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Brain and Language xxx (2006) xxx–xxx
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The role of neuronal signaling in controlling cerebral blood Xow
Carrie T. Drake ¤, Costantino Iadecola
Department of Neurology and Neuroscience, Division of Neurobiology, Weill Medical College of Cornell University,
411 East 69th St., New York, NY 10128, USA
Accepted 1 August 2006
Abstract
Well-regulated blood Xow within the brain is vital to normal function. The brain’s requirement for suYcient blood Xow is ensured by
a tight link between neural activity and blood Xow. The link between regional synaptic activity and regional cerebral blood Xow, termed
functional hyperemia, is the basis for several modern imaging techniques that have revolutionized the study of human brain activity.
Here, we review the mechanisms of functional hyperemia and their implications for interpreting the blood oxygen level-dependent
(BOLD) contrast signal used in functional magnetic resonance imaging (fMRI).
© 2006 Elsevier Inc. All rights reserved.
Keywords: Functional hyperemia; Cerebral blood Xow; Neurovascular unit; BOLD
1. Introduction
Although it is only 2% of total body weight, the brain
uses 20% of the total energy consumed by the body
(SokoloV, 1989). Well-regulated blood Xow within the brain
is vital to maintain energy-dependent processes and to clear
metabolic byproducts produced by neuronal activity, such
as CO2, excess lactate, other metabolites and heat. The
dependence of the brain on blood Xow is highlighted by the
fact that even relatively small reductions in cerebral blood
Xow (CBF) can have deleterious eVects on the brain. SpeciWcally, a 20% reduction in CBF inhibits cerebral protein
synthesis (Hossmann, 1994). A 50% CBF reduction leads to
extracellular accumulation of glutamate and lactate, and
water shift from intra- to extra-cellular compartments
(Hossmann, 1994). CBF reductions greater than 50%
impair ATP synthesis and decrease the ability of neurons to
Wre action potentials. If Xow is reduced by 80%, neurons
lose ionic gradients, a process termed anoxic depolarization, and undergo irreversible damage (Hossmann, 1994).
*
Corresponding author. Fax: +1 212 988 3672.
E-mail address: [email protected] (C.T. Drake).
Thus, even small reductions in CBF negatively aVect neuronal function, and large CBF reductions, such as are seen in
cerebral ischemia, can produce massive damage to the
brain. Moreover, cerebrovascular dysregulation is associated with Alzheimer’s disease and other neurodegenerative
conditions (see (Iadecola, 2004) for review).
The brain’s requirement for suYcient blood Xow is
ensured by a tight link between neural activity and blood
Xow. This link between regional synaptic activity and
regional CBF, termed functional hyperemia, is the basis for
several modern imaging techniques that have revolutionized the study of human brain activity (Logothetis & Wandell, 2004; Raichle, 1998). Here, we review the mechanisms
of functional hyperemia and their implications for interpreting functional magnetic resonance imaging (fMRI)
data.
1.1. Neuroanatomical basis of functional hyperemia: the
neurovascular unit
In both normal and injury conditions, neurons, glia and
blood vessels exhibit a close anatomical and functional
coupling (del Zoppo & Mabuchi, 2003; Woolsey et al.,
1996). These cells can be considered a functional entity,
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Please cite this article as: Carrie T. Drake, Costantino Iadecola, The role of neuronal signaling in controlling cerebral blood Xow, Brain
and Language (2006), doi:10.1016/j.bandl.2006.08.002
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C.T. Drake, C. Iadecola / Brain and Language xxx (2006) xxx–xxx
termed the neurovascular unit (Lo, Dalkara, & Moskowitz,
2003). As shown in Fig. 1, the cellular constituents of the
neurovascular unit vary with the type, size and location of
blood vessels.
On the surface of the brain, large cerebral arteries give
rise to smaller arteries and arterioles known as pial arteries
(Jones, 1970). Pial arteries are composed of an endothelial
cell layer, a smooth muscle cell layer and an outer layer of
leptomeningeal cells (adventitia), which is separated from
the brain by the Virchow-Robin space (Peters, Palay, &
Webster, 1991). Pial arteries are densely innervated by perivascular nerves that originate from autonomic and sensory
ganglia, mainly the sphenopalatine, trigeminal and superior
cervical ganglia (Edvinsson & Hamel, 2002). These nerves
contain several neurotransmitters and neuropeptides that
can either constrict or dilate arteries and arterioles (Edvinsson & Hamel, 2002). Because of the diVuse nature of the
innervation and the relatively large size of the vessels innervated, perivascular innervation by peripheral autonomic
nerves is unlikely to play a role in the highly localized
changes in Xow initiated by functional brain activity.
Rather, these neurons are likely to modulate global
increases in CBF that occur during epileptic seizures,
hypertension, or following transient interruption of CBF
(Iadecola, 1998).
As pial arteries and arterioles penetrate deeper into the
brain parenchyma, they are still separated from the substance of the brain by a virtual space (the Virchow-Robin
space) (Fig. 1). However, recent work (Takano et al.,
2006) has shown that arterioles are closely associated with
astrocytic end-feet, which can inXuence arteriole diameter. Cerebral endothelial cells are specialized to form the
blood–brain barrier: they lack fenestrations and are connected by small adhesions known as tight junctions.
