray matter to enable the extraordinary repertoire of human cognitive capacities. In this review, we present evidence from behavioral neurology that white matter lesions regularly disturb cognition, consider the role of white matter in the physiology of distributed neural networks, develop the hypothesis that white matter dysfunction is relevant to neurodegenerative disorders, including Alzheimer's disease and the newly described entity chronic traumatic encephalopathy, and discuss emerging concepts regarding the prevention and treatment of cognitive dysfunction associated with white matter disorders. Investigation of the role of white matter in cognition has yielded many valuable insights and promises to expand understanding of normal brain structure and function, improve the treatment of many neurobehavioral disorders, and disclose new opportunities for research on many challenging problems facing medicine and society.

Synaptic plasticity by antidromic firing during hippocampal network oscillations.

Learning and other cognitive tasks require integrating new experiences into context. In contrast to sensory-evoked synaptic plasticity, comparatively little is known of how synaptic plasticity may be regulated by intrinsic activity in the brain, much of which can involve nonclassical modes of neuronal firing and integration. Coherent high-frequency oscillations of electrical activity in CA1 hippocampal neurons [sharp-wave ripple complexes (SPW-Rs)] functionally couple neurons into transient ensembles. These oscillations occur during slow-wave sleep or at rest. Neurons that participate in SPW-Rs are distinguished from adjacent nonparticipating neurons by firing action potentials that are initiated ectopically in the distal region of axons and propagate antidromically to the cell body. This activity is facilitated by GABA(A)-mediated depolarization of axons and electrotonic coupling. The possible effects of antidromic firing on synaptic strength are unknown. We find that facilitation of spontaneous SPW-Rs in hippocampal slices by increasing gap-junction coupling or by GABA(A)-mediated axon depolarization resulted in a reduction of synaptic strength, and electrical stimulation of axons evoked a widespread, long-lasting synaptic depression. Unlike other forms of synaptic plasticity, this synaptic depression is not dependent upon synaptic input or glutamate receptor activation, but rather requires L-type calcium channel activation and functional gap junctions. Synaptic stimulation delivered after antidromic firing, which was otherwise too weak to induce synaptic potentiation, triggered a long-lasting increase in synaptic strength. Rescaling synaptic weights in subsets of neurons firing antidromically during SPW-Rs might contribute to memory consolidation by sharpening specificity of subsequent synaptic input and promoting incorporation of novel information.

Gap junction communication in myelinating glia.

Gap junction communication is crucial for myelination and axonal survival in both the peripheral nervous system (PNS) and central nervous system (CNS). This review examines the different types of gap junctions in myelinating glia of the PNS and CNS (Schwann cells and oligodendrocytes respectively), including their functions and involvement in neurological disorders. Gap junctions mediate intercellular communication among Schwann cells in the PNS, and among oligodendrocytes and between oligodendrocytes and astrocytes in the CNS. Reflexive gap junctions mediating transfer between different regions of the same cell promote communication between cellular compartments of myelinating glia that are separated by layers of compact myelin. Gap junctions in myelinating glia regulate physiological processes such as cell growth, proliferation, calcium signaling, and participate in extracellular signaling via release of neurotransmitters from hemijunctions. In the CNS, gap junctions form a glial network between oligodendrocytes and astrocytes. This transcellular communication is hypothesized to maintain homeostasis by facilitating restoration of membrane potential after axonal activity via electrical coupling and the re-distribution of potassium ions released from axons. The generation of transgenic mice for different subsets of connexins has revealed the contribution of different connexins in gap junction formation and illuminated new subcellular mechanisms underlying demyelination and cognitive defects. Alterations in metabolic coupling have been reported in animal models of X-linked Charcot-Marie-Tooth disease (CMTX) and Pelizaeus-Merzbarcher-like disease (PMLD), which are caused by mutations in the genes encoding for connexin 32 and connexin 47 respectively. Future research identifying the expression and regulation of gap junctions in myelinating glia is likely to provide a better understanding of myelinating glia in nervous system function, plasticity, and disease. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.

MicroRNA regulation of homeostatic synaptic plasticity.

Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling these processes are co-coordinately regulated during homeostatic synaptic plasticity is unknown. MicroRNAs (miRNAs) exert regulatory control over mRNA stability and translation and may contribute to local and activity-dependent posttranscriptional control of synapse-associated mRNAs. However, identifying miRNAs that function through posttranscriptional gene silencing at synapses has remained elusive. Using a bioinformatics screen to identify sequence motifs enriched in the 3'UTR of rapidly destabilized mRNAs, we identified a developmentally and activity-regulated miRNA (miR-485) that controls dendritic spine number and synapse formation in an activity-dependent homeostatic manner. We find that many plasticity-associated genes contain predicted miR-485 binding sites and further identify the presynaptic protein SV2A as a target of miR-485. miR-485 negatively regulated dendritic spine density, postsynaptic density 95 (PSD-95) clustering, and surface expression of GluR2. Furthermore, miR-485 overexpression reduced spontaneous synaptic responses and transmitter release, as measured by miniature excitatory postsynaptic current (EPSC) analysis and FM 1-43 staining. SV2A knockdown mimicked the effects of miR-485, and these effects were reversed by SV2A overexpression. Moreover, 5 d of increased synaptic activity induced homeostatic changes in synaptic specializations that were blocked by a miR-485 inhibitor. Our findings reveal a role for this previously uncharacterized miRNA and the presynaptic protein SV2A in homeostatic plasticity and nervous system development, with possible implications in neurological disorders (e.g., Huntington and Alzheimer's disease), where miR-485 has been found to be dysregulated.

Recovery of node of ranvier structure in optic nerve under visual deprivation.

Neural activity can increase the length of nodes of Ranvier (NOR) and slow impulse transmission; however, little is known about the biologically and clinically important recovery process. Sensory deprivation promotes neural plasticity in many phenomena, raising the question of whether recovery of NOR morphology is influenced by sensory deprivation. The results show that NOR gap length recovery in mouse optic nerve was not affected significantly by binocular visual deprivation imposed by maintaining mice in 24 hr dark for 30 days compared to mice recovering under normal visual experience. The findings provide insight into the cellular mechanism of NOR plasticity.

Nonsynaptic and nonvesicular ATP release from neurons and relevance to neuron-glia signaling.

Studies on the release of ATP from neurons began with the earliest investigations of quantal neurotransmitter release in the 1950s, but in contrast to ATP release from other cells, studies of ATP release from neurons have been narrowly constrained to one mechanism, vesicular release. This is a consequence of the prominence of synaptic transmission in neuronal communication, but nonvesicular mechanisms for ATP release from neurons are likely to have a broader range of functions than synaptic release. Investigations of activity-dependent communication between axons and myelinating glia have stimulated a search for mechanisms that could release ATP from axons and other nonsynaptic regions in response to action potential firing. This has identified volume-activated anion channels as an important mechanism in activity-dependent ATP release from axons, and renewed interest in micromechanical changes in axons that accompany action potential firing.

Changes in brain structure during learning: fact or artifact? Reply to Thomas and Baker.

In their review in this issue, Thomas and Baker question the validity of longitudinal human neuroimaging studies that have claimed to demonstrate structural plasticity. This commentary identifies problems with some of the arguments raised in their review and suggests that there is strong evidence, from both animal and human studies, that experience can alter brain structure.

Metallothionein promotes regenerative axonal sprouting of dorsal root ganglion neurons after physical axotomy.

Prior studies have reported that metallothionein I/II (MT) promote regenerative axonal sprouting and neurite elongation of a variety of central nervous system neurons after injury. In this study, we evaluated whether MT is capable of modulating regenerative axon outgrowth of neurons from the peripheral nervous system. The effect of MT was firstly investigated in dorsal root ganglion (DRG) explants, where axons were scratch-injured in the presence or absence of exogenous MT. The application of MT led to a significant increase in regenerative sprouting of neurons 16 h after injury. We show that the pro-regenerative effect of MT involves an interaction with the low-density lipoprotein receptor megalin, which could be blocked using the competitive antagonist RAP. Pre-treatment with the mitogen-activated protein kinase (MAPK) inhibitor PD98059 also completely abrogated the effect of exogenous MT in promoting axonal outgrowth. Interestingly, we only observed megalin expression in neuronal soma and not axons in the DRG explants. To investigate this matter, an in vitro injury model was established using Campenot chambers, which allowed the application of MT selectively into either the axonal or cell body compartments after scratch injury was performed to axons. At 16 h after injury, regenerating axons were significantly longer only when exogenous MT was applied solely to the soma compartment, in accordance with the localized expression of megalin in neuronal cell bodies. This study provides a clear indication that MT promotes axonal regeneration of DRG neurons, via a megalin- and MAPK-dependent mechanism.