receptorarchitecture and neural systems architecture and... · receptorarchitecture and neural...
TRANSCRIPT
Receptorarchitecture and Neural Systems
Karl Zilles
Institute of Neuroscience and Medicine INM-1 Research Centre Jülich
and University Hospital of Psychiatry, Psychotherapy and
Psychosomatics RWTH Universität Aachen
Receptors are protein complexes in the cell membrane, to which transmitters selectively bind.
ionotropic receptors have an integrated ion channel and regulate ion fluxes between extra- and intracellular space
metabotropic receptors are linked to intracellular second messenger systems, and control metabolic pathways, ion channels, gene activity, etc.
It provides insight into the molecular basis of the resting state condition.
Most of the brain‘s energy consumption is used for maintaining ion
channel functions during resting state. Only a minority of the energy is required during stimulation conditions.
Receptor mapping overcomes limitations of unimodal brain mapping approaches
It provides brain maps based on molecules which are key elements of
signal transmission within and between neural systems
Areas within a given functional system have similar multireceptor expression patterns. Different functional systems differ by those expression patterns
What does receptor mapping provide?
R
Example: Ionotropic Transmitter Receptors
postsynaptic ionotropic receptor
transmitter
ion channel
postsynaptic membrane
presynaptic ionotropic receptor
presynaptic membrane
axonal bouton
AMPA
Dendrite
PSD
postsynaptic
presynaptic
Dendrite
Spine
Postsynaptic density PSD
NMDA NR1
Joachim Lübke, Research Center Jülich, Germany (unpublished)
NMDA NR1
AMPA
NMDA and AMPA are the most abundant glutamate receptor types in the human cerebral cortex. Method: Cryo-Electron-Microscopy and Immunocytochemistry with specific antibodies labeled with gold nanoparticles of different size (for AMPA 9 nm, for NMDA 12 nm)
Adenosin A1 D1, D2, D4
D1, D2, D4
Dopamine
AMPA, NMDA, kainate
AMPA, NMDA, kainate
AMPA, NMDA, kainate
AMPA, NMDA, kainate
Glutamate
GABAA, bz.binding site
GABAA, bz.binding site
GABAA, bz.binding site
GABAA, bz.binding site
GABAB
GABAB
GABAA, bz.binding site
GABAB
GABA
nicotinic, M1, M2, M3
nicotinic, M1, M2, M3
Acetylcholine
α1, α2
α1, α2
Noradrenaline
5-HT1A, 5-HT2
5-HT1A, 5-HT2
Serotonin
How to map receptor distributions:
• in vivo receptor PET
• in vitro quantitative receptor autoradiography
• immunohistochemistry of receptor proteins and subunits
• transcriptomics
HG05/00
Sulcus centralis
slab 2 native
slab 2 frozen
at -70° C
slab 2
Quantitative in vitro Receptor Autoradiography: Method (1)
Gyrus praecentralis
Cryostate serial sections (10 – 20 µm) – mounting on glass slides
Incubation of alternating serial sections with tritium-labeled ligands Labeling of different receptors of all classical transmitter systems (Glutamate, GABA, Acetylcholine, Dopamine, Serotonin, Noradrenaline) Exposition against β-sensitive film together with radioactive scales Digitization, quantification and colour coding of the film Identification of cytoarchitectonic areas by comparison with neighbouring cell-body stained sections
Quantitative in vitro Receptor Autoradiography: Method (2)
Neurotransmitter Receptor [3H] Ligand Glutamate AMPA AMPA
Kainate kainate NMDA MK-801
GABA GABAA muscimol, SR 95531
GABAB CGP 54626
BZ Flumazenil Acetylcholine M1 pirenzepine
M2 oxotremorine-M, AF-DX 384
M3 4-DAMP
N epibatidine Noradrenaline α1 prazosin
α2 UK 14,304 RX-821002
Serotonin 5-HT1A 8-OH-DPAT
5-HT2 ketanserin
Dopamine D1
D2
SCH 23390 Fallypride or Raclopride
Histological staining: Cell bodies Myelin
Examined receptor binding sites
Gennari‘s stripe V2
V2
V1
V1
Myelin
vertical meridian
vertical meridian
GABAA Receptor
V2
V2
V1
V1
vertical meridian
Sulcus calcarinus
Zilles, K., Palomero-Gallagher, N. , Schleicher, A.: Transmitter receptors and functional anatomy of the cerebral cortex. J. Anat. 205: 417-432 (2004)
vertical meridian
Entorhinal-Hippocampal System
medial lateral
ventral
dorsal
Dent
CA4
CA1
Sub Prsub
Ent
35
36
n.d. n.d.
