Increases in brain blood flow, evoked by neuronal activity, power neural computation and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. Whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes, is controversial. We demonstrate that neuronal activity and the neurotransmitter glutamate evoke the release of messengers that dilate capillaries by actively relaxing pericytes. Dilation is mediated by prostaglandin E2, but requires nitric oxide release to suppress vasoconstricting 20-HETE synthesis. In vivo, when sensory input increases blood flow, capillaries dilate before arterioles and are estimated to produce 84% of the blood flow increase. In pathology, ischaemia evokes capillary constriction by pericytes. We show that this is followed by pericyte death in rigor, which may irreversibly constrict capillaries and damage the blood-brain barrier. Thus, pericytes are major regulators of cerebral blood flow and initiators of functional imaging signals. Prevention of pericyte constriction and death may reduce the long-lasting blood flow decrease that damages neurons after stroke.

In the past 20 years, an extra layer of information processing, in addition to that provided by neurons, has been proposed for the CNS. Neuronally evoked increases of the intracellular calcium concentration in astrocytes have been suggested to trigger exocytotic release of the 'gliotransmitters' glutamate, ATP and D-serine. These are proposed to modulate neuronal excitability and transmitter release, and to have a role in diseases as diverse as stroke, epilepsy, schizophrenia, Alzheimer's disease and HIV infection. However, there is intense controversy about whether astrocytes can exocytose transmitters in vivo. Resolving this issue would considerably advance our understanding of brain function.

A defining feature of glial cells has been their inability to generate action potentials. We now show that there are two distinct types of morphologically identical oligodendrocyte precursor glial cell (OPC) in situ in rat CNS white matter. One type expresses voltage-gated sodium and potassium channels, generates action potentials when depolarized, and senses its environment by receiving excitatory and inhibitory synaptic input from axons. The other type lacks action potentials and synaptic input. We show that when OPCs suffer glutamate-mediated damage, as occurs in cerebral palsy, stroke and spinal cord injury, the action potential generating OPCs are preferentially damaged because they express more glutamate receptors and in ischaemia receive increased spontaneous glutamatergic synaptic input. These data challenge the idea that only neurons generate action potentials in the CNS, and imply that the development of therapies for demyelinating disorders will require defining which OPC type can perform remyelination.Oligodendrocyte precursor glia, which express1 the proteoglycan NG2, transform into myelinating oligodendrocytes during development2, but are also present in the adult CNS3 where they comprise ∼5% of the cells and are the main proliferating cell type4,5. Damage to oligodendrocyte precursors, leading to reduced myelination, contributes to mental and physical impairment in periventricular leukomalacia (pre-or perinatal white matter injury leading to cerebral palsy)6. Adult OPCs may form new myelinating oligodendrocytes in multiple sclerosis and spinal cord injury7-12, and OPC transplants could serve as a basis for therapeutic remyelination13. However, the functions of OPCs are poorly understood: they may simply become oligodendrocytes in normal development and constitute a reservoir of cells which replace damaged myelin in the adult CNS, but they might also differentiate into other cell types and thus have some stem cell characteristics14. Understanding the diversity of NG2-expressing OPCs is crucial for understanding normal brain function, for appreciating the diversity of the brain's progenitor cell population, and for developing therapeutic strategies to treat demyelinating diseases. Results Identification of oligodendrocyte precursor gliaIn the cerebellum of postnatal day 7 (P7) rats, cells expressing NG2 constitute 14.8 ± 1.2% (n=1850 cells) of the cells present in the white matter (Fig. 1a). Essentially all of these cells (93 ± 2%, excluding perivascular NG2 cells15) also labelled for the oligodendrocyte transcription factor Olig2 (Fig. 1b-d Fig. 1e-h). In some experiments, more rapid identification of NG2-expressing OPCs was attained by labelling the living slice with an antibody to an extracellular epitope of NG2, which decorated the surface of the OPCs, allowing subsequent whole-cell clamping (Fig 1i-k). For both identification methods, OPCs fell into two distinct electrophysiological classes. Two classes of oligodendrocyte precursor gliaOne class of OPCs (which we call I Na cells) exhibi...

Because regional blood flow increases in association with the increased metabolic demand generated by localized increases in neural activity, functional imaging researchers often assume that changes in blood flow are an accurate read-out of changes in underlying neural activity. An understanding of the mechanisms that link changes in neural activity to changes in blood flow is crucial for assessing the validity of this assumption, and for understanding the processes that can go wrong during disease states such as ischaemic stroke. Many studies have investigated the mechanisms of neurovascular regulation in arterioles but other evidence suggests that blood flow regulation can also occur in capillaries, because of the presence of contractile cells, pericytes, on the capillary wall. Here we review the evidence that pericytes can modulate capillary diameter in response to neuronal activity and assess the likely importance of neurovascular regulation at the capillary level for functional imaging experiments. We also discuss evidence suggesting that pericytes are particularly sensitive to damage during pathological insults such as ischaemia, Alzheimer's disease and diabetic retinopathy, and consider the potential impact that pericyte dysfunction might have on the development of therapeutic interventions and on the interpretation of functional imaging data in these disorders.

In the gray matter of the brain, astrocytes have been suggested to export lactate (derived from glucose or glycogen) to neurons to power their mitochondria. In the white matter, lactate can support axon function in conditions of energy deprivation, but it is not known whether lactate acts by preserving energy levels in axons or in oligodendrocytes, the myelinating processes of which are damaged rapidly in low energy conditions. Studies of cultured cells suggest that oligodendrocytes are the cell type in the brain that consumes lactate at the highest rate, in part to produce membrane lipids presumably for myelin. Here, we use pH imaging to show that oligodendrocytes in the white matter of the rat cerebellum and corpus callosum take up lactate via monocarboxylate transporters (MCTs), which we identify as MCT1 by confocal immunofluorescence and electron microscopy. Using cultured slices of developing cerebral cortex from mice in which oligodendrocyte lineage cells express GFP (green fluorescent protein) under the control of the Sox10 promoter, we show that a low glucose concentration reduces the number of oligodendrocyte lineage cells and myelination. Myelination is rescued when exogenous L-lactate is supplied. Thus, lactate can support oligodendrocyte development and myelination. In CNS diseases involving energy deprivation at times of myelination or remyelination, such as periventricular leukomalacia leading to cerebral palsy, stroke, and secondary ischemia after spinal cord injury, lactate transporters in oligodendrocytes may play an important role in minimizing the inhibition of myelination that occurs.