Center for Brain Science
Dept Molecular Cellular Biology
Center on the Developing Child
Harvard University
FM Kirby Neurobiology Center
Department of Neurology
Children's Hospital Boston
Harvard Medical School
Takao K. Hensch
Brain Plasticity
Ability to alter brain function in response to experience
Plasticity
Molecules adjust circuit connectivity through neural activity
“Brain cells fire in patterns” - S Pinker
“Neurons that fire together, wire together” -DO Hebb
“Out of sync, lose a link” - G Stent
“the habits we form from childhood make
no small difference, but rather they make
all the difference”- Aristotle
Neu
ral
Pla
sti
cit
y
0 6 93 2 6 10 14 20 40
months yearsAge
Vision / Hearing Language
Higher Cognitive Function
(adapted from CA Nelson, From
Neurons to Neighborhoods, 2000)
Sequential windows of opportunity/vulnerability
acuity loss delay mental illness
Amblyopia in mice
1) E / I
balance
2) molecular
‘brakes’
3) implications
(other systems)
(Hubel, Wiesel et al)
tPA
(Mataga et al PNAS 2002;
Oray et al Neuron 2004)
(Mataga et al Neuron 2004;
Coleman et al JNeurosci 2010)
tPA
(Mataga et al Neuron 2004)
D. Hubel T. Wiesel
Pruning connections during a critical period for vision
(Hubel, Wiesel et al)
tPA
(Mataga et al PNAS 2002;
Oray et al Neuron 2004)
(Mataga et al Neuron 2004;
Coleman et al JNeurosci 2010)
tPA
(Mataga et al Neuron 2004)
Pruning connections during a critical period for vision
Baumgartner, 1959
Postnatal development of visual acuity (human)
Local circuits in the neocortex
Excitatory (80%) Inhibitory (20%)
Double
bouquet
cell
Long stringy
cell
100 µm
Neurogliaform
cellChandelier
cell
Basket cell
Pyramidal cells
(Jones 1987)
‘plasticity trigger’ cell‘plasticity effector’ cell
GAD65 KO
GABAAα1
(BDZs)
BDNF
Otx2
Dark-rearing
Otx2 KO
∆PSA
GABA circuit maturation triggers visual plasticity
LGN
(Hensch, Nat Rev Neurosci 2005)
(Di Cristo et al, Nat Neurosci 2007)
(Sugiyama et al, Cell, 2008)
MGE transplants
(Southwell et al, Science 2010)
Dark-rearing delays PV-circuit maturation
Parvalbumin (PV)
Light-reared Dark-reared
Orchestrating sequential plasticity across domains
S1 A1 V1 V4 TE . mPFC . .
age
plasticity
(Condé F, Lund JS, Lewis DA 1996)
Electrical
Locus Ceruleus Stimulation
Basal forebrain stimulation
Transcranial Magnetic
Stimulation
Surgical
Astrocyte Transplant
Embryonic Inhibitory Neuron
Precursor Transplant
GeneticASD genes
Crtl1 KO
NgR KO
PirB KO
dnNgR
Lynx1 KO
PharmacologicalNGF Infusion
chABC
Valproic acid/TSA
AChase Inhibitor
Fluoxetine (SRI)
L-threo-DOPS
cAMP Activation
Focal Demyelination
EnvironmentalHypoxic-ischemia
Sensory deprivation
Stress
Enrichment
Food restriction
Perceptual Learning
Video Games
E
I
Factors impacting E-I balance
(Hensch & Bilimoria,
Cerebrum 2012)
Sequential development of human language
Werker JF., Philos Trans R Soc Lond B Biol Sci. 2009
Acknowledgments
LGN
Critical
Period
Plasticity
E/I balance
Plasticity
postnatal age
brakes brakes
Biological constraints on critical period timing
(Hensch, Nat Rev Neurosci 2005)
(Bavelier et al J Neurosci 2010)
(Pizzorusso et al
2002, 2006)
chondroitinase
PNN PV
functional
structural
PNNs
Large
Basket cells
Perineuronal net (PNN) removal reactivates plasticity
(C. Golgi, 1898).
“…a delicate covering, mainly reticular in structure… in the form of little tiles or envelope…”
(Y Yazaki et al, Nature 2009)
Bidirectional plasticity in fast-spiking (FS) cells
PNNs enriched in chondroitin sulphate proteoglycans
Sensory experience promotes PV-cell maturation
by Otx2 transfer
(Sugiyama et al Cell, 2008)
(Beurdeley et al J Neurosci, 2012)
E I
pre-CP critical period (CP) adult
E I
Re-set functional E-I balance
Remove structural “brakes”
Biological mechanisms of critical period timing
5-HTT
lynx1
PNN /Otx2
NgR/PirB
HDACs
(Morishita & Hensch, Curr Op Neurobiol 2008)
(Bavelier et al, J Neurosci 2010)
E I
GAD65
GABAAα1
BDNF
Otx2
∆PSA
Cholinergic System Nicotinic Receptor
Neuromodulatory systems in the brain
Over-Activating nAChRs
Lynx1 KO
Cholinesterase inhibitor
Releasing a cholinergic ‘brake’ rescues amblyopia
(Morishita et al, Science 2010)
Over-Activating nAChRs
Lynx1 KO
Cholinesterase inhibitor
Releasing a cholinergic ‘brake’ rescues amblyopia
(Morishita et al, Science 2010)
SSRI
cholinesterase
inhibitors
Local E/I circuit balance remodels long-range afferents
across systems
“genius is nothing more nor less than
childhood recovered at will”
-Baudelaire