Review
White matter in learning, cognition and psychiatric disorders

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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.

Introduction

New findings together with experiments spanning 40 years are forcing a pivotal shift in views of white matter in the brain. White matter comprises over half the human brain, a far greater proportion than in other animals [1]. Only vertebrates have myelin (Figure 1), which greatly increases the speed and power of nervous system function [2]. Recently, unanticipated changes in myelin genes and alterations in white matter structure have been observed in a wide range of psychiatric disorders. Together with new data showing that white matter structure is dynamic and myelin can be regulated by impulse activity, these new findings implicate myelin in cognitive function beyond pathology, and illuminate an underappreciated role of myelin in information processing and learning.

This article considers evidence that white matter is involved in learning, information-processing, neurological and psychological disorders. It examines historical evidence and information from new techniques indicating that white matter changes with functional experience, and it explores the molecular mechanisms. It presents possible mechanisms for white matter effects on synaptic function and cognition, and it outlines unanswered questions and directions for future research.

Section snippets

White matter in cognition and mental illness

A surprisingly diverse range of psychiatric and nervous system disorders are accompanied by changes in white matter structure or abnormalities in myelin genes (see Box 1). Polymorphisms for several myelin genes have emerged as unexpected risk factors for schizophrenia 3, 4, depression [4] and obsessive-compulsive disorder [5]. Post mortem examination of brain tissue from patients suffering schizophrenia 4, 6, major depression [7] and bipolar disorder [4] reveals reduced abundance of several

Experience changes white matter

Myelination is a developmental process, but it has been known for decades that myelination of the human brain continues into the third decade of life [11], and this can now be tracked by noninvasive brain imaging [17]. However, the significance of this was not fully appreciated. If myelin is simply insulation, why is the process not completed by birth?

Myelination is nearly completed by birth in animals, such as horses [28] or wild mice (Acomys) [29], which are precocial and can walk and feed

Myelin in information processing

White matter plasticity in response to environmental experience is puzzling when viewed from the older perspective of myelin. Why should insulation on transmission lines change after neural computation that is carried out in gray matter? The emerging answer is that myelin controls the speed of impulse conduction through axons, and the synchrony of impulse traffic between distant cortical regions is critical for optimal mental performance and learning.

A central concept in synaptic plasticity

Activity-dependent myelination: cellular and molecular mechanisms

Evidence that impulse activity can affect myelination has been in the literature since the 1960s, from experiments rearing mice in the dark [81] or opening the eye of neonatal rabbits prematurely [82]. Rearing animals in the dark reduces the number of myelinated axons in optic nerve, and premature eye opening increases myelin protein expression. Electrical activity also promotes proliferation of oligodendrocyte progenitor cells in optic nerve [83] and, in cell culture, stimulating firing of

Future directions

The signals mediating activity-dependent communication between axons and oligodendrocytes, the developmental time course of activity-dependent effects and the cellular mechanisms that would regulate myelin to optimize conduction velocity are only beginning to be explored.

Is myelin plasticity strictly a change in the number of axons that become myelinated, or a change in the myelin sheath that would regulate impulse conduction speed? Current evidence best supports changes in the number of

Conclusions

Research from new techniques and recent insights into neuron–glial interactions [103] are providing a new perspective on studies of myelin plasticity that have been in the literature for decades. Myelin is not simply a developmental process; it continues for decades in humans; it is modifiable, and it is an important contributor to psychiatric disorders and other diseases affecting cognition.

White matter changes are associated with learning in people, but the extent to which these changes

Acknowledgements

Supported by funds for intramural research, NIH, NICHD.

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