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Before hindlimb stimulation From Neuronal to Hemodynamic Activity 183 A1 A2 C B After hindlimb stimulation D A1 A2 C B D 50 mm 50 mm 50 mm Figure 6.17 The change in diameter of arterioles following sciatic (hindlimb) stimulation. Arterioles that perfuse the cortical region corresponding to the hindlimb of the rat (A1 and A2) increase in diameter. Nearby vessels (B) and those that perfuse the forepaw region (C and D) do not increase in diameter. (After Ngai et al., 1988.) have proliferated in the past decade, and have identified plausible mechanisms at several levels of control that we consider next. vasoactive substances Substances that change the diameter of blood vessels. Feedback and feedforward control of blood flow In their seminal work, Roy and Sherrington proposed that blood flow was regulated by the by-products of neuronal metabolism. In this feedback model, functionally specific changes in blood flow are initiated when active neurons release substances that diffuse through the extracellular space and reach nearby3eblood vessels. These vasoactive substances cause the vessels to dilate, Huettel fMRI, Sinauer Associates and because the increase in diameter reduces the vessels’ resistance, flow inHU3e06.17.ai Jun 26 2014 creases. SeveralDate candidate substances have been identified for the local control Version 5 Jen of blood flow. These include potassium ions (K+), which enter the extracellular space as a result of synaptic activity; adenosine, which is created during the dephosphorylation of ATP and which increases in concentration during times of high metabolic activity; and lactate, a by-product of anaerobic glycolysis. Indeed, many molecules are vasoactive; that is, they cause blood vessels to dilate or contract in laboratory preparations. For the conjecture of Roy and Sherrington to be validated, however, those or other vasoactive substances must play a role in controlling blood flow in the intact brain. By the late 1980s, researchers suggested that the feedback model proposed by Roy and Sherrington might require revision. The vasodilation caused by ©2014 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. 184 Chapter 6 acetylcholine (ACh) An important neurotransmitter used throughout the central and peripheral nervous systems and at the neuromuscular junction. Within the brain, ACh projections from certain cell groups in the basal forebrain may stimulate widespread changes in blood flow. noradrenaline (NA) Neurotransmitter used extensively in the central and peripheral nervous systems. Within the brain, NA projections from the locus coeruleus nuclei of the brain stem plays a role in a number of psychological processes, including attention and alertness. Also known as norepinephrine (NE). nuclei Anatomically discrete and identifiable clusters of neurons within the brain that typically serve a particular function. K+ and other by-products of synaptic activity was too slow to be a credible agent for neurovascular coupling, which argued for the necessity of a more rapid initiating process. In an alternative feedforward model, neurons would directly participate in the control of blood flow by influencing the properties of blood vessels, such as arterioles. It has long been known that larger cortical arteries are surrounded by intertwining processes arising from neurons, raising the possibility that some aspects of blood flow may be controlled by neurons themselves. For example, surface arteries receive extrinsic projections from peripheral nerve ganglia, and these projections surround the smooth muscles that encase the vessel. Studies have shown that the neurotransmitters released by these projections can dilate or constrict the vessel. This innervation of cerebral arteries probably plays a role in central autoregulation. Whether neurogenic control of blood flow at this far upstream level is related to functional hyperemia at the local neuronal level is doubtful. The innervation of arteries from peripheral nerves and sensory ganglia ends at the cortical surface and does not extend into the parenchyma among the intracortical arterioles and capillaries. However, extensive direct and indirect intrinsic neuronal innervation of intracortical vessels has been identified (Figure 6.18). For example, stimulation of cell groups in the basal forebrain that use acetylcholine (ACh) as a neurotransmitter causes widespread changes in blood flow. Stimulation dilates intracortical vessels within the gray matter, but not the upstream pial arteries on the surface of the brain. Moreover, anterograde tracers introduced into the basal forebrain cell bodies reveal that their terminals are located closely to intracortical arterioles. These results indicate two potential mechanisms by which neurons in the basal forebrain can influence intracortical blood flow either directly (through projections to the intracortical vessels) and indirectly (through GABA interneurons that themselves project to intracortical vessels). Other groups of subcortical cell bodies with widespread cortical projections are also known to influence vessel dilation and contraction. These areas (and their associated neurotransmitters) include the locus coeruleus (noradrenaline), the raphe nucleus (serotonin), and the ventral tegmental area (dopamine). The fact that neuromodulators such as acetylcholine, dopamine, serotonin, and noradrenaline influence CBF allows for the possibility that small clusters of neurons in the basal forebrain, ventral tegmentum, and brain stem can orchestrate blood flow, and thus the delivery of oxygen and glucose, widely in the brain. Let’s consider in more detail the example of noradrenaline (NA). Most NA in cerebral cortex comes from neurons located in two small bilateral clusters, or nuclei, in the brain stem. These nuclei have been named the locus coeruleus (LC) due to the bluish pigment of the neurons. Although containing relatively few neurons—only about 30,000 to 40,000 per hemisphere in humans—the LC sends unmyelinated axons widely throughout the cerebral cortex. LC-derived NA (LC-NA) plays a role in a number of psychological processes, including attention and alertness. Researchers