Partnerforum - UiO
Transcript of Partnerforum - UiO
Rektor
Professor Ole Petter Ottersen, MD, PhD
University of Oslo
Partnerforum
Innovativ ledelse i kreative
organisasjoner
Nancy Andreasen, Andrew H. Woods Chair of
psychiatry and Director of the Mental Health Clinic
Research Center at the University of Iowa Carver
College of Medicine: "The Creating Brain”
What is creativity?
”Creativity is the capacity of seeing
new things, new relationships, create
novel things, spread across the arts and
sciences.”
”It is not possible to capture the ability to
be creative with a test. That person who
invents the test has to be more creative than
creative people, and generally they are less
creative.”
PLoS ONE. 2008; 3(2): e1679. Published online 2008
February 27.
Neural Substrates of Spontaneous Musical
Performance: An fMRI Study of Jazz Improvisation
Charles J. Limb and Allen R. Braun
Language Section, Voice, Speech and Language Branch,
National Institute on Deafness and Other Communication
Disorders, National Institutes of Health, Bethesda,
Maryland, United States of America
I fravær av en ”test” la oss se
hvordan hjernen fungerer i en
situasjon som assosieres med
”kreativitet”
Musiker spiller inne i en MR-magnet (spesiallaget klaviatur!)
Sammenligner spill etter noter (venstre) og improvisert spill (høyre)
Hvilke deler av hjernen er involvert i improvisasjon (~kreativitet)?
Blodgjennomstrømning i hjernen ved improvisasjon.
Blå: nedsatt blodgjennomstrømning (~nedsatt aktivitet)
Rødt, gult, orange: økt blodgjennomstrømning
•Mens aktivering av fremre del av pannelappen synes å
støtte fokusert oppmerksomhet er deaktivering koblet til
spontane, ikke planlagte assosiasjoner (innfall) og
”plutselig” og ”ny” innsikt
Fronto-temporal Dementia
(Miller et al 1998)
None of these people were artistic before they became demented
Negative
influences on creativity ??
_
_
Probably, but not nearly
this simple….
Hvorfor dette sidespranget til
hjerneforskningen?
• Kreativitet er en egenskap som
involverer spesifikke deler av hjernen
• Må være kritisk overfor forsøk å
korrelere kreativitet til lett målbare
egenskaper (f. eks. IQ)
• Malcolm Gladwell i ”Outliers”: hvor
mange måter kan man bruke en
murstein på? Ingen/svak sammenheng
med IQ.
”There are personality traits that characterize creative people,
and one is just sheer persistence: people who are creative force
themselves to work. When they don't - when they have that blank
page in front of them, they have to terror but they put words on it.
The other thing about people who are creative is that they push
the limits. They get rejected. They have the pain of rejection.”
Nancy Andreasen
(in interview)
Evidens-basert medisin –
evidensbasert forvaltning?
• Kan en ny tilnærming til sammenstilling og formidling
av forskningsbasert kunnskap gi et bedre
kunnskapsgrunnlag for politikkutforming og
forvaltning? Hva virker – hva virker ikke?
• Evidens – ultimat prioriteringsmekanisme eller
”ekstrempositivisme”?
Refleksjoner om kreativitet (1)
• Vanskelig å definere, derfor lite fokus
• Forskningsmeldingen ”Klima for forskning”:
Kreativitet nevnt 1 gang, innovasjon
(operasjonalisering av kreative ideer) > 20 ganger!
• UiO vil danne en kreativitetsallianse
• Moderne hjerneforskning tyder på at kreativitet
”kontrolleres” fra spesifikke hjerneregioner
• Må advare mot direkte kobling med andre kognitive
funksjoner – slik som IQ
Refleksjoner om kreativitet (2)
• Kreativitet handler om trygghet
• Også om trygghet til å DELE idéer: Idéer vokser ved å deles!
