Download Feedback and feedforward control of blood flow

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,
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creases. SeveralDate
candidate
substances have been identified for the local control
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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
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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
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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.)
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“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
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