have shown that LC-NA afferent terminals are closely apposed to astrocytes and blood vessels in cerebral cortex in a manner suggestive of volume transmission. Indeed, the astrocytic processes that are wrapped around intracortical arterioles and capillaries may be the target of many NA terminals. Researchers have shown that stimulating the LC generates Ca2+ waves in cortical astrocytes (see Figure 6.6), and that the application of an NA antagonist eliminates these Ca2+ transients. These and other results suggest that NA input can directly influence astrocytes, and can do so independently of local neuronal activity. Astrocytes therefore appear to be the final common mediator of LC-NA increases in CBF. However, other possible ©2014 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. From Neuronal to Hemodynamic Activity SCG SPG/OG TG Ganglia of the PNS (NOS, ACh) (VIP) (NPY) 185 (NA) (CGRP, SP) (5-HT, NKA, PACAP) “Extrinsic” neurons (PNS) Pial artery Arteriole Interneuron Astrocyte End-foot of astrocyte Capillaries Cerebral cortex: •Astrocytes •GABA interneurons (VIP, ACh, NOS, NPY, SOMs) •Neurovascular units Neurovascular unit (see Figure 6.20B) Subcortical areas: •Locus coeruleus (NA) •Raphe nuclei (5-HT) •Basal forebrain (ACh) •Thalamus (Glu) Figure 6.18 The different levels of neuronal control over the cerebral circulation. A major distinction is made between intrinsic innervation and extrinsic innervation. Extrinsic innervation is exerted by nerves originating in ganglia of the peripheral nervous system (PNS) and include both sympathetic (constriction) and parasympathetic (dilation) input. Sites of origin include the trigeminal (TG), sphenopalatine (SPG), otic (OG), and superior cervical (SCG) ganglia. These nerves innervate pial arteries on the cortical surface and use a variety of neurotransmitters (listed in parentheses) to constrict or dilate vessels. Extrinsic innervation plays an important role in central autoregulation and help maintain a constant flow of blood to the brain. Intrinsic innervation occurs within the brain’s parenchyma, where neural control is exerted by local interneurons and from subcortical neuronal cell groups. These subcortical cell groups make up the major neuromodulatory systems of the brain, including the locus coeruleus (noradrenaline, NA), the raphe nuclei (serotonin, 5-HT), and the basal forebrain (acetylcholine, ACh). ACh, acetylcholine; CGRP, calcitonin generelated peptide; GABA, γ-aminobutyric acid; NA, noradrenaline or norepinephrine; NKA, neurokinin-A; NOS, nitric oxide synthase; NPY, neuropeptide Y; PACAP, pituitary adenylate-cyclase activating polypeptide; SOM, somatostatin; SP, substance P; VIP, vasoactive intestinal polypeptide; 5-HT. (After Cipolla, 2009.) Huettel 3e HU3e06.18.ai ©2014 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher. “Intrinsic” neurons (CNS) 186 Chapter 6 Figure 6.19 Evidence of direct innervation of capillaries by dopaminergic neurons. (A) An electron micrograph that shows a large dopamine terminal (arrow) adjacent to a capillary. As can be seen in the light-microscopic inset, which shows a cross section of the same spatial location, the terminal lies along this capillary over a large spatial extent. (B) An enlargement of this dopamine terminal. The terminal is separated from the basal lamina (b) of the blood vessel by only a process from an adjacent pericyte (p), a cell with contractile properties. The inset in (C) shows a light-microscopic image depicting a string of three terminals adjacent to a capillary. The electron micrograph in (C), enlarged in (D), shows that one of the terminals is directly apposed to the basal lamina of the capillary. (From Krimer et al., 1998.) (A) (B) p p b b (C) (D) b p dopamine An important neurotransmitter that is produced within cells in the substantia nigra and ventral tegmentum that project broadly to the striatum and cortex (especially the frontal lobe). neurovascular unit A functional unit consisting of astrocytes and neurons that impinge on a local microvessel to control blood flow. functions for this NA input may exist, such as influencing the permeability of the blood–brain barrier or stimulating metabolic processes in astrocytes. The neurotransmitter dopamine also influences blood flow. Dopamine is produced by small clusters of midbrain neurons that project broadly to the striatum and cerebral cortex, and has historically been associated with facilitating motor movements and processing rewards. More recently, dopamine terminals have been found in apposition to small intracortical arterioles and capillaries, including adjacent to the pericytes that can constrict or dilate the capillary and thus influence local flow patterns (Figure 6.19). The time course of vasoactive changes evoked by dopamine release is slower than the change in the BOLD-contrast fMRI signal, which can peak 4 s to 5 s after the onset of a stimulus. However, these data raise the interesting possibility that intrinsic projections from small cell groups in the midbrain could influence blood flow independently of local neuronal activity, leading to long-duration changes in MRI signal that are maintained over many minutes. If convincingly demonstrated, this finding would suggest that the brain’s energy distribution is not driven entirely by the immediate metabolic needs of active neurons, but is instead more strategic and coordinated, perhaps to anticipate upcoming needs or to modulate a response to a stimulus. The neurovascular unit Local neuronal activity strongly influences local blood flow. The concept of the tripartite synapse introduced earlier in this chapter can now be extended to the concept of the neurovascular unit by including microvasculature elements like arterioles, capillaries, endothelial cells, and pericytes (Figure 6.20). The astrocyte extends protoplasmic processes that envelop synapses and other processes that cover intracortical arterioles and capillaries. The astrocyte Huettel 3e fMRI, Sinauer Associates HU3e02.01.ai Date Apr 03 2014 Version 4 Jen ©2014 Sinauer Associates, Inc. This material cannot be copied, reproduced, manufactured or disseminated in any form without express written permission from the publisher.