• Jared Diamond: ”Guns, Germs, and Steel”
Og ikke glem Steve Jobs (tok kurs i kalligrafi 17 år gml.): ”But ten years later, when we were designing the first Macintosh computer, it all came back to me…” (s 318, The World is Flat, av Thomas L. Friedman)
Høstkonferansen 2009: Kommunikasjonspolitikken i staten
”Det paaligger Statens Myndigheder at
lægge Forholdene til Rette for en
aaben og oplyst offentlig Samtale”
• Toveis kommunikasjon fornyelse
• Reformer, beslutninger basert på forskning
What constitutes a
leading university?(Strategy plan 2010 -2020)
Qualitycutting-edge research and research-based education
Relevanceeducation and research for unforeseen needs and the benefit of society
Breadtha comprehensive, research-intensive university with multiple disciplines
and faculties and interdisciplinary research
Readinessthe potential to restructure rapidly and recombine our unique range
of knowledge in novel ways to address the many increasingly important
trans-disciplinary issues in society today
Engagement – “The engaged university”
Two-way communication with external stakeholders and with the society at large –
“kindle and amplify ideas and innovations” (Jared Diamond: Guns, Germs, and Steel)
Partnerforum
• 19 medlemsvirksomheter
• Medlemsskap bør være et ”must”
• Faglig møteplass for utveksling og utvikling av ny
kunnskap som er relevant for velferdsstaten
• Dugnadspreget arbeidsform – 17
fellesarrangementer i 2009
• Takk til arbeidsgruppen!
UiO ønsker dere et godt og aktivt møte!
Brain and Creativity- and debunking the myth of the hardwired brain
Ole Petter Ottersen
University of Oslo
“Lidenskap og Phantasie 26-29 October, 2009
THE BRAIN IS MALLEABLE
-it is no transistor radio
The brain is capable of being
altered by environmental
influences
Nature 420(6917):751-2.
•Plasticity at the level of synapses
•Plasticity (mobility) at the level of
neurotransmitter receptors
•100 000 000 000 000 synapses in brain
•Synapses are the brain’s computational
units
An important premise for the discussion
of brain and creativity:
Signal transfer in a synapse:
transmitter (glutamate) release
Signal transfer in a synapse:
transmitter binds to and activate receptors
It’s all about deception
Microscopical analyses
(”nonvital imaging”) give a
false impression of rigidity and
immobility
0.2 um Takumi, Ramirez-Leon,
Laake, Rinvik & Ottersen,
Nature Neuroscience 2:989-
998
1000 synapses side by side add up to 1 mm
The brain cannot be properly understood without
access to analyses in ”real time”
… just as the plot of Casablanca is not easily
understood on the basis of single frames
Laser technology
allows analysis of
synapses ”in real
time”
VISIBLE LIGHT IS
ABSORBED BY LIVE TISSUE
….AND PRODUCES
PHOTOTOXICITY
Time-lapse images of
a dendritic region
(yellow box in c).
Examples of
transient, semi-
stable, and stable
spines are labeled
with blue, red, and
yellow
MULTIPHOTON LASER
MICROSCOPY ALLOWS
CHRONIC IMAGING OF
SPINES IN THE CORTEX
OF LIVE MICE
SVOBODA ET AL., NATURE 19 DECEMBER 2002
.
Altering sensory
experience
increases spine
turnover rates.
Spine density for cells lying
within (green) or outside
(black) the barrel cortex.
Spine density does not
change in response to
deprivation.
Turnover ratio increased
after deprivation within
(green) but not
outside (black) barrel
cortex.
Single molecule detection
< 50 nm
Receptor trajectory
Nanotechnology allows analysis of receptor mobility « in real time »
D. Choquet
Quantum dot
Nanotechnology: receptors move in and out of synapses
Post-synapses
Homer-GFP
QD anti-GluR1
QDot
AMPAR
Courtesy of Daniel Choquet
Increased cortical representation of the fingers of the left hand in string
players. (Science. 1995 Oct 13;270(5234):305-7)
Elbert T et al.
Department of Psychology, University of Konstanz, Germany.
Magnetic source imaging revealed that the cortical representation of the
digits of the left hand of string players was larger than that in controls.
The effect was smallest for the left thumb, and no such differences were
observed for the representations of the right hand digits. The amount of
cortical reorganization in the representation of the fingering digits was
correlated with the age at which the person had begun to play. These
results suggest that the representation of different parts of the body in the
primary somatosensory cortex of humans depends on use and changes to
conform to the current needs and experiences of the individual.
