Critical periods in development - “nature” vs. “nurture” - Part 2 Raghav Rajan Bio 334 – Neurobiology I September 2nd 2013 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Bio 334 - Neurobiology I - Critical periods in development 2 How do we know it is a critical period? What starts the critical period? What closes it? What determines that it is closed? what are the changes that can be made during the critical period? what changes cannot be made outside of the critical period? 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Bio 334 - Neurobiology I - Critical periods in development 2 Closing one eye changes representations in the visual cortex only when done early Kittens 2 days of monocular deprivation Shows that there does exist a critical period 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2 Mark F Bear, Barry W Connors, Michael A Paradiso. Neuroscience: Exploring the brain (2007) – Chapter 23

Bio 334 - Neurobiology I - Critical periods in development 2 Theoretical models predicted that the balance of excitation and inhibition could shape column width First shown in cats through injections into visual cortex Agents that reduced or increased inhibition 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2 Takao Hensch, Nature Reviews Neuroscience 2005 http://henschlab.files.wordpress.com/2012/06/hensch-nat-rev-neuro-2005.pdf

Bio 334 - Neurobiology I - Critical periods in development 2 Ocular dominance plasiticity in mouse visual cortex (without ocular dominance columns) Individual cells in the binocular zone can be tested for their response to contralateral and ipsilateral visual stimuli Mice provide an excellent genetic system to work out the molecular mechanisms 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2 Levelt and Hubener. Critical period plasticity in the visual cortex. Annual Reviews in Neuroscience 2012

