Molecular linking of the brain to mind...Human & mouse brain A mind is the set of cognitive...
Transcript of Molecular linking of the brain to mind...Human & mouse brain A mind is the set of cognitive...
Molecular linking
of the brain to mind
INCF, Warsaw April 16, 2015
Leszek Kaczmarek, Nencki Institute, Warsaw
Human & mouse brain
A mind is the set of cognitive faculties that enables consciousness, perception, thinking, judgement, and memory—a characteristic of humans, but which also may apply to other life forms
Wikipedia
the cellular connectionist approach, which derived
from Cajal’s idea that memory is stored as an
anatomical change in the strength of synaptic
connections (Cajal, 1894). (In 1948 Konorski
renamed Cajal’s idea synaptic plasticity [the ability
of neurons to modulate the strength of their
synapses as a result of use (Konorski, 1948)].
Kandel, Dudai & Mayford, Cell, 2014
Human brain: 85 billions of neurons; mouse brain: 70 mln; over 1 000 connections for each one
Glutamate
Glu Receptor
c-Fos
The joint term learning and memory (L&M) refers to
an animal (or human) ability to respond adequately
to environmental signals that in either exact or
similar nature have been encountered before and
might have important consequences, such as
allowing to withdraw from dangerous or unpleasant
conditions (aversive learning) or, alternatively,
approach the positive ones (appetitive learning).
After: Konopka, Schütz & Kaczmarek, Neuroscientist, 2011
IntelliCage H.P.Lipp, Zurich
Knapska et al., Learn. Mem, 2006
Central amygdala in appetitive learning
Place PreferencePlace Avoidance
c-Fos drives TIMP-1 & MMP-9:
Extracellular (synaptic) proteolytic system
Based on: Michaluk & Kaczmarek Cell Death Differ., 2007
TIMP-1TIMP-1
MMP-9
Jaworski et al., J.Biol. Chem., 1999
Kaczmarek et al., EMBO J., 2002
Kuzniewska et al., Mol. Cell. Biol., 2013
Ganguly et al., J.Biol.Chem., 2013
Gawlak et al., Neuroscience, 2009
MAP-2
MMP
activity
NR1
Appetitive conditioning is defective in MMP-9 KO
Knapska et al. J. Neurosci., 2013
Central amygdala-dependent appetitive conditioning
requires MMP-9 activity
. .
Knapska et al. J. Neurosci., 2013
Synaptic plasticity requires MMP-9
MMP-9
Michaluk et al., J. Neurosci., 2009; J. Cell. Sci., 2011;
Szepesi, et al., PLoS One, 2014
Rolipram+forskolin+picrotoxin
Before
40 min.
40 min.
w/o MMP-9
Glutamate GluA1 Receptor
Glutamate GluA1 Receptor
Knapska et al.,
PNAS, 2012
0 min
15 min
Stawarski et al.,
Biomaterials, 2014
How much do we know?
PNAS, 2013
How much do we know?
PNAS, 2013
Christ Church College Oxford
Michaluk et al. J. Neurosci. 2009
MMP-9 gene may be associated
with psychiatric disorders
Rybakowski et al., Schizophr. Res., 2009
& NeuroMolecular Medicine, 2009
-1562 C/T polymorphism affects MMP-9 gene expression
Samochowiec et al., Brain Res, 2010
0
10
20
30
40
50
60
Control, N=136
Alcoholics,N=139
Bipolar, N=416
Control, N=558
Schizophrenia,N=432
% of people with either T/T or T/C genotype, resulting in a higher expression
P=0.03P=0.03
P=0.001
High MMP-9 activity levels in Fragile X Syndrome are lowered
by minocycline that produces improvement
Bilousova et al., J. Med. Genet., 2009
� Fmr1 gene mutation is the
most common cause of
hereditary intellectual
disability in boys (IQ 20-70)
� Other symptoms: autistic
spectrum disorders,
behavioral disorders
� Epilepsy (25%)
� Neurons exhibit numerous
long, filopodia-like immature
dendritic spines
� FMRP KO mice reproduce the
human phenotype
Dziembowska et al.,
Am J Med Genet Part A, 2013
Minocycline treatment for 3 months in children with FXS
resulted in greater global improvement than placebo. Leigh et al., J Dev Behav Pediatr., 2013
MMP-9 mRNA
FMRP Co-localization
Janusz et al., J. Neurosci., 2013
M.Stefaniuk & M. Stawarski
Imaging the Brain
before clearing after clearing
clearing (CUBIC reagent)
Light-sheet fluorescence microscopy
is our choice for Method of the Year
2014 for its ability to image three-
dimensional biological samples at
high speed and with low toxicity.
Knapska i wsp., PNAS, 2012
Seeing the mind: Transgenic „Venus” rat to map
functional connectomics
Nencki Institute: E.Nikolaev, B.Kaminska, T.Werka, A.Szklarczyk, J.Jaworski, J.Dzwonek, P.Okulski, K.Duniec,
M.Rylski, E.Knapska, G.Wilczynski, F.Konopacki, M.Balcerzyk, P.Michaluk, A.Kowalczyk, V.Lioudyno,
L.Kolodziej, T.Gorkiewicz, R.Amborska, M.Gawlak, E.Wilczek, K.Duniec, Z.Lasiecka, I.Figiel, M.Wawrzyniak,
M.Yeghiazaryan D.Owczarek, K.Radwanska, J.Wlodarczyk, A.Walczak, M.Mikosz, Z.Szepesi, M.Chaturvedi,
K.Kalita, B.Kuzniewska, M.Stawarski, M.Stefaniuk, M.Dziembowska, K.Lepeta, O.Sakharczuk, K.Ganguly,
B.Pijet, A.Suska, A.Janusz, J.Milek, D.Gierej, A.Kaliszewska, M.Kossut
Szczecin: J.Samochowiec et al.
Poznan: J.Rybakowski et al. , Adamiak et al..
Wroclaw: J.Mozrzymas, G.Wiera et al.
Magdeburg: H.J.Matthies, W.Tischmeyer, M.Krug, W.Zuschratter, R.Frischknecht, M.Heine, A.Bikbaev
Oslo: O.-P.Ottersen
Bordeaux: D.Choquet, L.Mikasova, L.Groc, E.Hosy
Geneve: D.Muller, M.De Roo
Groton, PA: C.Strick
Los Angeles: R.Costa, A.Matynia, A.Silva
New York City: V.Nagy, O.Bozdagi, G.Huntley
San Francisco: Z.Werb , M.Sheng Montreal: S.Hanessian Rome: T.Petrucci
Heidelberg: W.Konopka, G.Schutz et al.
Milton Keynes: M.G.Steward, N.Medvedev
Zurich: H.P.Lipp, D.Wolfer
Davis & Sacramento: D.I.Pretto, M.J.Leigh, N.Gabriel, B.Durbin-Johnson, R.J.Hagerman, F.Tassone
Marseille: S.Rivera, M.Khrestchatisky
Rome & Leuven: C.Bagni, L.Paccini
College Station, TX: S.Maren
Jerusalem: E.Nelken
Goettingen: H.Ehrenreich, B.Stepniak, L.de Hoz
Bergen: C.R.Bramham
Lausanne: C.Sandi et al.