Thanks to modern technologies we now
understand ”the plot”:
The brain is much more malleable (less
hardwired) than previously anticipated
Heraclitus: Panta rei -
Everything is
constantly changing
…one does not step
into the same river
twice
…and your brain is not
the same when you
leave as when you
arrived
Environmental
factors impact
the structure
and wiring of
brain:
•Experience
•Nutrition
•Hormones
•Music?
Nancy Andreasen, Andrew H. Woods Chair of
psychiatry and Director of the Mental Health Clinic
Research Center at the University of Iowa Carver
College of Medicine: "The Creating Brain”
What is creativity?
”Creativity is the capacity of seeing
new things, new relationships, create
novel things, spread across the arts and
sciences.”
It is not possible to capture the ability to be
creative with a test. That person who
invents the test has to be more creative than
creative people, and generally they are less
creative.
PLoS ONE. 2008; 3(2): e1679. Published online 2008
February 27.
Neural Substrates of Spontaneous Musical
Performance: An fMRI Study of Jazz Improvisation
Charles J. Limb and Allen R. Braun
Language Section, Voice, Speech and Language Branch,
National Institute on Deafness and Other Communication
Disorders, National Institutes of Health, Bethesda,
Maryland, United States of America
In the absence of a ”test” let’s see
how the brain works in a setting
commonly assumed to require
”creativity”
•Low complexity (Scale) and high complexity (Jazz) experimental paradigms used to
study spontaneous musical creativity.
•Non-ferromagnetic MIDI piano keyboard.
•For Jazz's control condition, subjects played a novel melody that was memorized prior
to scanning (JazzCtrl, lower left). For Jazz's improvisation condition, subjects
improvised using the composition's underlying chord structure as the basis for
spontaneous creative output (example shown under JazzImprov, lower right).
Three-dimensional surface projection of activations
and deactivations associated with improvisation during
the Jazz paradigm.
Medial prefrontal cortex activation, dorsolateral
prefrontal cortex deactivation, and sensorimotor
activation. Abbreviations: a, anterior; p, posterior; d,
dorsal; v, ventral; R, right; L, left.
•Our data indicate that spontaneous improvisation,
independent of the degree of musical complexity, is
characterized by widespread deactivation of lateral portions
of the prefrontal cortex together with focal activation of
medial prefrontal cortex.
•This unique pattern may offer insights into cognitive
dissociations that may be intrinsic to the creative process.
•Whereas activation of the lateral regions appears to support
self-monitoring and focused attention, deactivation may be
associated with defocused, free-floating attention that
permits spontaneous unplanned associations, and sudden
insights or realizations
Right side
Suppression of creativity
Risk-reward analysis
Winning in gambling
Fronto-temporal dementia
Fronto-temporal Dementia
(Miller et al 1998)
None of these people were artistic before they became demented
Negative
influences on creativity ??
_
_
Probably, but not nearly
this simple….
”There are personality traits that characterize creative people,
and one is just sheer persistence: people who are creative force
themselves to work. When they don't - when they have that blank
page in front of them, they have to terror but they put words on it.
The other thing about people who are creative is that they push
the limits. They get rejected. They have the pain of rejection.”
Nancy Andreasen
(in interview)
”Outliers – The Story of Success”
By Malcolm Gladwell
There are areas of the brain that promote creative
activity and areas that inhibit it
And – like all other cognitive processes – creativity
grows by learning: the brain is malleable
Nature
Neuroscience
januar 2001:
”What makes a
prodigy”
Rüdiger Gamm kan
operere med 9.
potens og 5. rot med
stor nøyaktighet
….og aktiverer
barkområder (røde)
som ikke aktiveres
hos ”normale”
GROUP LEADERS:
Jan G. Bjaalie (UiO)
Magnar Bjørås(RH)
Niels Christian Danbolt (UiO)
Arne Klungland (RH)
Michael Koomey (UiO)
Stefan Krauss (BiO)
Ole Petter Ottersen (UiO)
Torbjørn Rognes (RH)
Johan Storm (UiO)
Jon Storm-Mathisen (UiO)
Tone Tønjum (RH) Associate Director
Thanks to members
of CMBN
Thank you for your attention
THE BRAIN IS MALLEABLE
The brain is capable of being
altered by outside forces or
influences
An important premise for the
discussion of “nutrition and brain”:
•Plasticity (mobility) at the level of
neurotransmitter receptors: single
molecule tracking
•Plasticity at the level of synapses and
glia: multiphoton imaging technology
•Plasticity is restrained by extracellular
matrix molecules: the importance of
extracellular matrix proteinases
THE BRAIN IS MALLEABLE
The brain is capable of being
altered by environmental
influences
Nature 420(6917):751-2.