Endothelial cells are further connected by gap junctions,
which allow transmission of intracellular responses
between adjacent cells (Segal, 2000; Sokoya et al., 2006).
Endothelial cells can release a variety of vasoactive
Virchow-Robin space
Perivascular
nerves
Smooth
muscle
cells
Smooth
muscle
cell
Central
neuron
Endothelial
cell
Pial artery
Glial
end-foot
Interneuron
Intraparenchymal arteriole
Glial end-feet
Central neuron
Glial
end-foot
Projections from:
Locus coeruleus
Raphe
Ventral tegmental area
Nucleus basalis
Interneuron
Pericyte
Capillary
Fig. 1. The neurovascular unit consists of functionally coupled neurons, glia, smooth muscle cells and endothelial cells. Its cellular constituents vary with
the type, size and location of blood vessels. Cross-sections (dashed lines) are shown for pial arteries, intraparenchymal arterioles, and capillaries. Notably,
innervation of pial arteries is provided by peripheral nerves, while arterioles and capillaries are innervated by central neurons (local interneurons and projection neurons) and are closely apposed by glial end-feet.
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substances (Busse & Fleming, 2003). These include the
vasodilators nitric oxide, reactive oxygen species (which
can cause vascular dysregulation at high concentrations
(Faraci & Heistad, 1998)) prostacyclin, and endotheliumderived hyperpolarizing factor, and the vasoconstrictors
endothelin and endothelium-derived constrictor factor
(Faraci & Heistad, 1998; Golding, Marrelli, You, &
Bryan, 2002). In addition, carbon monoxide, possibly
derived from the endothelium, has been proposed to produce vasodilation in the piglet cerebral microcirculation
(Kanu, WhitWeld, & LeZer, 2006). Astrocytes also can
release a factor derived from lipoxygenase metabolism
that produces endothelium-dependent relaxation of cerebral arteries (Murphy, Rich, Orgren, Moore, & Faraci,
1994). The Wnal targets of these vasoactive substances,
whether released from endothelial cells, astrocytes, or
neurons, are the smooth muscle cells and pericytes. Studies in the retinal microcirculation suggest that pericytes
respond to vasoactive signals by constricting or relaxing
to alter vascular diameter (Kawamura et al., 2003; Wu,
Kawamura, Sakagami, Kobayashi, & Puro, 2003).
Smooth muscle cells also respond directly to increased
intravascular pressure with constriction (Prewitt, Rice, &
Dobrian, 2002). This property allows smooth muscle cells
to counter pressure-induced changes in the rate of blood
Xow, and contributes to the ability of cerebral blood vessels to maintain Xow in the face of changes in arterial
pressure (cerebrovascular autoregulation). Additionally,
gap junctions between smooth muscle cells facilitate propagation of vascular signals along the vessel (Kawamura
et al., 2003; Lagaud, Karicheti, Knot, Christ, & Laher,
2002).
As vessels penetrate deeper into the brain, the Virchow-Robin space is no longer found and vessels become
intraparenchymal arterioles and capillaries. At this level
the vascular basal lamina, and to a lesser extent smooth
muscle cells and pericytes, directly contact neural processes and astrocytic end-feet (Cohen, Bonvento,
Lacombe, & Hamel, 1996; Rennels & Nelson, 1975)
(Fig. 1). Intracerebral arterioles and capillaries are likely
to be involved in the local regulation of microvascular
Xow, and chemical signals to these vessels from astrocytes
and neurons are important inXuences on local Xow.
Astrocytic end-feet occupy a much greater proportion of
the vascular surface than do neural processes (Jones,
1970; Maynard, Schultz, & Pease, 1957), and evidence has
emerged for a direct role of astrocytes in inXuencing vascular diameter (Hirase, 2005; Mulligan & MacVicar,
2004; Zonta & Angulo et al., 2003a). Neuronal processes
that contact intraparenchymal blood vessels originate
from local interneurons or from neurons whose cell
bodies are located in subcortical regions and project to
neocortex (Fig. 1). To date, subcortical regions known to
contribute to cortical perivascular innervation include
the basal forebrain, raphe, ventral tegmental area and
locus coeruleus (Van Lieshout, Wieling, Karemaker, &
Secher, 2003).
3
Thus, the close anatomical and functional associations
between microvessels, neurons, and astrocytes in the brain
suggest the importance of conceptualizing them as a neurovascular unit. The ability of this unit to regulate CBF
involves several types of interactions between all of the
components.
2. Mechanisms of functional hyperemia
2.1. DiVusion of synaptically released neurotransmitters
More than a century ago, Roy and Sherrington (Roy &
Sherrington, 1890) proposed that working neurons release
vasoactive agents in the extracellular space, and these
agents reach blood vessels by diVusion and produce relaxation of vascular smooth muscles. Considerable evidence has
since accumulated supporting vasoactive consequences of
neurotransmitter release, in particular for the synaptically
released fast transmitters glutamate and GABA, but the
mechanisms are far more complex and indirect than simple
diVusion to vascular targets.