fi
Parsub
1
2
3 trisynaptic glutamatergic system: 1 perforant path 2 mossy fibers 3 Schaffer collaterals
general neocortical input CA2
CA3
INPUT:
temporal and perirhinal input to subiculum
OUTPUT: from the subiculum and CA1 to temporal, parahippocampal, perirhinal, cingulate, prefrontal, and orbitofrontal areas
cingulate, superior temporal, dorsolateral prefrontal, and IPL input to presubiculum
Why are architectonic studies essential for understanding the organization of neural systems?
sub CA1 mol
CA2
fimbria CA3
Kainate NMDA
AMPA
perforant path
mossy fibres
Schaffer collateral
CA1 mol
CA1
mol CA3 CA2
Glutamatergic terminals of the perforant path and the Schaffer collaterals
Glutamatergic terminals of the mossy fibers
Glutamatergic terminals of the perforant path and the Schaffer collaterals
295 464 633 802
221 357 493 629 417 632 486 1061 fmol/mg protein fmol/mg protein
fmol/mg protein
Primary Sensory Cortices
96 208 320 432 fmol/mg protein
cholinergic muscarinic M2 receptor
Toga AW, Thompson PM, Mori S, Amunts K, Zilles K (2006) Towards multimodal atlases of the human brain. Nature Rev. Neurosci. 7: 952-966 Zilles K, Amunts K (2009) Receptor mapping: Architecture of the human cerebral cortex. Current Opinion Neurol. 22: 331–339
primary auditory
multimodal temporal
association
cingulate
unimodal auditory
pre/para- subiculum
entorhinal
insular
motor
parietal
primary somatosensory 3b
3a
Macaque Brain
Human Brain
primary somatosensory cortex
low density high density
primary auditory cortex
motor cortex
motor cortex sc
sc
Cholinergic muscarinic M2 receptor
primary auditory cortex
primary somatosensory cortex
Kainate receptor [3H] kainate
AMPA receptor [3H] AMPA
154 379 604 829
GLUTAMATE SYSTEM
668 1084 1499 1915
pre/para- subiculum
entorhinal
multimodal temporal
association
cingulate
unimodal auditory
primary auditory
sensorimotor
primary auditory
multimodal temporal
association
cingulate
fmol/mg protein
unimodal auditory
pre/para- subiculum
entorhinal
insular insular
sensorimotor
Receptor Fingerprints
Dopamine
Acetylcholine
Serotonin
Glutamate
Noradrenaline GABA
Low denisty
High density
AMPA Kainate NMDA M1 M2 M3 nicotinic
α1 α2 GABAA 5-HT1A 5-HT2 D1 D2
Multimodal visualization of receptor organization in human cerebral cortex
Zilles, K., Schleicher, A., Palomero-Gallagher, N., Amunts, K.: Quantitative analysis of cyto- and receptorarchitecture of the human brain, pp. 573-602. In: Brain Mapping: The Methods, 2nd edition (A.W. Toga and J.C. Mazziotta, eds.). Academic Press (2002)
A receptor fingerprint is… AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
nACh
α1
α2
5-HT1A
5-HT2
D1
area 4
caudate putamen
0
500
1000
1500
2000
2500
3000
„Receptor Fingerprints“
AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT2
D1
1000
2000
3000
Hippocampus CA1-3
0
primary motor cortex
AMPA kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT2
D1
0
5-HT1A 5-HT1A 1000
2000
3000
What receptors tell us about laminar segregation and input-output relations
in the cerebral cortex
molecular layer I
outer granular layer II
inner granular layer IV
outer pyramidal layer III
inner pyramidal layer V
polymorphic layer VI