•Plasticity at the level of synapses
•Plasticity (mobility) at the level of
neurotransmitter receptors
•100 000 000 000 000 synapses in brain
•Synapses are the brain’s computational
units
The brain is no transistor radio
The dream:
Microscopic
analysis of the
structure,
physiology, and
pathophysiology of
the living brain
”East is east and
west is west ….”Nase et al. 2004
•Infrared light penetrates live
tissue better than visible light
•1931: Maria Göppert-Mayer
predicts that optical electronic
transitions in molecules can be
achieved in response to low-
energy (infrared) photons if the
photon flux is high enough
•This prediction was borne out
after the invention of the laser
• Research as an instrument to remove
prejudices and myths
• Research as an instrument to foster
tolerance
• Research as a pillar of society
New spines establish
synapses
And new synapses
may appear from one
day to the next
Two new spines appeared
between the 7th and 8th
imaging day (boxes in d and
e)
Electron micrographs
showing synapses
established by these new
spines.
SVOBODA ET AL., NATURE
19 DECEMBER 2002
How
”dynamic” is
this scheme?
SPINE
…and how
static are the
volumes?
Centre for Molecular Biology and Neuroscience (2003 – 2012) www.cmbn.no
Nordic Centre of Excellence in Molecular Medicine (WIRED)
(2004 – 2009)
Letten Research Centre/Institute of Molecular Medicine Norway - Nordic EMBL partnership
EU Projects: KARTRAP and GRIPANNT
The data
presented derive
from:
THE BRAIN IS MALLEABLE
The brain is capable of being
altered by outside forces or
influences
Nature 420(6917):751-2.
An important premise for the
discussion of brain and creativity:
•Plasticity at the level of synapses and
glia: multiphoton imaging technology
•Plasticity (mobility) at the level of
neurotransmitter receptors: single
molecule tracking
•Plasticity is restrained by extracellular
matrix molecules: the importance of
extracellular matrix proteinases 1014 synapses in brain?
It’s all about deception
Microscopical analyses
(”nonvital imaging”) signal
rigidity, immobility, and an
”empty” extracellular space
0.2 um
Landsend et al,
J Neurosci 1997
An overview of the
glutamate synapse
-based on the ”gold
standard”
•Ionotropic receptors in
postsynaptic specialization
•Metabotropic receptors peri-
and extrasynaptically
•Glutamate transporters occur
in neuronal as well as in glial
membranes
•There is a substantial regional
heterogeneity
Takumi, Ramirez-Leon, Laake,
Rinvik & Ottersen,
Nature Neuroscience 2:989-998
How
”dynamic” is
this scheme?
SPINE
…and how
static are the
volumes?
Centre for Molecular Biology and Neuroscience (2003 – 2012) www.cmbn.no
Nordic Centre of Excellence in Molecular Medicine (WIRED)
(2004 – 2009)
Letten Research Centre/Institute of Molecular Medicine Norway - Nordic EMBL partnership
EU Projects: KARTRAP and GRIPANNT
The data
presented derive
from:
Glutamate receptor mobility and synaptic plasticity (KARTRAP and GRIPANNT)
Craig and Lichtman, Nature Neuroscience 4:219, 2001
SINGLE
MOLECULE
TRACKING
ALLOWS
MONITORING
RECEPTOR
MOBILITY
Single molecule detection
< 50 nm
Receptor trajectory
Quantum Dot
Pointing accuracy ~30 nm
300 nm
Single molecule tracking of surface receptors
D. Choquet
Promiscuity at the synaptic level – receptors
move in and out of synaptic sites
AMPA
glutamate
receptors
alternate
within
seconds
between
rapid
diffusive and
stationary
behaviour
Choquet et al, 2005
MOVIE
Quantum dot single molecule
tracking of AMPA glutamate
receptors in cultured
hippocampal pyramidal cells
(courtesy of D. Choquet)
AMPAR move in and out spines
Post-synapses
Homer-GFP
QD anti-GluR1
QDot
AMPAR
Quantum dots (green) representing single
glycine receptors move between synapses (red)
Quantum dots can be
silver intensified for EM
Dahan et al., Science
2005
Variation in receptor numbers participate in plasticity
AMPAR
NMDAR
Increase in AMPAR number
mediate potentiation
Decrease in AMPAR number
mediate depression
Courtesy of D. Choquet
Long lasting changes
in synaptic
transmission underlie
learning and memory
NMDAR
AMPAR
Diffusion
Interplay between recycling and diffusion of AMPARs ?