2.1.1. Glutamate
There is substantial evidence from studies of cerebellum,
hippocampus and neocortex that glutamate inXuences
blood Xow. In cerebellar cortex, the Purkinje cells, which
are the only cerebellar output neurons, receive their major
excitatory synaptic inputs from parallel Wbers and climbing
Wbers. The parallel Wbers are known to be glutamatergic
(Ito, 1991), and the climbing Wbers utilize an excitatory
amino acid such as glutamate, aspartate or N-acetyl-aspartyl-glutamate (Ross, Bredt, & Snyder, 1990). Focal activation of these excitatory inputs leads to an increased blood
Xow that is blocked by antagonists at non-NMDA-type
glutamate receptors, and is mimicked by exogenous glutamate application (Yang & Iadecola, 1996; Yang & Iadecola, 1997) . Glutamate also has vasodilatory actions in
neocortical and hippocampal slice preparations. Exogenous
glutamate or selective glutamate receptor agonists dilate
pial arterioles and/or precapillary microvessels. In contrast
to cerebellum, this eVect in hippocampus and neocortex
does involve NMDA-type glutamate receptors (Fergus &
Lee, 1997a; Lovick, Brown, & Key, 1999).
Glutamate does not act directly on smooth muscle cells
to produce vasodilation (Faraci & Breese, 1993). Rather,
this neurotransmitter increases CBF by inducing the release
of vasoactive factors from other cells through several calcium-dependent mechanisms (Fig. 2). In all brain areas
studied, the vasoactive actions of glutamate are attenuated
by blocking nitric oxide synthase (NOS) (Akgören, Fabricius, & Lauritzen, 1994; Faraci & Breese, 1993; Fergus &
Lee, 1997a; Li & Iadecola, 1994; Lovick et al., 1999; Yang,
Chen, Ebner, & Iadecola, 1999) or in NOS null mice (Yang,
Zhang, Ross, & Iadecola, 2003). Neuronal NOS (NOS I) is
present in neurons and glia, and is the synthetic enzyme for
nitric oxide (NO), a potent vasodilator that is released during synaptic activity (Strijbos, 1998). Several region-speciWc
Please cite this article as: Carrie T. Drake, Costantino Iadecola, The role of neuronal signaling in controlling cerebral blood Xow, Brain
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C.T. Drake, C. Iadecola / Brain and Language xxx (2006) xxx–xxx
NOS
COX-2
Ca++
ATP
Glu
Ado
GJ
Glu
mGluR
K+ H+
NO
PGs
Ado
Ca++ waves
Ca++
Ca++
PGs
COX-2
Central neuron
EETs
P450
ATP
Ado
K+ siphoning
NO
GABA
5HT
NE
ACh
DA
SP
NT
VIP
SOM
NPY
Fig. 2. Neuronal activity releases vasoactive mediators. Glutamate (Glu) increases the intracellular concentration of Ca++ in neurons and glia, which activates the synthesis of nitric oxide (NO) from NO synthase (NOS), prostaglandins (PGs) from cyclooxygenase-2 (COX-2), and epoxyeicosatrienoic acids
(EETs) from cytochrome P450 epoxygenase. Calcium elevations in astrocytes are produced by activation of metabotropic glutamate receptors (mGluRs)
and by propagation of Ca++ waves from adjacent astrocytes via gap junctions (GJ). Neurons release H+ and K+ ions during synaptic transmission and
astrocytes release K+ (K+ siphoning) from perivascular end-feet during spatial buVering. Neurovascular terminals originating from cortical aVerents and
local interneurons release vasoactive neurotransmitters and neuromodulators including NO, GABA, serotonin (5-HT), norepinephrine (NE), acetylcholine (ACh), dopamine (DA), substance P (SP), neurotensin (NT), vasoactive intestinal peptide (VIP), somatostatin (SOM), and neuropeptide Y (NPY).
eVects of glutamate are also seen. In cerebellum, pharmacological and genetic studies have shown that NOS-dependent CBF increases are responsible for the vast majority of
the response to functional activation (Li & Iadecola, 1994;
Yang et al., 1999; Yang et al., 2003), whereas in somatosensory cortex, NOS-related mechanisms are less prominent
(Lindauer, Megow, Matsuda, & Dirnagl, 1999). Cyclooxygenase-2 (COX-2), an enzyme that synthesizes prostaglandins from arachidonic acid and is associated with
glutamatergic synapses (Kaufmann, Worley, Pegg, Bremer,
& Isakson, 1996), is also involved in the regulation of CBF
during synaptic activity (Niwa, Araki, Morham, Ross, &
Iadecola, 2000). In neocortex, glutamate-induced increases
in intracellular calcium also activate the synthesis of
epoxyeicosatrienoic acids from cytochrome P450 epoxygenase (Alkayed et al., 1997).
