Transcript An energy budget for the grey matter of the brain David

Brain energy use,
control of blood flow, and
the basis of BOLD signals
David Attwell
University 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
FLOW
Hb
HbO2
blood vessels
O2
stellate
basket
Purkinje
granule
input
climbing fibre
input mossy fibres
output
Golgi
VOL
FLOW
Hb
HbO2
blood vessels
O2
?
stellate
basket
Purkinje
granule
input
climbing fibre
input mossy fibres
output
Golgi
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?
3Na 2K
3Na 2K
ATP
Pre-Synaptic
Neuron
ATP
GLN
ATP
3Na+
GLU
GLUTAMATE
H+
K+
3Na
Na +
2K
Na +
Ca 2+
ATP
Post-Synaptic
Neuron
Glial
Cell
distribution of ATP consumption in rat grey matter
for a mean action potential rate of 4Hz
action potentials 47%
resting
potentials 13%
3%
3%
postsynaptic receptors 34%
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 matter
for a mean action potential rate of 4Hz
action potentials 10%
resting potentials 3%
presynaptic Ca2+ 7%
glu recycling 5%
postsynaptic receptors 74%
Energy use by neuronal microcircuits: the cerebellum as an example
stellate
basket
Purkinje
granule
input
climbing fibre
output
Golgi
input mossy fibres
stellate
basket
Purkinje
granule
input
climbing fibre
output
cerebral cortex
distribution of ATP consumption in rat grey matter
for a mean action potential rate of 4Hz
action potentials 47%
Golgi
input mossy fibres
cerebellar cortex
resting potentials 28%
resting
potentials 13%
3%
3%
postsynaptic receptors 34%
glu recycling
action potentials 50%
3%
presynaptic Ca2+
2%
postsynaptic
receptors 17%
presynaptic
glu/GABA recycling
stellate
basket
Purkinje
granule
input
climbing fibre
output
Golgi
input mossy fibres
Predicted total ATP usage: 26.6 mmoles/g/min
Measured: 20 mmoles/g/min
(Sokoloff & Clarke in anaesthetized albino rats)
stellate
basket
Purkinje
granule
input
climbing fibre
output
ATP/sec/cell
20x109
15x109
10x109
5x109
0
Golgi
input mossy fibres
stellate
basket
Purkinje
granule
input
climbing fibre
output
ATP/sec/cell
20x109
15x109
Golgi
input mossy fibres
ATP/sec/m2
100x1018
80x1018
60x1018
10x109
40x1018
5x109
0
20x1018
0
ATP/sec/cell
ATP Usage
by Subcellular Task
action
potentials
resting
potential
rp
pre-syn
postsynaptic
action
potentials
glu
postsynaptic
Granule Cell
Purkinje Cell
action
potentials
action
potentials
rp
rp
pre-syn
glu
postsynaptic
Stellate/Basket Cell
postsynaptic
Golgi Cell
Effect of altering firing rate in a single cell type
180
160
granule cells
2
ATP/m /sec
140
120
100
80
60
mossy fibres
40
20
Purkinje cell (simple spikes)
0
0
20
40
60
Firing Rate (Hz)
80
100
Energy use by neuronal microcircuits: the cerebellum as an example
stellate
basket
Purkinje
granule
input
climbing fibre
output
Golgi
input mossy fibres
(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
Energy use by neuronal microcircuits: the cerebellum as an example
stellate
basket
Purkinje
granule
input
climbing fibre
output
Golgi
input mossy fibres
(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 inputoutput associations), or 2x1016 ATP/GB/s = (3.3x10-8moles/sec)x31kJ
= 1mW/GB. Computer hard disks now use ~5mW/GB
How is blood flow controlled?
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?
VOL
FLOW
Hb
HbO2
blood vessels
O2
energy lack?
stellate
basket
Purkinje
granule
input
climbing fibre
input mossy fibres
output
Golgi
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
Negative feedback
Neuronal activity
Energy falls
Increase CBF
-
Feedforward
Neuronal activity
Increase CBF
Energy supplied
3Na 2K
3Na 2K
ATP
Pre-Synaptic
Neuron
ATP
GLN
ATP
3Na+
GLU
GLUTAMATE
H+
K+
3Na
Na +
2K
Na +
Ca 2+
Ca 2+
PLA2
PLA2
ATP
NOS
Post-Synaptic
Neuron
AA,PG
NO
Glial
Cell
Glutamate is responsible for
cerebellar CBF increase
Parallel fibre
stimulation
Climbing fibre
stimulation
Purkinje cell spikes
CBF
CBF
Matthiesen et al., 1998
VOL
FLOW
Hb
HbO2
blood vessels
O2
stellate
Glutamate (via
neurons and glia)
basket
Purkinje
granule
input
climbing fibre
input mossy fibres
output
Golgi
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
VOL
FLOW
Hb
HbO2
blood vessels
O2
stellate
Glu
AMINES
NA, DA, 5-HT
basket
Purkinje
granule
input
climbing fibre
input mossy fibres
output
Golgi
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): a2
• Serotoninergic neurons (from raphe) constrict cerebral
arteries and microvessels (Cohen et al., 1996): 5-HT1,2
• All are wide ranging systems - control CBF globally
endothelial cells
blood flow
smooth muscle
Smooth Muscle vs Pericytes
pericytes
capillary
10 µm
SM
s
s
5 µm
10 µm
p
p
5 µm
endothelial cells
blood flow
smooth muscle
Smooth Muscle vs Pericytes
pericytes
65% of noradrenergic
innervation is of capillaries,
not arterioles
capillary
10 µm
SM
s
s
5 µm
10 µm
p
p
5 µm
Noradrenaline constricts and glutamate dilates
cerebellar capillaries
a
c
b
d
o
•
70s
1mM NA
10
diameter (microns)
295s
185s
1mM
Glu
8
6
4
2
0
0
100
200
300
400
time (s)
Peppiatt, Howarth, Auger & Attwell, unpublished
390s
Pericytes communicate with each other
and could communicate from
neurons near capillaries
to precapillary arterioles
Implications of control of CBF by amines
for 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
VOL
FLOW
Hb
HbO2
blood vessels
O2
stellate
Glu
AMINES
NA, DA, 5-HT
basket
Purkinje
granule
input
climbing fibre
input mossy fibres
output
Golgi
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