NMDAR
AMPAR
Diffusion
Interplay between recycling and diffusion of AMPARs
Homer 1C
1 µm
Clathrin
Rascz et al. 2004
Blanpied et al. 2002;
Petrini et al. unpublished
Recycling
D. Choquet
ControlMobile AMPARs
X-linkImmobile AMPARs
50 ms
50 pA
50 ms
Post-synaptic depression is modulated by the
mobility of synaptic receptors
C O
DC
C C
C
C
C O
DC
C C
C
C
C O
DC
C C
C
C
C O
D
C
C C
C
C
D
Recovery from paired pulse depression
Heine et al., Science 2008
cyclothiazide
+ X-link
Top view of the PSD
Glutamate release
20 µm
Homer 1c
2 µm
DIC
Iontophoresis to
remove the pre-
synaptic component
r = 0.943
100
110
120
130
140
150
160
0 10 20 30 40 50 60 70
Exercise (Km)
NR
2B
(%
Co
ntr
ol)
80
90
100
110
120
130
140
150
160
170
180
190
Sedentary Exercise
NR
2B
(%
Co
ntr
ol)
RD
DHA
*
**
#
#
Membrane fluidity affects function of embedded
receptors
MEMBRANE
FLUIDITY
STX-3
DHA DIET EXERCISE
DHA
sPLA2
Free
DHA
TOXICITY/
METABOLITES
SYNAPTIC
PLASTICITY/
COGNITION
Other
Membr.
Recept.
NR2B/
NMDA
Recept.
Chytrova et al, Neuroscience, Brain Res, in press
Courtesy of Fernando Gomez Pinilla
THE BRAIN IS MALLEABLE
The brain is capable of being
altered by outside forces or
influences
An important premise for the
discussion of “nutrition and brain”:
•Plasticity (mobility) at the level of
neurotransmitter receptors: single
molecule tracking
•Plasticity at the level of synapses and
glia: multiphoton imaging technology
•Plasticity is restrained by extracellular
matrix molecules: the importance of
extracellular matrix proteinases
The dream:
Microscopic
analysis of the
structure,
physiology, and
pathophysiology of
the living brain
”East is east and
west is west ….”Nase et al. 2004
WHY CANNOT
STANDARD
MICROSCOPICAL
TECHNIQUES BE
USED FOR
ANALYSES OF
INTACT BRAIN?
VISIBLE LIGHT IS
ABSORBED BY LIVE TISSUE
….AND PRODUCES
PHOTOTOXICITY
•Infrared light penetrates live
tissue better than visible light
•1931: Maria Göppert-Mayer
predicts that optical electronic
transitions in molecules can be
achieved in response to low-
energy (infrared) photons if the
photon flux is high enough
•This prediction was borne out
after the invention of the laser
Time-lapse images of
a dendritic region
(yellow box in c).
Examples of
transient, semi-
stable, and stable
spines are labeled
with blue, red, and
yellow
MULTIPHOTON
MICROSCOPY ALLOWS
CHRONIC IMAGING OF
SPINES IN THE CORTEX
OF LIVE MICE
SVOBODA ET AL., NATURE 19 DECEMBER 2002
.
New spines establish
synapses
And new synapses
may appear from one
day to the next
Two new spines appeared
between the 7th and 8th
imaging day (boxes in d and
e)
Electron micrographs
showing synapses
established by these new
spines.