CYTOARCHITECTURE
thalamo- cortical input
cortico- cortical input
CONNECTIVITY SYNAPTIC DENSITY
cortico- -cortical, -striatal,
-thalamic, -bulbar, and
-spinal output
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
L. I
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
Ll. II-III
Receptor Fingerprints of the primary visual cortex: layer specificity
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
L. IV
L. V
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1 L. VI
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
Layer IV: Thalamo-cortical Input
4
modality-specific balance between receptors
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
primary somatosensory (touch)
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
primary visual
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
parietal association (visually guided grasping)
0
1000
2000
3000 AMPA
kainate
NMDA
GABAA
GABAB
BZ
M1
M2 M3
N
α1
α2
5-HT1A
5-HT2
D1
prefrontal association (working memory)
Cluster analysis of the multi-receptor fingerprints of BROCA‘s region, prefrontal and motor cortex
6r1
4
47
6v1
op9
op8
45
44
prefrontal
primary motor
premotor
language
0.2 0.3 0.4 0.5 0.6 0.7 0.8
cort
ical
are
a
Amunts, K., Lenzen, M., Friederici, A.D., Schleicher, A., Morosan, P., Palomero-Gallagher, N., Zilles, K.: Broca's region: Novel organizational principles and multiple receptor mapping. PLoS Biology 8(9): e1000489. doi:10.1371/journal.pbio.1000489 (2010)
4
6v1
6r1
44 45
47
op8 op9
Whole brain hierarchical cluster analysis based on multi-receptor fingerprints - Normalization: divide by mean - Euclidean distances, Ward linkage - Cophrenetic coefficient: 0.58
Eucl
idea
n di
stan
ce
0 1
2 3
4 5
6
7lp
7mp 31
7la
7ma
v2d
v2v
Oc4
d O
c3d
d23 29
30
BA1
3a
Te
1 Te
2 Te
3 Te
4 B
A2
5m
7pc 5l
BA3
8 B
A4
BA8
p2
4'
BA4
4 B
A45 3b
Oc3
v v4
v FG
1 FG
2 v1
6d
a24'
O
P 24
v23
32'
PF
PFm
PG
p PG
a PF
cm
PFop
PF
t B
A47
10m
s3
2 p3
2 25
BA2
0‘
BA3
6 dg
subi
c en
t C
A
motor Broca somato -
-sensory domaine
auditory anterior cingulate- prefrontal
entorhinal -hippocampal
circuit
inferior parietal
multimodal cortex perilimbic
proisocortex
visual
ventral stream
retro- splenial
visual superior parietal
dorsal stream
sensorimotor limbic
Cluster analysis of the human cingulate cortex: A multi-region model based on receptor fingerprints
Palomero-Gallagher, N., Vogt, B.A., Schleicher, A., Mayberg, H.S., Zilles, K. (2009) Receptor architecture of human cingulate cortex: Evaluation of the four-region neurobiological model. Human Brain Mapping 30: 2336-2355
Eucl
idea
n di
stan
ce (W
ard
linka
ge)
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
23d
23c 31
d23
v23 30
29l
29m
24a
24b
24cv
24cd
32
p24a
'
p24b
'
24dv
24dd
24c'
v
24c'
d
32'
25
a24b
'
a24a
'
33
24a
24b
24cv
24cd
32
p24a
'
p24b
'
24dv
24dd
24c'
v
24c'
d
32'
25
a24b
'
a24a
'
33
25
33
RSC ACC
MCC
PCC aMCC pMCC
emotion
decision motor control
visuo- spatial
attention memory
limbic memory
auto
nom
ic
cont
rol
Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich
Katrin Amunts Svenja Caspers Joachim Lübke Hartmut Mohlberg Nicola Palomero-Gallagher Axel Schleicher
Thanks to: