Glial and neuronal control of brain blood flow.
TL;DR: It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles.
Abstract: Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches.
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TL;DR: The history of investigations into pericytes, the mural cells of blood microvessels, are reviewed, emerging concepts are indicated, and problems and promise are pointed out.
2,120 citations
Cites background from "Glial and neuronal control of brain..."
...For a detailed description of molecular pathways engaged in response to vasoactive molecules and neurotransmitters in a ‘‘generic’’ pericyte, leading to capillary constriction or dilation, the reader is referred to recent review articles on the topic (Attwell et al., 2010; Hamilton et al., 2010)....
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...This process, called functional hyperemia, is neurotransmitter mediated and occurs at the level of arterioles (reviewed in Attwell et al., 2010)....
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TL;DR: Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.
Abstract: Blood vessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of these barrier properties are an important component of pathology and progression of different neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of the blood vessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.
1,839 citations
Cites background from "Glial and neuronal control of brain..."
...This neurovascular coupling enables astrocytes to relay signals that regulate blood flow in response to neuronal activity (Attwell et al. 2010; Gordon et al. 2011)....
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TL;DR: This review focuses on the cellular aspects of brain energy metabolism, with a particular emphasis on the metabolic interactions between neurons and astrocytes.
1,678 citations
TL;DR: The development of an immunopanning method to acutely purify astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures is reported, finding that human astroCytes have abilities similar to those of murine astroicytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes.
1,593 citations
TL;DR: It is demonstrated that neuronal activity and the neurotransmitter glutamate evoke the release of messengers that dilate capillaries by actively relaxing pericytes, which are major regulators of cerebral blood flow and initiators of functional imaging signals.
Abstract: 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.
1,404 citations
References
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TL;DR: These findings suggest that the BOLD contrast mechanism reflects the input and intracortical processing of a given area rather than its spiking output, and that LFPs yield a better estimate of BOLD responses than the multi-unit responses.
Abstract: Functional magnetic resonance imaging (fMRI) is widely used to study the operational organization of the human brain, but the exact relationship between the measured fMRI signal and the underlying neural activity is unclear. Here we present simultaneous intracortical recordings of neural signals and fMRI responses. We compared local field potentials (LFPs), single- and multi-unit spiking activity with highly spatio-temporally resolved blood-oxygen-level-dependent (BOLD) fMRI responses from the visual cortex of monkeys. The largest magnitude changes were observed in LFPs, which at recording sites characterized by transient responses were the only signal that significantly correlated with the haemodynamic response. Linear systems analysis on a trialby-trial basis showed that the impulse response of the neurovascular system is both animal- and site-specific, and that LFPs yield a better estimate of BOLD responses than the multi-unit responses. These findings suggest that the BOLD contrast mechanism reflects the input and intracortical processing of a given area rather than its spiking output.
6,140 citations
TL;DR: The estimates of energy usage predict the use of distributed codes, with ≤15% of neurons simultaneously active, to reduce energy consumption and allow greater computing power from a fixed number of neurons.
Abstract: Anatomic and physiologic data are used to analyze the energy expenditure on different components of excitatory signaling in the grey matter of rodent brain. Action potentials and postsynaptic effects of glutamate are predicted to consume much of the energy (47% and 34%, respectively), with the resting potential consuming a smaller amount (13%), and glutamate recycling using only 3%. Energy usage depends strongly on action potential rate--an increase in activity of 1 action potential/cortical neuron/s will raise oxygen consumption by 145 mL/100 g grey matter/h. The energy expended on signaling is a large fraction of the total energy used by the brain; this favors the use of energy efficient neural codes and wiring patterns. Our estimates of energy usage predict the use of distributed codes, with
2,912 citations
TL;DR: Transient increases in neural activity cause a tissue uptake of glucose in excess of that consumed by oxidative metabolism, acutely consume much less energy than previously believed, and regulate local blood flow for purposes other than oxidative metabolism.
Abstract: Brain glucose uptake, oxygen metabolism, and blood flow in humans were measured with positron emission tomography, and a resting-state molar ratio of oxygen to glucose consumption of 4.1:1 was obtained. Physiological neural activity, however, increased glucose uptake and blood flow much more (51 and 50 percent, respectively) than oxygen consumption (5 percent) and produced a molar ratio for the increases of 0.4:1. Transient increases in neural activity cause a tissue uptake of glucose in excess of that consumed by oxidative metabolism, acutely consume much less energy than previously believed, and regulate local blood flow for purposes other than oxidative metabolism.
1,725 citations
TL;DR: In vivo blockade of glutamate-mediated [Ca2+]i elevations in astrocytes reduced the blood flow increase in the somatosensory cortex during contralateral forepaw stimulation and showed that neuron-to-astrocyte signaling is a key mechanism in functional hyperemia.
Abstract: The cellular mechanisms underlying functional hyperemia--the coupling of neuronal activation to cerebral blood vessel responses--are not yet known. Here we show in rat cortical slices that the dilation of arterioles triggered by neuronal activity is dependent on glutamate-mediated [Ca(2+)](i) oscillations in astrocytes. Inhibition of these Ca(2+) responses resulted in the impairment of activity-dependent vasodilation, whereas selective activation--by patch pipette--of single astrocytes that were in contact with arterioles triggered vessel relaxation. We also found that a cyclooxygenase product is centrally involved in this astrocyte-mediated control of arterioles. In vivo blockade of glutamate-mediated [Ca(2+)](i) elevations in astrocytes reduced the blood flow increase in the somatosensory cortex during contralateral forepaw stimulation. Taken together, our findings show that neuron-to-astrocyte signaling is a key mechanism in functional hyperemia.
1,409 citations
"Glial and neuronal control of brain..." refers background in this paper
...Extends, to the in vivo situation, the Zonta et al. (2003) result that astrocytes control cerebral blood flow....
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Journal Article•
1,358 citations