Bio 334 - Neurobiology I - Critical periods in development 2 Mice knockout for GAD-65 (reduced inhibition) show no ocular dominance plasticity GAD-65 – one of two isoforms of an enzyme that synthesizes GABA – an inhibitory neurotransmitter No shift in ocular dominance after monocular deprivation http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851625/ 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Increasing inhibition restores ocular dominance plasticity Injecting diazepam (increasing inhibition) restores ocular dominance plasticity http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851625/ 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Bio 334 - Neurobiology I - Critical periods in development 2 Change in the amount of inhibition controls ocular dominance plasticity Red circles mark the start, peak and end of normal plasticity Modifying inhibition can advance or delay the critical period Takao Hensch, Nature Reviews Neuroscience 2005 http://henschlab.files.wordpress.com/2012/06/hensch-nat-rev-neuro-2005.pdf 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Synaptic changes occur after monocular deprivation Monocular deprivation triggers increase in spine motility Spines can then be eliminated Axons retract Spines can then recover Other axon outgrowth Takao Hensch, Nature Reviews Neuroscience 2005 http://henschlab.files.wordpress.com/2012/06/hensch-nat-rev-neuro-2005.pdf 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Bio 334 - Neurobiology I - Critical periods in development 2 Current understanding of ocular dominance plasticity – molecular mechanisms Takao Hensch, Nature Reviews Neuroscience 2005 http://henschlab.files.wordpress.com/2012/06/hensch-nat-rev-neuro-2005.pdf 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Can ocular dominance plasticity be re-induced in adulthood Onset of this plasticity determined by maturation of inhibitory interneurons Structural modifications are associated with critical period Few methods to induce ocular dominance plasticity again One is to dissolve the extracellular matrix that inhibits axonal sprouting and growth Another is to transplant inhibitory interneuron precursors from donors http://www.jneurosci.org/content/30/45/14964/F1.expansion.html 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Facets of critical periods Functional competition between inputs – tunes circuits to individual and its environment Structural modifications become impossible Regulation of onset and duration by experience, not age Timing is variable for different systems – one critical period may open only when another one is done Inhibition plays a key role Attention, motivation are also very important Potential for reactivation in adulthood – lifelong learning!! 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Bio 334 - Neurobiology I - Critical periods in development 2 Critical periods for higher functions like language – learning a second language as an adult is difficult Evidence for a critical period for language acquistion Socially isolated children lose ability to acquire normal language later Language recovery is better after cerebral damage only if damage occurs early in life Second language learning is difficult in adulthood Takao Hensch. Critical Period Regulation. Annual Review of Neuroscience 2004 http://henschlab.files.wordpress.com/2012/06/hensch-ann-rev-neurosci-2004.pdf 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Broadly language learning involves perception and production Both these aspects are affected later in life If you can perceive sounds properly, you can produce them better – and vice versa 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Bio 334 - Neurobiology I - Critical periods in development 2 Only some animals are vocal learners and among them songbirds are the most experimentally tractable 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Early work done on the chaffinch, a common European songbird http://www.birdsongs.it/songs/fringilla_coelebs/fringilla_coelebs.html# Spectrogram 4 http://en.wikipedia.org/wiki/Common_Chaffinch 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Song learning requires sensory experience Birds raised in auditory isolation have abnormal songs Birds deafened early also have abnormal songs Fernando Nottebohm. Ontogeny of bird song. Science 1970 http://www.psy.fsu.edu/~mnl/CNL/private/Neuroeth/Nottebohm%201970.pdf 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Song learning requires intact auditory feedback Deafening early in life (107 or 88d after hatching) results in poor songs as adults So, song is an example of vocal learning Fernando Nottebohm. Ontogeny of bird song. Science 1970 http://www.psy.fsu.edu/~mnl/CNL/private/Neuroeth/Nottebohm%201970.pdf 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Existence of sensitive period for song learning Hand-raised white crowned sparrows learned from tape tutors only during 10-50 days post-hatch 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Bio 334 - Neurobiology I - Critical periods in development 2 Some birds have only one sensitive period, while others have multiple sensitive periods Brainard and Doupe What songbirds teach us about learning. Nature 2002 http://www.summer10.isc.uqam.ca/Page/docs/readings/WHITE_Stephanie/Brainard%20and%20Doupe%20review.pdf 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Bio 334 - Neurobiology I - Critical periods in development 2 Sensitive periods are not age-dependent but instead rely on sensory experience Isolated birds will learn well after their sensitive period Birds reared in white noise conditions also have an extended sensitive period Castrated birds with lower testosterone also have an extended sensitive period In all cases, sensitive period is not extended indefinitely 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Hormones appear to be an important determinant of sensitive periods Testosterone early in life for a zebra finch can prematurely crystallize song In open-ended learners, testosterone can trigger changes in brain nuclei size, etc. in the breeding season 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Bio 334 - Neurobiology I - Critical periods in development 2 Testosterone levels, brain nuclei size and song change with breeding season http://people.eku.edu/ritchisong/birdcommunication.htmlhttp://classes.uleth.ca/2010 01/biol4420a/BirdPaper.Iwaniuk.Tramontin2000.pdf 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Neural substrates for song learning Brainard and Doupe What songbirds teach us about learning. Nature 2002 http://www.summer10.isc.uqam.ca/Page/docs/readings/WHITE_Stephanie/Brainard%20and%20Doupe%20review.pdf 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Structural modifications post first tutor song exposure can be imaged Image spines on GFP labelled neurons Isolated juvenile birds are tutored and spine stability is imaged that night Blue spines remain Yellow spines are lost Green spines are added http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918377/ 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Better song learning is correlated with increased spine turnover Lower spine turnover in adult birds that have finished learning http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918377/ 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Spines get stabilised within 24hrs of tutor song exposure Most changes in spine stability occur within 48 hours of tutor song exposure Low spine turnover birds learn less High spine turnover birds learn more http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918377/ 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Spines also get bigger after tutor song exposure http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918377/ 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2

Bio 334 - Neurobiology I - Critical periods in development 2 Thus, overall, for sensory, motor and higher functions, critical periods exist Critical periods represent periods when circuits tune themselves to the environment and the individual A period of “nurture” to adapt to “nature”!! (both genes and environment) An understanding might help facilitate life-long learning 2nd September 2013 Bio 334 - Neurobiology I - Critical periods in development 2