Recent evidence suggests a prominent role for astrocytes
in glutamate-mediated vasoactivity. Astrocytes are known
to possess metabotropic glutamate receptors (mGluRs) and
to respond to glutamate with a transient increase in intracellular Ca++ that spreads to more distant portions of the
cell (Kang, Jiang, Goldman, & Nedergaard, 1998; Pasti,
Volterra, Pozzan, & Carmignoto, 1997; Porter & McCar-
thy, 1996). Zonta et al. (Zonta & Angulo et al., 2003a)
found that in somatosensory cortex slices, neuronal activity
or certain subtype-selective mGluR agonists trigger astrocytic Ca++ waves that correspond temporally with activityinduced vasodilation of local arterioles. Antagonism of the
same mGluR subtypes diminishes astrocytic Ca++ waves
without aVecting neurons, and direct stimulation of individual astrocytes produces rapid vasodilation of nearby
arterioles. The astrocytic eVect is largely dependent on a
COX product, perhaps the powerful vasodilator prostaglandin E2, which is released from somatosensory cortical
astrocytes by Ca++ waves (Zonta & Sebelin et al., 2003b). It
was suggested that synaptically released glutamate spills
over from the synapse and activates nearby astrocytes; if
the resulting intracellular Ca++ wave is suYcient to reach
an end-foot contacting a microvessel, vasodilation will
occur (Zonta & Angulo et al., 2003a). On the other hand,
others have shown that increases in Ca++ in astrocytes produce vasoconstriction rather than vasodilation by releasing
P450 metabolites (Mulligan & MacVicar, 2004). The discrepancy could be explained by the fact that Zonta et al.
preconstricted the vessels in the slice with L-NAME, a
blocker of NO synthesis (Zonta & Angulo et al., 2003a).
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Although the observed eVects in slices may not completely
mimic in vivo responses, given the limitations inherent in
the slice model, these studies clearly show that glutamate
can have direct eVects on astrocytes that inXuence vascular
tone.
2.1.2. GABA
Exogenous GABA, acting via GABAA receptors, dilates
precapillary microvessels in hippocampus and neocortex
(Fergus & Lee, 1997b). Furthermore, local neurons mediate
the neocortical vasodilation resulting from cerebellar stimulation (Iadecola, Arneric, Baker, Tucker, & Reis, 1987).
However, in the cerebellar cortex itself GABA is not
involved in activation-induced increases in Xow (Li & Iadecola, 1994; Mathiesen, Caesar, Akgoren, & Lauritzen,
1998). The vasoactive eVects of GABA in the forebrain are
interesting in light of continued controversy over whether
inhibitory neurotransmission contributes to brain energy
use or to functional imaging signals. In cerebral cortex,
GABAergic interneurons substantially innervate microvessels, suggesting they may act as integrators of local vascular
responses (Vaucher, Tong, Cholet, Lantin, & Hamel, 2000).
Interestingly, some GABAergic interneurons also contain
NOS (Cauli et al., 2004), and NOS-containing neurons are
known to contact large cerebral arteries and microvessels
(Estrada & De, 1998; Iadecola et al., 1993)
2.1.3. Other vasoactive mediators released by neural activity
During neurotransmission, potassium ions are released
during neuronal repolarization and astrocytic spatial buVering; the latter process particularly involves perivascular endfeet, where K+ conductance is greatest (Iadecola, Li, Yang, &
Xu, 1996). Activity-evoked rises in extracellular K+ have
been shown to moderately increase blood Xow (Caesar,
Akgoren, Mathiesen, & Lauritzen, 1999; Iadecola & Kraig,
1991), an eVect in part mediated by NO (Dreier et al., 1995).
Neural activity also produces extracellular increases in
hydrogen ions, as well as in adenosine produced by ATP
catabolism (IliV, D’Ambrosio, Ngai, & Winn, 2003).
2.2. Vascular and glial innervation
In addition to diVusion of synaptically released vasoactive agents, central neurons could inXuence vascular tone
through direct contacts with arterioles, capillaries, and perivascular glial processes (Fig. 2). These neurons contain neuromodulators and neuropeptides, which contrast with
GABA and glutamate in that they can be released from
non-synaptic portions of the neuron to act on nearby cellular targets. The neuromodulators identiWed in terminals
forming perivascular contacts have been shown to inXuence
vascular diameter to regulate CBF, suggesting important
roles in controlling blood Xow in the normal brain.
Many studies have suggested vasoactive roles for monoaminergic and cholinergic neurons in the brain. Serotonergic axons and terminals contact parenchymal microvessels
(Reinhard, Liebmann, Schlosberg, & Moskowitz, 1979).
5
These neurons originate in the brainstem raphe and project
diVusely throughout the brain. Serotonin has a pronounced
vasoconstrictor eVect, although it can be vasodilatory
under some conditions. This dual eVect is consistent with
the complex distribution of serotonin receptors to both
neurons and astrocytes, the large number of serotonin
receptor subtypes, and the demonstrated ability of serotonin to aVect vessels directly as well as indirectly through
astrocytes (Cohen et al., 1996). Norepinephrine-containing
terminals from locus coeruleus contact scattered cortical
microvessels (Cohen, Molinatti, & Hamel, 1997; Raichle,
Hartman, Eichling, & Sharpe, 1975), particularly capillaries
(Cohen et al., 1997), and norepinephrine applied in vivo
produces vasoconstriction and a reduced CBF (Raichle
et al., 1975). These terminals more frequently contact astrocytic end-feet that are associated with microvessels (Cohen
et al., 1997; Paspalas & Papadopoulos, 1996). The functional relevance of this association is suggested by recent
evidence that norepinephrine can produce vasoconstriction
that is tightly associated with direct norepinephrineinduced eVects on astrocytes (Mulligan & MacVicar, 2004).
Dopaminergic projections from ventral tegmental area contact penetrating arterioles and cerebral capillaries in cerebral cortex. These aVerents terminate either directly on the
vascular basal lamina or on perivascular astrocytic endfeet, or are near capillary pericytes (Krimer, Muly, Williams, & Goldman-Rakic, 1998). In cortical slice preparations, iontophoretic microapplication of dopamine near
cerebral microvessels produces vasoconstriction in approximately 50% of the microvessels studied (Krimer et al.,
1998). Similarly, in isolated cerebral arteries and in pial
arterioles in situ, dopamine produces vasoconstriction
(Sharkey & McCulloch, 1986). Finally, axons and terminals
containing choline acetyl transferase, the acetylcholine synthetic enzyme, are apposed to the basal laminae of capillaries and small arterioles, and to capillary endothelial cells
(Arneric et al., 1988; Parnavelas, Kelley, & Burnstock,
1985). Neurons in the basal forebrain are a major source of
this cholinergic perivascular innervation, which is particularly prominent in cerebral cortex (Arneric, 1989; Arneric
et al., 1988). The functional signiWcance of cholinergic
innervation is suggested by Wndings that stimulation of
basal forebrain neurons produces vasodilation and
increases blood Xow in the cerebral cortex (reviewed in
(Sato & Sato, 1992)). This increase in CBF is not associated
with increased cortical energy metabolism (Sato & Sato,
1992) and is likely to involve production of NO in endothelial cells (Zhang, Xu, & Iadecola, 1995). More recently, evidence has also emerged for direct actions of acetylcholine
on pericytes in retinal microvessels (Wu et al., 2003).
Additionally, several types of neuropeptide-containing
terminals have been found to make perivascular associations. For example, the brainstem parabrachial nuclei contain substance P and neurotensin in perivascular processes
(Milner & Pickel, 1986a, 1986b). Vasoactive intestinal peptide
(VIP) is in perivascular terminals in cortex (Paspalas &
Papadopoulos, 1998), and application of VIP dilates cortical
Please cite this article as: Carrie T. Drake, Costantino Iadecola, The role of neuronal signaling in controlling cerebral blood Xow, Brain
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vessels (Yaksh, Wang, & Go, 1987). Moreover, stimulation
of individual cortical GABAergic neurons containing VIP
and NOS produces local vasodilation, and vasodilation can
be evoked by application of VIP to slices (Cauli et al., 2004).
Somatostatin and neuropeptide Y (NPY) appear to play the
opposite role: vasoconstriction is produced following exogenous application of either peptide (Cauli et al., 2004; Long,
Rigamonti, Dosaka, Kraimer, & Martinez-Arizala, 1992) or
by stimulation of individual GABAergic somatostatin-containing neurons (Cauli et al., 2004). In addition to microvessels, some major cerebral arteries are surrounded by
perivascular NPY-containing terminals, and constrict in
response to NPY application (Tuor, Kelly, Edvinsson, &
McCulloch, 1990). However, it must be noted that the vasoactive eVects of neurotransmitters and neuropeptides vary in
diVerent animal species (Faraci & Heistad, 1998). Therefore,
the species needs to be taken into account in the interpretation of their physiological eVect.
The function of the innervation of intracerebral microvessels has been debated extensively (Edvinsson & Hamel,
2002). One possible function of neuromodulatory innervation of blood vessels may be to focus the vascular response
to regions experiencing neural activity. That is, when local
Xow increases, more distant pial arteries that supply the activated region must also increase Xow. This raises the possibility of increasing Xow in other microvessels supplied by the
arteries. In order to restrict the increase in Xow to the area of
increased activity, microvascular adjustments involving
both the activated area and surrounding areas must be
made. Although there is certainly a role for intravascular
control of upstream blood supply (see below), it is possible
that perivascular neuromodulators also play a role. Additionally, as has been suggested (Krimer et al., 1998; Raichle
et al., 1975), innervation of endothelial cells could modulate
the transfer of substances across the blood–brain barrier.
2.3. Energy deWcit as the stimulus for functional hyperemia
Increases in CBF have been correlated with local energy
use during activity, although the extent to which energy deWcit drives the increase in CBF is still a subject of active
inquiry (see reviews by (Attwell & Laughlin, 2001; Shulman,
Rothman, Behar, & Hyder, 2004)). Certainly, understanding
functional hyperemia requires addressing how the brain uses
energy, and which processes are most energy demanding.
This question has been recently addressed by several studies.
Attwell and Laughlin (Attwell & Laughlin, 2001) used a
“bottom-up” approach in which speciWc cellular functions
were given an energy cost based on published data, and then
summed up to construct an “energy budget” for the rodent
and primate brain. The results of this analysis (Fig. 3) indicate that over 80% of the energy in the primate brain is used
for processes related to glutamate signaling at synapses, a
conclusion also reached by Ames (Ames, 2000) and Shulman and colleagues (Sibson et al., 1998).
The energy used by inhibition has remained controversial. Some reports suggest that inhibitory synapses use less
energy than excitatory synapses (Waldvogel et al., 2000),
while others have noted that increased glucose usage was
associated with inhibition of hippocampal pyramidal and
auditory cells (Ackermann, Finch, Babb, & Engel, 1984;
Nudo & Masterton, 1986). Although the ion Xuxes that
generate resting and action potentials are the same in inhibitory neurons and excitatory neurons, the electrochemical
gradient down which Cl¡ moves postsynaptically at inhibitory synapses is less than that down which Na+ moves at
excitatory synapses, implying less energy expenditure to
pump the ions back. Furthermore, cortical inhibitory neurons and synapses are only one tenth as numerous as excitatory neurons (Abeles, 1991; Braitenberg & Schuz, 1998).
Most of the energy used by the brain derives from oxidative metabolism. Energy can also be produced, albeit less
eYciently, by the anaerobic metabolism of glucose or glycolysis. The telltale sign of glycolysis is lactate production,
which increases with activation (Frahm, Kruger, Merboldt,
& Kleinschmidt, 1996; Prichard et al., 1991; Ueki, Linn, &
Hossmann, 1988). Why does the brain need to use glycolysis? Gusnard and Raichle (Gusnard & Raichle, 2001) have
recently examined this issue. One possibility is that, because
glycolysis generates energy faster than glucose oxidation,
the rapid increase in energy demands at the onset of activation is best met by anaerobic metabolism of glucose
released from glycogen. With sustained activation, the
increase in CBF has time to develop fully, resulting in an
increase in the tissue delivery of oxygen and glucose. At this
point the energy metabolism switches from anaerobic to
aerobic glucose metabolism. This view is supported by the
following observations. First, brain activation increases the
utilization of glycogen, which in brain is present mainly in
glial cells (Brown, Tekkok, & Ransom, 2003; Swanson,
Morton, Sagar, & Sharp, 1992). Second, during sustained
activation lactate production is maximal at the onset of
activation and then decreases with time (Prichard et al.,
1991). Third, oxygen consumption increases only minimally
at the onset of activation and then rises progressively as the
activation continues (Fox & Raichle, 1986; Fox, Raichle,
Mintun, & Dence, 1988; Mintun, Vlassenko, Shulman, &
Snyder, 2002). Thus, it would seem that the brain uses
anaerobic glycolysis at the onset of activation and, if energy
demands are sustained, oxidative metabolism.
Magistretti and colleagues have proposed a model that
Wts well with the idea of a shift between anaerobic and aerobic glucose metabolism during activation (Magistretti, Pellerin, Rothman, & Shulman, 1999; Pellerin & Magistretti,
2003). Glutamate released during synaptic activity is taken
up by astrocytes through speciWc glutamate transporters
(GT), GLAST and GLT-1, coupled to Na+, so that for each
glutamate transported 3 Na+ enter the cell (Fig. 3). To reestablish the ionic gradient, Na+ is pumped out of the cell by
activation of the Na/K ATPase, which is fueled by glycolytically derived ATP. The lactate so produced is passed on to
neurons that metabolize it aerobically, generating ATP. ATP
is then used to fuel the ion pumps that reestablish ionic gradients after depolarization. Therefore, it is conceivable that the
Please cite this article as: Carrie T. Drake, Costantino Iadecola, The role of neuronal signaling in controlling cerebral blood Xow, Brain
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C.T. Drake, C. Iadecola / Brain and Language xxx (2006) xxx–xxx
7
tate shuttle” idea remains a useful working hypothesis that
Wts well with the available data on glucose-oxygen coupling
in the activated brain.
A recent study indicates that NADH, produced during
energy metabolism by transfer of electrons and protons from
glucose to cytosolic free NAD(+), augments blood Xow (Ido,
Chang, & Williamson, 2004). In retina and visual cortex of
rats, visual stimulation produces an elevated blood Xow that
is enhanced by the injection of lactate and diminished by
injection of pyruvate. This photostimulation-induced Xow is
prevented by inhibition of NOS. The authors suggest that
lactate provided additional electrons and protons for transfer
to NAD(+), converting it to NADH, while pyruvate received
transferred electrons and protons from NADH, converting it
to NAD(+). These data led to the suggestion that cytosolic
free NADH fuels a signaling cascade that increases nitric
oxide production, which in turn augments blood Xow in
photostimulated retina and visual cortex. The signiWcance
and generality of this Wnding is still unclear.
increase in lactate observed at the onset of activation is
derived from astroglial glycolysis. The subsequent reduction
in lactate and rise in oxygen consumption reXects the aerobic
metabolism of lactate by neurons. This hypothesis, which has
generated considerable interest and controversy (Chih &
Roberts, 2003; Pellerin & Magistretti, 2003), is supported by
a growing body of evidence indicating that: (1) glutamate
stimulates anaerobic glycolysis in astrocyte cultures leading
to lactate release into the medium (Pellerin & Magistretti,
1994; Takahashi, Driscoll, Law, & SokoloV, 1995); (2) neurons and astrocytes in culture have the potential of metabolizing both glucose and lactate, but neurons prefer
extracellular lactate and astrocytes favor glucose (BouzierSore, Voisin, Canioni, Magistretti, & Pellerin, 2003; Itoh
et al., 2003); (3) MCT2, the monocarboxylic acid transporter
that carries lactate, is preferentially located in neurons
(Pierre, Magistretti, & Pellerin, 2002); (4) downregulation of
glial glutamate transporters attenuates cerebral glucose utilization (Cholet et al., 2001; Voutsinos-Porche et al., 2003).
Because the critical evidence supporting the astrocytes-toneurons lactate shuttle hypothesis is based on in vitro experiments, the biological relevance of the model has been questioned (Chih & Roberts, 2003). Therefore, there is a need for
in vivo evidence supporting the cellular compartmentalization of these metabolic processes. In the meantime, the “lac-
2.4. Propagation of responses along cerebral blood vessels
During functional hyperemia, local vasodilation
increases Xow most eVectively if the upstream arterioles
also dilate (Duling et al., 1987). This has been observed in
Resting potential
2%
Na+
K+
Astrocyte
6%
lactate
glycolysis
ATP
Glu
Action potentials
10%
K+
Na+
Glutamine
Glu
K+
K+
MCAT2
lactate+O2
Na+
Presynaptic
7%
ATP
Ca++
Na+
Na+
Postsynaptic
75%
Fig. 3. Energy budget of the brain. The predicted expenditure of energy by gray matter in the primate brain. Postsynaptic processes make up the majority
of energy use. Action potentials and neurotransmitter release use approximately 17% of the energy, while maintaining the resting potential uses 2%. The
activity of astrocytes uses about 6%. The ion pumps (Na+/K+ and Na+/Ca++) are shown to indicate that most signaling energy is used to restore transmembrane ionic gradients.
Please cite this article as: Carrie T. Drake, Costantino Iadecola, The role of neuronal signaling in controlling cerebral blood Xow, Brain
and Language (2006), doi:10.1016/j.bandl.2006.08.002
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C.T. Drake, C. Iadecola / Brain and Language xxx (2006) xxx–xxx
several brain areas, for example, activation of whisker barrel cortex increases vascular diameter in pial arterioles that
are several hundred micrometers away from the site of activation (Cox, Woolsey, & Rovainen, 1993; Erinjeri & Woolsey, 2002; Ngai, Ko, Morii, & Winn, 1988). In cerebellum,
direct electrical stimulation of parallel Wbers increases vascular diameter of local arterioles and of the upstream
branches from which these arterioles originate (Iadecola,
Yang, Ebner, & Cheng, 1997).
Several possible mechanisms have been proposed for
controlling upstream vasodilation, including widespread
neurovascular innervation and “intramural” signaling
within the vascular wall. The former possibility seems
increasingly unlikely: the main innervation of larger pial
arterioles originates from outside the brain (Fig. 1), and is
not well linked to the localized neural pathways involved in
activation. Moreover, cutting the nerves innervating pial
arterioles does not attenuate their dilation in response to
somatosensory stimulation (Ibayashi et al., 1991). Intramural vascular signaling, in contrast, is supported by several
lines of evidence. Endothelial cells and smooth muscle cells
in the brain are connected by homocellular gap junctions,
and can propagate vasodilation in a retrograde fashion
(Dietrich, Kajita, & Dacey, 1996; Sokoya et al., 2006).
Flow-mediated vasodilation also could contribute to intramural vascular signaling (Fujii, Faraci, & Heistad, 1991).
Local vasodilation increases Xow velocity in upstream
branches, which, due to increased shear stress, leads to the
local release of endothelium-dependent vasodilators (Busse
& Fleming, 2003). These vasodilators relax the larger arteries and amplify the increase in Xow. However, it is unclear
to what extent shear stress induces vasodilation in cerebral
vessels (Bryan, Marrelli, Steenberg, Schildmeyer, & Johnson, 2001a; Bryan, Steenberg, & Marrelli, 2001b; Madden
& Christman, 1999; Ngai & Winn, 1996; Wilkerson et al.,
2005) and the mechanisms of retrograde propagation of
vasodilation need to be explored further.
