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