SVOBODA ET AL., NATURE
19 DECEMBER 2002
Altering sensory
experience
increases spine
turnover rates.
Spine density for cells lying
within (green) or outside
(black) the barrel cortex.
Spine density does not
change in response to
deprivation.
Turnover ratio increased
after deprivation within
(green) but not
outside (black) barrel
cortex.
Meyer-Luehmann et al.,
Nature 2008.
Multiphoton imaging allows analyses of disease mechanisms:
identification of ”popcorn plaques” in an animal model of
Alzheimer’s disease
Reconstructed amyloid deposit
Nuntagij, Torp et al. 2008
3D reconstructions of
astrocytes reveal
volume changes after
hypo-osmotic stress
(150 ml/kg water i.p.)
Nase, Helm & Ottersen, 2008
Multiphoton imaging to identify mechanisms of brain edema formation
Hypo-osmotic stress
causes swelling of
perivascular
astrocytes (red) and
no change in the
volume of astrocytes
more distant from
brain microvessels
(blue)
…indicating that
astrocytes are
primary sites of
water entry
This fits with the idea that
water enters through
perivascular aquaporins
ASTROCYTE
ENDFOOT
CAPIL-
LARY
Amiry-Moghaddam et al., PNAS 2003;
Amiry-Moghaddam & Ottersen, Nature Neurosci
Rev 2003
THE BRAIN IS MALLEABLE
The brain is capable of being
altered by outside forces or
influences
An important premise for the
discussion of “nutrition and brain”:
•Plasticity (mobility) at the level of
neurotransmitter receptors: single
molecule tracking
•Plasticity at the level of synapses and
glia: multiphoton imaging technology
•Plasticity is restrained by
extracellular matrix molecules: the
importance of extracellular matrix
proteinases
Aquaporin-4 is anchored to the
extracellular matrix through
dystrophin and dystroglycan
(Neely, Amiry-Moghaddam et al., PNAS 2001; Amiry-Moghaddam
et al., PNAS 2003)
Amiry-Moghaddam &
Ottersen
Dystroglycans
(and other
extracellular
matrix molecules)
can be cleaved by
matrix
metalloproteinases
(including MMP9)
Matrix
Metalloproteinase-9
(MMP9) is
associated with
astrocytic endfeet
as well as spines
Wilczynski et al,
J Cell Biol 2008
MMP-9 deficiency diminishes seizure-evoked
pruning of dendritic spines and decreases
aberrant synaptogenesis after mossy fiber
sprouting
Wilczynski et al, J Cell Biol
2008
Brain extracellular matrix affects AMPA receptor
lateral mobility and short-term synaptic plasticity
Renato Frischknecht, Martin Heine, David
Perrais, Constanze I Seidenbecher, Daniel
Choquet, Eckart D Gundelfinger
Nature Neuroscience, May 29, 2009
THE BRAIN IS
MALLEABLE – not
hardwired
An important premise for the
discussion of “nutrition and brain”:
•Plasticity at the level of
synapses and glia:
multiphoton imaging
technology
•Plasticity (mobility) at the
level of neurotransmitter
receptors: single molecule
tracking
•Plasticity is restrained by
extracellular matrix
molecules: the importance of
extracellular matrix
proteinases
The brain cannot be properly understood without
access to analyses in ”real time”
… just as the plot of Casablanca is not easily
understood on the basis of single frames
Heraclitus: Panta rei -
Everything is
constantly changing
…one does not step
into the same river
twice (and your brain is not the
same when you leave as when you
arrived)
The malleability of brain instils hope when it
comes to the prospect of nutritional intervention
The team: Laboratory of Molecular Neuroscience
Laboratory of Molecular Neuroscience
Professors
Eric Rinvik
Finn Mogens S. Haug (em.)
Kirsten Osen (em.)
Associate Professor
Svend Davanger
Senior researchers
Reidun Torp
Gabriele Nase
Erlend Nagelhus
Mahmood Amiry-Moghaddam
Torgeir Holen
Postdocs
Elise Rundén-Pran
Janniche Hammer
Anna Thoren
Undergraduate students:
Didrik Søli Frydenlund
Jan-Øyvind Lorgen
Jan Gunnar Sørbø
Svein Erik Moe
Hussain Suleman
Rune Enger
Georg Andreas Gundersen
Martine Eilert-Olsen
Katja Stahl
EM engineer
Bashir A. Hakim
Laboratory engineers
Karen Marie Gujord
Jorunn Knutsen
Bjørg Riber
Marianne Vaadal
Laboratory Physicist
P. Johannes Helm
Editorial Assistant Neuroscience
Mette Ljungqvist Johannessen
Administration
Maria Beatriz Rocha
PhD students
Maria Niki Mylonakou
Hanna Ahlgren
Nadia Nabil Haj Yasein
Lisa Olsson
Laura Camassa
Jing Yang
Tom Tallak Solbu
Guest researchers
Tomohiro Oguchi
Luciene Covolan
GROUP LEADERS:
Jan G. Bjaalie (UiO)
Magnar Bjørås(RH)
Niels Christian Danbolt (UiO)
Arne Klungland (RH)
Michael Koomey (UiO)
Stefan Krauss (BiO)
Ole Petter Ottersen (UiO)
Torbjørn Rognes (RH)
Johan Storm (UiO)
Jon Storm-Mathisen (UiO)
Tone Tønjum (RH) Associate Director
Thanks to members
of CMBN
Plus Vilhelm Bohr, Vidar Gundersen, Reidun Torp, Stig Omholt
Thank you for your attention
And I hope you have had some
food for thought
Thank you for your attention
Scanbalt etec MahmoodTranslasjonsinstitutt ageing
Uio rangering EvafARMasiUtenlandsk evalueringChem biolLife science centreHistfilstyresammensetn
THE PROBLEM: Cell death and edema
formation are parts of a
vicious cycle
There is a need for a two-
pronged approach to
therapy:
•Cytoprotection
There is a need to
understand the mechanisms
of glutamate transmission
and toxicity
•Curbing edema formation
There is a need to
understand the cellular and
molecular mechanisms of
edema formation
Stroke Cell death and edema
Which are the first cells to
accumulate water in brain
edema?
Does the perivascular AQP4
pool serve as an influx route
for water?
ASTROCYTE
ENDFOOT
CAPIL-
LARY
3D reconstructions of
astrocytes reveal
volume changes after
hypo-osmotic stress
(150 ml/kg water i.p.)
Nase, Helm & Ottersen,
2008
Recording of cell volume changes in individual cells in vivo
Hypo-osmotic stress
causes swelling of
perivascular
astrocytes (red) and
no change in the
volume of astrocytes
more distant from
brain microvessels
(blue)
…indicating that
astrocytes are
primary sites of
water entry
Multiphoton analysis is also applicable to brain slices
Multiphoton imaging of cell volume
slices reveals mechanisms underlying
cell volume control
Multiphoton imaging analysis
supports the idea that
perivascular AQP4 serves as an
influx route for water
ASTROCYTE
ENDFOOT
CAPIL-
LARY
In vivo imaging offers
a unique tool for testing
effect of putative AQP4
inhibitors
Opportunities •New building 2010,
”interaction through key
technologies”
•High throughput tissue processing
•Proteomics/structure biology
•Imaging – including multiphoton
imaging and PET/MR
•Neuro/bioinformatics
•Transgene technology/animal
facilities
•Animal models
•The new building is meant to serve as
a hub for international collaborative
networks
Acknowledgements
Thanks to Letten F. Saugstad and the
Letten Foundation, for invaluable
support
Our thanks are also extended to:
•The University of Oslo
•The Medical Faculty and Institute of Basic Medical
Sciences
•The Norwegian Research Council
•The University Library
•The technical staff
The team
A BRIGHT FUTURE FOR BRAIN
RESEARCH: THE POTENTIALS OF
MULTIPHOTON LASER SCAN
IMAGING
Ole Petter Ottersen,
Centre for Molecular Biology and Neuroscience
and Department of Anatomy,
Institute of Basic Medical Sciences,
University of Oslo
The dream come
true: microscopical
analysis of the
structure,
physiology, and
pathophysiology of
the living brain
WHY CANNOT
STANDARD
MICROSCOPICAL
TECHNIQUES BE
USED FOR
ANALYSES OF
INTACT BRAIN?
