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Transcript of Brain energy use, control of blood flow, and the basis of BOLD signals David Attwell University...
Brain energy use, control of blood flow, and the basis of BOLD signals
David AttwellUniversity College London
BOLD imaging
Hariri et al. (2002) Science 297, 400
Overview• Brief review of BOLD imaging
• Coupling of neural activity to CBF, by (i) energy use or (ii) other signalling pathways
• Energy budget for cerebral cortex
• Energy use in neuronal microcircuits: cerebellum
• Local regulation of CBF by glutamate
• Global regulation of CBF by amines
• Regulation of CBF by arterioles and capillaries
• What does BOLD measure
blood vessels
HbO2Hb
O2
FLOW
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
blood vessels
HbO2Hb
O2
FLOW
?
VOL
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
Signalling from neurons to blood vessels
• The neuron to CBF signal is often assumed to be energy usage or energy lack (assumes CBF increases to maintain glucose/O2 delivery to neurons)
• So where does the brain use energy?
GLUTAMATE
GlialCell
3Na+
H+
K+
Na +
Post-Synaptic
Neuron
Pre-Synaptic
Neuron
Na +
Ca2+
GLU
GLN
ATP
2K3Na
ATP
2K3Na
ATP
2K3Na
ATP
distribution of ATP consumption in rat grey matterfor a mean action potential rate of 4Hz
action potentials 47%
postsynaptic receptors 34%
resting potentials 13%
3%3%
glu recycling
presynaptic Ca2+
Primates vs rodents• Primates: 3-10 times less cell density with
same synapse density (so 3-10 times more synapses/cell)
• Predicts a lower overall energy usage (54% for 10-fold - experimental value is 54%)
• Increases fraction on glutamatergic signalling (from 34% to 74%)
distribution of ATP consumption in primate grey matterfor a mean action potential rate of 4Hz
action potentials 10%
postsynaptic receptors 74%
resting potentials 3%
glu recycling 5%
presynaptic Ca2+ 7%
Energy use by neuronal microcircuits: the cerebellum as an example
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
distribution of ATP consumption in rat grey matterfor a mean action potential rate of 4Hz
action potentials 47%
postsynaptic receptors 34%
resting potentials 13%
3%3%
glu recycling
presynaptic Ca2+
resting potentials 28%
action potentials 50%
postsynaptic receptors 17%
presynaptic3%
2%glu/GABA recycling
cerebral cortex cerebellar cortex
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
Predicted total ATP usage: 26.6 moles/g/min
Measured: 20 moles/g/min (Sokoloff & Clarke in anaesthetized albino rats)
0
5x109
10x109
15x109
20x109
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
Purkin
je
bask
et/st
ellat
e
Golgi
gran
ule ce
ll
mos
sy fib
re
clim
bing
fibre
Bergm
ann
ATP/sec/cell
astro
cyte
0
5x109
10x109
15x109
20x109
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
Purkin
je
bask
et/st
ellat
e
Golgi
gran
ule ce
ll
mos
sy fib
re
clim
bing
fibre
Bergm
ann
ATP/sec/cell
0
20x1018
40x1018
60x1018
80x1018
100x1018
Purkin
je
Golgibc
/sc
gran
ule ce
ll
mos
sy fib
re
clim
bing
fibre
Bergm
ann
astro
astro
cyte
ATP/sec/m2
ATP/sec/cell
resting potential
action potentials
post-synaptic
pre-syn
action potentials
post-synaptic
Granule Cell Purkinje Cell
action potentials
rp
rp
post-synaptic
glu
pre-synglu
Stellate/Basket Cell Golgi Cell
post-synaptic
rp
action potentials
ATP Usage by Subcellular Task
Firing Rate (Hz)
0 20 40 60 80 100
AT
P/m
2/s
ec
0
20
40
60
80
100
120
140
160
180
granule cells
mossy fibres
Purkinje cell (simple spikes)
Effect of altering firing rate in a single cell type
Energy use by neuronal microcircuits: the cerebellum as an example
(1) Most energy goes on granule cells re-mapping the sensory and motor command input arriving on the mossy fibres into a sparse coded representation used by the Purkinje cells to retrieve motor output patterns
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
Energy use by neuronal microcircuits: the cerebellum as an example
(1) Most energy goes on granule cells re-mapping the sensory and motor command input arriving on the mossy fibres into a sparse coded representation used by the Purkinje cells to retrieve motor output patterns
(2) 1011 ATP molecules are used per second to be able to retrieve 5kB of information from each Purkinje cell (which can store 40,000 input-output associations), or 2x1016 ATP/GB/s = (3.3x10-8moles/sec)x31kJ = 1mW/GB. Computer hard disks now use ~5mW/GB
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
How is blood flow controlled?
ML
GLPC
Does an energy-lack signal increase blood flow?
• When [ATP] (or [O2] or [glucose]) falls, or [CO2] or [H+] or [lactate] rises, does that make blood flow increase?
• In other words, do BOLD signals reflect the presence of a feedback system to conserve energy supply?
blood vessels
HbO2Hb
O2
FLOW
energy lack?
VOL
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
What controls cerebral blood flow during brain activation?
