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.
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.
If “the connectome” represents a complete map of anatomical and functional connectivity in the brain, it should also include glia. Glia define and regulate both the brain’s anatomical and functional ...connectivity over a broad range of length scales, spanning the whole brain to subcellular domains of synaptic interactions. This Perspective article examines glial interactions with the neuronal connectome (including long-range networks, local circuits, and individual synaptic connections) and highlights opportunities for future research. Our understanding of the structure and function of the neuronal connectome would be incomplete without an understanding of how all types of glia contribute to neuronal connectivity and function, from single synapses to circuits.
Determining the brain’s connectome will require detailed analysis of non-neuronal cells (glia). The Perspective by Fields et al. examines how oligodendrocytes, astrocytes, and microglia define and regulate anatomical and functional connectivity of neurons from subcellular domains to long-distant networks.
White matter is the brain region underlying the gray matter cortex, composed of neuronal fibers coated with electrical insulation called myelin. Previously of interest in demyelinating diseases such ...as multiple sclerosis, myelin is attracting new interest as an unexpected contributor to a wide range of psychiatric disorders, including depression and schizophrenia. This is stimulating research into myelin involvement in normal cognitive function, learning and IQ. Myelination continues for decades in the human brain; it is modifiable by experience, and it affects information processing by regulating the velocity and synchrony of impulse conduction between distant cortical regions. Cell-culture studies have identified molecular mechanisms regulating myelination by electrical activity, and myelin also limits the critical period for learning through inhibitory proteins that suppress axon sprouting and synaptogenesis.
Formation of myelin, the electrical insulation on axons produced by oligodendrocytes, is controlled by complex cell-cell signaling that regulates oligodendrocyte development and myelin formation on ...appropriate axons. If electrical activity could stimulate myelin induction, then neurodevelopment and the speed of information transmission through circuits could be modified by neural activity. We find that release of glutamate from synaptic vesicles along axons of mouse dorsal root ganglion neurons in culture promotes myelin induction by stimulating formation of cholesterol-rich signaling domains between oligodendrocytes and axons, and increasing local synthesis of the major protein in the myelin sheath, myelin basic protein, through Fyn kinase-dependent signaling. This axon-oligodendrocyte signaling would promote myelination of electrically active axons to regulate neural development and function according to environmental experience.
Human brain imaging has identified structural changes in gray and white matter that occur with learning. However, ascribing imaging measures to underlying cellular and molecular events is ...challenging. Here we review human neuroimaging findings of structural plasticity and then discuss cellular and molecular level changes that could underlie observed imaging effects. Greater dialog between researchers in these different fields would help to facilitate cross-talk between cellular and systems level explanations of how learning sculpts brain structure.
Working memory is of great interest because of its importance in cognitive function, its relation to consciousness, and impairments in disease, but the cellular mechanisms remain elusive and ...controversial. A recent article by Barbosa and colleagues overturns the conclusions of an influential study by Wolff and colleagues, which concluded that working memory can be maintained in a hidden state by transient plasticity of synaptic connections that form dynamic ensembles of neurons encoding information temporarily. A reanalysis of the data reveals that there is a persistent electrically active signature in the EEG recordings that is sustained for the duration of the working memory. This reanalysis adds to a large body of evidence indicating that working memory is encoded by sustained action potential firing. However, several studies show that unconscious (unattended) working memories can be recalled even in the absence of measurable neural activity, suggesting that electrically silent mechanisms may be involved. Testing that hypothesis is problematic, given that it posits no neuronal firing that could be easily measured.
The role of the brain's white matter in active learning and memory may be underestimated.
“Gray matter” is only one of two types of brain tissue; the other “white matter” is rarely mentioned. Yet ...white matter makes up half the human brain and has not been thought to be important in cognition or learning outside the context of pathology. That view could change. Imaging and cellular and molecular studies are revealing white matter plasticity with possible implications for normal cognitive function and psychological disorders.
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