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

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