Brain Plasticity. Takao K. Hensch. Center for Brain Science Dept Molecular Cellular Biology Center on the Developing Child Harvard University

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1 Brain Plasticity Takao K. Hensch FM Kirby Neurobiology Center Department of Neurology Children's Hospital Boston Harvard Medical School Center for Brain Science Dept Molecular Cellular Biology Center on the Developing Child Harvard University

2 Plasticity Ability to alter brain function in response to experience 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

3 the habits we form from childhood make no small difference, but rather they make all the difference - Aristotle

4 Sequential windows of opportunity/vulnerability acuity loss delay mental illness Vision / Hearing Language Neural Plasticity Higher Cognitive Function months years Age (adapted from CA Nelson, From Neurons to Neighborhoods, 2000)

5 Amblyopia in mice 1) E / I balance 2) molecular brakes 3) implications (other systems)

(Mataga et al Neuron 2004; Coleman et al JNeurosci 2010) D.

6 Pruning connections during a critical period for vision tpa (Mataga et al PNAS 2002; Oray et al Neuron 2004) tpa (Mataga et al Neuron 2004; Coleman et al JNeurosci 2010) D. Hubel T. Wiesel (Hubel, Wiesel et al) (Mataga et al Neuron 2004)

7 Pruning connections during a critical period for vision tpa (Mataga et al PNAS 2002; Oray et al Neuron 2004) tpa (Mataga et al Neuron 2004; Coleman et al JNeurosci 2010) (Hubel, Wiesel et al) (Mataga et al Neuron 2004)

8 Postnatal development of visual acuity (human) Baumgartner, 1959

9 Local circuits in the neocortex Excitatory (80%) Inhibitory (20%) plasticity effector cell plasticity trigger cell Pyramidal cells 100 µm Double bouquet cell Basket cell Chandelier cell Long stringy cell Neurogliaform cell (Jones 1987)

10 GABA circuit maturation triggers visual plasticity LGN GABA A α1 (BDZs) BDNF Otx2 PSA GAD65 KO Dark-rearing Otx2 KO MGE transplants (Hensch, Nat Rev Neurosci 2005) (Sugiyama et al, Cell, 2008) (Di Cristo et al, Nat Neurosci 2007) (Southwell et al, Science 2010)

11 Dark-rearing delays PV-circuit maturation Light-reared Dark-reared Parvalbumin (PV)

12 Orchestrating sequential plasticity across domains plasticity S1 A1 V1 V4 TE. mpfc.. age (Condé F, Lund JS, Lewis DA 1996)

Factors impacting E-I balance Environmental Hypoxic-ischemia Sensory deprivation Stress

chabc Valproic acid/tsa AChase Inhibitor Fluoxetine (SRI) L-threo-DOPS camp Activation Focal

Transplant Embryonic Inhibitory Neuron Precursor Transplant Electrical Locus Ceruleus

13 Factors impacting E-I balance Environmental Hypoxic-ischemia Sensory deprivation Stress Enrichment Food restriction Perceptual Learning Video Games Pharmacological NGF Infusion chabc Valproic acid/tsa AChase Inhibitor Fluoxetine (SRI) L-threo-DOPS camp Activation Focal Demyelination Genetic ASD genes Crtl1 KO NgR KO PirB KO dnngr Lynx1 KO E I Surgical Astrocyte Transplant Embryonic Inhibitory Neuron Precursor Transplant Electrical Locus Ceruleus Stimulation Basal forebrain stimulation Transcranial Magnetic Stimulation (Hensch & Bilimoria, Cerebrum 2012)

14 Sequential development of human language Werker JF., Philos Trans R Soc Lond B Biol Sci. 2009

15 Acknowledgments

17 Biological constraints on critical period timing Plasticity Plasticity E/I balance LGN brakes brakes (Hensch, Nat Rev Neurosci 2005) (Bavelier et al J Neurosci 2010) Critical Period postnatal age

18 Perineuronal net (PNN) removal reactivates plasticity (Pizzorusso et al 2002, 2006) functional a delicate covering, mainly reticular in structure in the form of little tiles or envelope PNN PV Large Basket cells PNNs chondroitinase structural (C. Golgi, 1898).

19 Bidirectional plasticity in fast-spiking (FS) cells (Y Yazaki et al, Nature 2009)

20 PNNs enriched in chondroitin sulphate proteoglycans

21 Sensory experience promotes PV-cell maturation by Otx2 transfer (Sugiyama et al Cell, 2008) (Beurdeley et al J Neurosci, 2012)

22 Biological mechanisms of critical period timing Re-set functional E-I balance pre-cp critical period (CP) adult E I GAD65 GABA A α1 BDNF Otx2 PSA E I 5-HTT lynx1 PNN /Otx2 NgR/PirB HDACs E I Remove structural brakes (Morishita & Hensch, Curr Op Neurobiol 2008) (Bavelier et al, J Neurosci 2010)

23 Neuromodulatory systems in the brain Cholinergic System Nicotinic Receptor

24 Releasing a cholinergic brake rescues amblyopia (Morishita et al, Science 2010) Over-Activating nachrs Lynx1 KO Cholinesterase inhibitor

25 Releasing a cholinergic brake rescues amblyopia (Morishita et al, Science 2010) Over-Activating nachrs Lynx1 KO Cholinesterase inhibitor

26 SSRI cholinesterase inhibitors

27 Local E/I circuit balance remodels long-range afferents across systems

28 genius is nothing more nor less than childhood recovered at will -Baudelaire

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