VISIBLE LIGHT IS
ABSORBED BY LIVE
TISSUE
….AND PRODUCES
PHOTOTOXICITY
Time-lapse images of
a dendritic region
(yellow box in c).
Examples of
transient, semi-
stable, and stable
spines are labeled
with blue, red, and
yellow
MULTIPHOTON
MICROSCOPY ALLOWS
CHRONIC IMAGING OF
SPINES IN THE
CEREBRAL CORTEX OF
LIVE MICE
SVOBODA ET AL., NATURE 19 DECEMBER 2002
.
New spines establish
synapses
And new synapses
may appear from one
day to the next
Two new spines appeared
between the 7th and 8th
imaging day (boxes in d and
e)
Electron micrographs
showing synapses
established by these new
spines.
Altering sensory
experience
increases spine
turnover rates.
Spine density for cells lying
within (green) or outside
(black) the barrel cortex.
Spine density does not
change in response to
deprivation.
Turnover ratio increased
after deprivation within
(green) but not
outside (black) barrel
cortex.
Meyer-Luehmann et al.,
Nature 2008.
Multiphoton imaging allowed
identification of ”popcorn plaques”
Beta- AMYLOID
deposits detected
by multiphoton
imaging using
methoxy-XO4
MULTIFOTON TECHNOLOGY PERMITS
”ON LINE” ANALYSIS OF DISEASE
MECHANISMS
University of OsloLaboratory of Molecular Neuroscience
This means that the
development of amyloid
plaques can now be
examined at different
levels of resolution – from
EM to PET
Torp et al., 2001
dendrite
Developing
amyloid deposit
Combination of imaging techniques holds great
promise for a better understanding of disease
mechanisms
EM MULTIFOTON PET
THE PROBLEM: Cell death and edema
formation are parts of a
vicious cycle
There is a need for a two-
pronged approach to
therapy:
•Cytoprotection
There is a need to
understand the mechanisms
of glutamate transmission
and toxicity
•Curbing edema formation
There is a need to
understand the cellular and
molecular mechanisms of
edema formation
Stroke Cell death and edema
Which are the first cells to
accumulate water in brain
edema?
Does the perivascular AQP4
pool serve as an influx route
for water?
ASTROCYTE
ENDFOOT
CAPIL-
LARY
3D reconstructions of
astrocytes reveal
volume changes after
hypo-osmotic stress
(150 ml/kg water i.p.)
Nase, Helm & Ottersen,
2008
Recording of cell volume changes in individual cells in vivo
Hypo-osmotic stress
causes swelling of
perivascular
astrocytes (red) and
no change in the
volume of astrocytes
more distant from
brain microvessels
(blue)
…indicating that
astrocytes are
primary sites of
water entry
Multiphoton analysis is also applicable to brain slices
Multiphoton imaging of cell volume
slices reveals mechanisms underlying
cell volume control
Quantitative analyses reveal heterogeneous
mechanisms for volume control
Multiphoton imaging analysis
supports the idea that
perivascular AQP4 serves as an
influx route for water
ASTROCYTE
ENDFOOT
CAPIL-
LARY
In vivo imaging offers
a unique tool for testing
effect of putative AQP4
inhibitors
Synthetic peptide inhibits water uptake through AQP4
(collaboration with Inst. Pharmacy)
There are also
limitations to
the technique:
The thinned
scull
interferes
Nase et al., J
Neurosci Meth, in
press
The
thinned
scull
interferes
The shapes of small objects are distorted
Opportunities •New building 2010,
”interaction through key
technologies”
•High throughput tissue processing
•Proteomics/structure biology
•Imaging – including multiphoton
imaging and PET/MR
•Neuro/bioinformatics
•Transgene technology/animal
facilities
•Animal models
•The new building is meant to serve as
a hub for international collaborative
networks
BRODAL AND WALBERG
Single molecule detection
< 50 nm
Receptor trajectory
Quantum Dot
Pointing accuracy ~30 nm
300 nm
Single molecule tracking of surface receptors