• Not glucose lack (Powers et al., 1996)
• Not oxygen lack (Mintun et al., 2001)
• Not CO2 evoked pH change (pHo goes alkaline due to CBF increase removing CO2: Astrup et al., 1978; Pinard et al., 1984)
• So CBF is not driven directly by energy lack maintaining O2/glucose delivery to neurons and keeping [ATP] high Powers et al., 1996
What controls cerebral blood flow during brain activation?
• CBF is not driven by energy lack• Not the spike rate of principal neurons (Mathiesen et
al., 1998; Lauritzen 2001)• BOLD correlates (slightly!) better with synaptic
field potentials than spike output (Logothetis et al., 2001)
• So does synaptic signalling control CBF (i.e. is it a feedforward, rather than a feedback, system)?
Feedforward vs feedback control of CBF
Neuronal activity
Neuronal activity
Energy falls Increase CBF
Increase CBF Energy supplied
-
Negative feedback
Feedforward
GLUTAMATE
GlialCell
3Na+
H+
K+
Na +
Post-Synaptic
Neuron
Pre-Synaptic
Neuron
+NaCa 2+
GLU
GLN
ATP
2K3Na
ATP
2K3Na
ATP
2K3Na
ATP
PLA2
NOS
AA,PG
NO
Ca2+
PLA2
Glutamate is responsible for cerebellar CBF increase
Purkinje cell spikes
CBF
Parallel fibrestimulation
Climbing fibrestimulation
Matthiesen et al., 1998
CBF
blood vessels
HbO2Hb
O2
FLOW
Glutamate (vianeurons and glia)
VOL
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
Glutamate controls CBF and BOLD signals
• Energy calculations implicate postsynaptic currents as the main energy consumer - so if energy use drove BOLD signals, BOLD would reflect the release of glutamate
• In fact energy use does not drive CBF, but glutamate does - so BOLD is still likely to reflect glutamate release (via its postsynaptic actions)
What does BOLD measure?
• If BOLD signals largely reflect glutamate release:• (a) BOLD does not tell us about the spike output of an
area, and will only reflect principal cell activity if most glutamate is released onto principal cells
• (b) altered processing with no net change of glu release might produce no BOLD signal
• (c) altered glu release with no change of the spike output of an area could produce a BOLD signal
blood vessels
HbO2Hb
O2
FLOW
Glu
VOL
AMINESNA, DA, 5-HT
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
Control of cerebral blood flow by distributed systems using amines and ACh
• Dopaminergic neurons (from VTA) innervate microvessels - DA constricts (Krimer et al., 1998): D1,2,4,5
• Noradrenergic neurons (from locus coeruleus) also constrict microvessels (Raichle et al., 1975): 2
• Serotoninergic neurons (from raphe) constrict cerebral arteries and microvessels (Cohen et al., 1996): 5-HT1,2
• All are wide ranging systems - control CBF globally
Smooth Muscle vs Pericytes
blo
od
flo
w
capillary
sm
oo
th m
us
cle
end
oth
elia
l cel
ls
10 µm
SM
10 µm
5 µm
s
p 5 µm
s p
pericytes
Smooth Muscle vs Pericytes
blo
od
flo
w
capillary
sm
oo
th m
us
cle
end
oth
elia
l cel
ls
10 µm
SM
10 µm
5 µm
s
p 5 µm
s p
pericytes
65% of noradrenergic innervation is of capillaries,not arterioles
390s185s
b
295s
c d
10
8
6
4
2
0
diam
eter
(m
icro
ns)
4003002001000
time (s)
1mM Glu1M NA
70s
a
o
•
Peppiatt, Howarth, Auger & Attwell, unpublished
Noradrenaline constricts and glutamate dilates cerebellar capillaries
Pericytes communicate with each other and could communicate from neurons near capillariesto precapillary arterioles
Implications of control of CBF by aminesfor neuropsychiatric imaging
• Clinical disorders often involve disruption of amine function (schizophrenia, Parkinson’s, ADHD)
• In imaging we would like a change in BOLD signals to imply an effect of the amine disorder on cortical processing
• If amines control CBF, altered amine function may alter the relation between neural activity and BOLD signals (extreme example: amine depletion maximally dilates vessels, so no further dilation or BOLD signal possible)
• Consequently altered BOLD signals may just reflect altered control of CBF, and provide no information on neural processing
blood vessels
HbO2Hb
O2
FLOW
VOL
AMINESNA, DA, 5-HT
basket
stellate
granule Golgi
Purkinje
input mossy fibresoutput
input climbing fibre
Glu
BOLD imaging
Hariri et al. (2002) Science 297, 400
Conclusions• In primates, most of the brain’s energy goes on postsynaptic currents (and
action potentials)
• CBF changes and BOLD aren’t driven by O2/glucose lack nor by CO2 production, so are not driven by energy lack
• CBF changes and BOLD don’t correlate well with spiking• Glutamate controls local CBF so BOLD signals will reflect glutamatergic
signalling• Amines control CBF more globally - could confound studies on amine-
related diseases• CONCLUSION: to interpret BOLD signals you need to consider the
neural wiring of the area being studied
Collaborators
Clare Howarth
Claire Peppiatt
Céline Auger
Simon Laughlin