3. Functional brain imaging
Changes in CBF are measured as a proxy for neural
activity in several modern imaging techniques, including
positron-emission tomography (PET), single photon emission computed tomography (SPECT), and fMRI. One of
the most widely utilized is fMRI, and the most common
technique used in fMRI is the blood oxygen level-dependent (BOLD) contrast signal. When hemoglobin (Hb) in
red blood cells loses oxygen, its iron becomes paramagnetic,
which generates magnetic Weld gradients between the
deoxyHb-containing compartments and protons of neighboring water molecules (Ogawa, Lee, Kay, & Tank, 1990).
This oxygen-dependent Weld contrast can be detected with
magnetic resonance imaging, and confers the dual advantages of non-invasive imaging and high spatiotemporal resolution. The BOLD contrast signal depends on CBF,
cerebral blood volume, and blood oxygenation (Ogawa
et al., 1993).
Several uncertainties remain as to the mechanisms
underlying the BOLD signal. For example, as detailed
above, both neurotransmitter-related signaling and energy
demand are correlated with increased CBF, but controversy remains over the relative contribution of each process
to the BOLD signal (reviewed in (Attwell & Laughlin, 2001;
Shulman et al., 2004)). Another issue is the extent to which
the BOLD signal accurately reXects the location and magnitude of the neural events that produce it. Clearly, this is
important in determining the degree to which fMRI data
yields quantitative information about particular brain
regions, and the spatial precision of this information.
3.1. Correlation between the BOLD signal and neural
activity
Accurate interpretation of the BOLD signal requires
understanding what sort of neural activity produces it
(Logothetis & Wandell, 2004). Increasing evidence supports
a linkage between CBF changes and local somatic and dendritic activity, rather than output spikes (synchronized
action potentials). In the cerebellar cortex, stimulation of
the excitatory parallel Wbers increases CBF, but inhibits
Purkinje cell spiking (Lauritzen, 2001; Mathiesen et al.,
1998). In cerebral cortex, the BOLD signal correlates well
with local Weld potentials, which reXect inputs, local-circuit
activity, and somatodendritic processing and integration of
these inputs in cortical neurons (Logothetis, Pauls, Augath,
Trinath, & Oeltermann, 2001). In contrast, cortical neuron
output spikes are less well correlated with the BOLD signal
(Logothetis et al., 2001).
An important question is whether the spatial extent of
the BOLD signal exactly matches that of neuronal activity.
As discussed in the preceding sections, local neural activity
produces an increase in blood Xow that propagates to a
larger area (Iadecola et al., 1997; Malonek & Grinvald,
1996). Potentially, contributions from both upstream vasodilation and from downstream draining vessels carrying
away deoxyHb could enlarge the BOLD signal beyond the
area of neural activity. However, these factors can be minimized by knowing local vasoarchitecture and by optimizing
the scanning conditions (Logothetis, 2003). Indeed, in
paired physiological recordings and fMRI, there is a linear
correlation between electrical activity and the BOLD signal
using a voxel size of approximately 3–5 mm2, suggesting
good spatial accuracy at this level of resolution (Kim et al.,
2004; Logothetis et al., 2001). At smaller voxel sizes, the
correlation between BOLD contrast and physiological
activity varies considerably, with false positives occurring
outside the area of neural activity (Kim et al., 2004).
Interpretation of BOLD signals can also be confounded
by regional variations in the BOLD response. It has been
widely observed in visual cortex that an initial negative
“dip” in the BOLD signal precedes the increase in CBF and
the secondary increase in the BOLD signal (Logothetis &
Wandell, 2004; Ugurbil, Toth, & Kim, 2003). This transient
dip has been attributed to a brief local increase in deoxyHb
Please cite this article as: Carrie T. Drake, Costantino Iadecola, The role of neuronal signaling in controlling cerebral blood Xow, Brain
and Language (2006), doi:10.1016/j.bandl.2006.08.002
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before the increase in CBF brings an oversupply of oxyHb
(Fox & Raichle, 1986; Fox et al., 1988). The initial dip has
been observed across species and in awake as well as anesthetized animals. However, in the rat somatosensory cortex,
the initial “dip” was not seen, rather CBF changes occur
before BOLD signal (Silva, Lee, Iadecola, & Kim, 2000).
This discrepancy suggests that regional and/or species
diVerences may exist in the coupling between deoxyHb levels and CBF.
In conclusion, neurotransmission alters blood Xow
through several processes working in concert. Synaptic
activity triggers neurons and astrocytes to release vasoactive mediators. These mediators act on local blood vessels
to produce vasodilation of arterioles, and perhaps capillaries, at the site of activation. Concurrent activation of neurovascular projections and local interneurons can restrict the
Xow response to the activated area through the coordinated
release of vasodilator and vasoconstrictor agents. Vascular
endothelial cells and smooth muscle cells further communicate among themselves to propagate vasodilation upstream
and Wne tune the local distribution of blood Xow. These factors together contribute to the neural activity-induced
alterations in CBF that form the basis of functional brain
mapping techniques. There is still much debate concerning
the speciWc sources of the BOLD signal used in fMRI studies. Although the neurovascular mechanisms of BOLD are
not completely understood, this technique remains a powerful tool for exploring the function of the behaving human
brain.
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