dhoogePP

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Onze hersenen en ons gedrag

Moleculaire psychologie en neuroplasticiteit

Prof. Dr. Rudi D’Hooge

Laboratorium voor Biologische Psychologie

K.U.Leuven

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•

• huge neural matrix for information representation

more than 100 x 10

9

_{brain cells & each cell may receive thousands of synaptic contacts}

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―MOLECULAR

PSYCHOLOGY‖

Jon Franklin, 1987

• molecules of the brain, neuropsychofarmacologie, therapeutische toepassingen

Synaptic plasticity & molecular psychology:

• hersenen gevormd door vroege ervaring (Rosenzweig, Hubel & Wiesel)

• Hebbiaanse plasticiteit in het volwassen zenuwstelsel (leervermogen,

compensatorische mechanismen, ziekteprocessen)

Solomon H. Snyder

Eric Kandel – Nobelprijs 2000

―Every human thought, hope, fear, passion, yearning, and insight results from

chemical interactions between transmitters and receptors‖

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RESPONSE

US

CS

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Hebb’s postulate

"When an axon of cell A is near enough to excite a cell B

and repeatedly or persistently takes part in firing it, some

growth process or metabolic change takes place in one or

both cells such that A’s efficiency, as one of the cells

firing B, is increased."

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•

• INFORMATION STORAGE IN THE BRAIN

localized vs. diffuse

diffuse network of cell

assemblies established by

strengthening of synaptic

connections between the

building blocks

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NEOCORTEX

HIPPOCAMPUS

STORAGE & RECALL

INPUT

MEMORY DEFECT AFTER HIPPOCAMPAL DAMAGE

Donald O. Hebb Award (Canadian Society for Brain,

Behaviour and Cognitive Sciences, 2001):

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Hippocampus

Thalamus Corpus callosum Striatum

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MOUSE BRAIN

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•

• LONG-TERM POTENTIATION (LTP)

HIGH-FREQUENCY STIMULATION

rat hippocampal slice

S

: stimulation of Schaffer collaterals

R

: field excitatory postsynaptic

potentials (EPSPs) recorded from CA1

potentiation of responses

20 min after HFS

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Molecules of the Hebbian Synapse

Ca

2+

NMDA-R

AMPA-R

GLUTAMATE

RELEASE

CALCIUM-DEPENDENT

PROCESSES

PRESYNAPTIC

TERMINAL

POSTSYNAPTIC

TERMINAL

mGluR

Ras

activation

Raf

Mek

Mapk

→ LR genes → IEG pCREB

vGluT

_Spred1

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Assessing learning & memory in

laboratory mice

• mazes or labyrinths

• passive or active avoidance protocols

• contextual fear conditioning

• operant chamber training

• discrimination learning...

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TRIAL 1

TRIAL 8

TRIAL 16

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•

• Acquisition

TRIAL BLOCK

1 2 3 4

ESC

A

P

E LATENC

Y

(in s)

0 50 100 150 200 250 300 350 400 % TIME IN QU AD RA NT 0 10 20 30 40 50 60 target adjacent 1 adjacent 2 opposite

(path length, swimming velocity)

(target entries)

Testing

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MWM PERFORMANCE

IN HIPPOCAMPUS-LESIONED RATS

Swimming paths during

Trial 28 (end of training)

Probe trial

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•

• Molecules of the Hebbian Synapse

Ca

2+

NMDA-R

AMPA-R

GLUTAMATE

RELEASE

CALCIUM-DEPENDENT

PROCESSES

PRESYNAPTIC

TERMINAL

POSTSYNAPTIC

TERMINAL

mGluR

Ras

activation

Raf

Mek

Mapk

→ LR genes → IEG pCREB

vGluT

_Spred1

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•

• Ca

2 +

NMDA-R

AMPA-R

GLUTAMATE

RELEASE

CALCIUM-DEPENDENT

PROCESSES

PRESYNAPTIC

TERMINAL

POSTSYNAPTIC

TERMINAL

m GluR

m GluR7

Ras

activation

Raf

Mek

Mapk

→ LR genes → IEG pCREB

vGluT

_Spred1

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•

Deletion of VGLUT1 impairs robust LTP induced by strong, triple tetanization theta-burst stimulation (TBS) in the CA1 region of the hippocampus.

(A) Input/output-curves of VGLUT1-deficient heterozygous mice and wild-type controls. fEPSP-slopes were recorded at increasing stimulation intensities until a maximum was attained. There were no significant differences between both groups.

(B) Paired-pulse facilitation (PPF), calculated from the ratio of the second fEPSP-slope to the first fEPSP-slope. At all interpulse intervals, no significant differences were observed between VGLUT1+/- and VGLUT1+/+mice.

(C) Examples of LTP recordings from a VGLUT1+/+ slice (upper row) and a VGLUT1+/- slice (lower row). The insets represent analogue traces, taken during baseline recording (1), 10 min after tetanization to exclude post-tetanic potentiation (2) and 3 hours post-tetanus (3). The superimposed traces 1 + 3 indicate the remaining potentiation after 3 hours.

(D) Average values calculated as percentage of baseline measures. Note the lower initial magnitude of potentiation in VGLUT1 +/- mice and the

continuous increase of fEPSP-slope during the triple TBS as compared with the saturation of potentiation in wild-type mice after the 2nd TBS.

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0 1 2 3 4 5 6 7 8 9 10 0 20 40 60 80 100 P1 P2 Acquisition L a te n c y ( s ) 1 2 3 30 40 50 60 70

*

# # Reversal trial Di s ta n c e t o p la tf o rm ( c m ) O 0 5 10 15 20 1 2 3 1 2 3 * # D u ra ti o n c lo s e t o p o o l w a ll (s ) Ne w position Forme r position VGLUT1+/+ Pe riphe ral zone s

T

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•

• Ca

2 +

NMDA-R

AMPA-R

GLUTAMATE

RELEASE

CALCIUM-DEPENDENT

PROCESSES

PRESYNAPTIC

TERMINAL

POSTSYNAPTIC

TERMINAL

m GluR

m GluR7

Ras

activation

Raf

Mek

Mapk

vGluT

_Spred1

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NMDA receptor

distribution

Immu

nostaining

of

NR2C sub

un

its

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Effect of NMDA receptor

antagonist on MWM learning

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•

• Ca

2+

NMDA-R

AMPA-R

GLUTAMATE

RELEASE

CALCIUM-DEPENDENT

PROCESSES

PRESYNAPTIC

TERMINAL

POSTSYNAPTIC

TERMINAL

mGluR

mGluR7

Ras

activation

Raf

Mek

Mapk

vGluT

_Spred1

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Water maze

performance in mGluR7

knockout mice

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•

• Ca

2 +

NMDA-R

AMPA-R

GLUTAMATE

RELEASE

CALCIUM-DEPENDENT

PROCESSES

PRESYNAPTIC

TERMINAL

POSTSYNAPTIC

TERMINAL

m GluR

m GluR7

Ras

activation

Raf

Mek

Mapk

vGluT

_Spred1

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Making New Connections:

Role of ERK/MAP Kinase

Signaling in Neuronal Plasticity

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•

• mouse models for therapeutic experiments

Preclinical research on Alzheimer’s disease

Amyloid plaque

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b

- Amyloid vaccination in mice

A

b

vaccinated

Normal

A

b

RADIAL

ARM

MAZ

E (

ERRO

RS)

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Aph1BC-deficient

Plaques in mouse mutant

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