Early Experience and Developmental Learning

Overview Increasing differentiation of areas of cortex Infant is born during height of brain development Tertiary sulci develop from 1 month before to 12 months after birth

Four (very brief) Levels of Brain Development

Creation of a tube

Neural migration Many elements of initial neural migration specified genetically By 20 weeks gestation, 100 billion neurons! 50,000 – 500,000 neurons per minute Neurons follow path of glial cells outward from ventricles To form 6 layers of cortex

Neural development: Synaptogensis Once in place, synapses are overproduced somewhat haphazardly 1 year old has 150% more synapses than adult These are pruned (diminish) during development Repetition of sensory-motor patterns create more specific set of experience dependent synaptic linkages

Increase in complexity of neural connections                                                                                                                                        Increase in complexity of neural connections Like a growing forest

How do the correct synapses form? 15,000 synapses for every cortical neuron 1.8 million per second in first 2 years! Cerebral cortex triples in thickness in 1st year Sensory and motor neurons must extend to correct brain are and form correct synapses This quantity of information cannot be genetically micro-managed

Three models

What does individual development look like? Individuals Group

Two Types of Experience in Brain Development Experience-expectant Experience dependent

Experience-expectant How common early experiences provide essential catalysts for normal brain development Early visual stimulation, hearing, exposure to language, coordinating vision and movement, The developing brain “expects” and requires these typical human experiences, and relies on them as a component of its growth.

Experience-dependent How individual experience fosters new brain growth and refines existing brain structures Can be unique to an individual Reading Singing, music

Neural Darwinism (Edelman) Use it or lose it What is not used, is pruned What is used, develops stronger connections Organism & environment are system that shapes brain Brain development is guided by environment Brain enables behavior which shapes brain Synaptic development is not teleological

The fetus as constructing its own development Fetal behavior impacts physical development In chicks prevented from moving, cartilage turns to bone Fetal sensory experience impacts sensory development Mice whose tongues were anesthetized had malformed cleft palates

Prenatal sensory experience impacts sensory development Hearing typically develops before sight Rats, ducklings, and quail chicks exposed to visual stimulation prenatally before they normally would lose hearing ability at birth

Normal sensory development contingent on extra-fetal environment Differences in the timing of augmented prenatal stimulation led to different patterns of subsequent auditory and visual responsiveness following hatching. No effect on normal visual responsiveness to species-typical maternal cues was found when exposure to tactile and vestibular stimulation coincided with the emergence of visual function (Days 14-19) When exposure took place after the onset of visual functioning (Days 17-22), chicks displayed enhanced responsiveness to the same maternal visual cues. When augmented tactile and vestibular stimulation coincided with the onset of auditory function (Days 9-14), embryos subsequently failed to learn a species-typical maternal call prior to hatching. Honeycutt, H. & R. Lickliter (2003). Developmental Psychobiology 43: 71-81. The influence of prenatal tactile and vestibular stimulation and visual responsiveness in bobwhite quail: A matter of timing

Prenatal behavioral development 9 weeks - movement 16 weeks - frowning, grimacing 25 weeks - moves to drumbeat 26 weeks - remembers sounds 32 weeks - all brain areas functioning 34 weeks - can habituate

1st Trimester Behavioural Repertoire: 8 weeks: Startle (arms and legs shoot outward) 9 weeks: “graceful” general movements of the head, trunk, limbs 10 weeks: Stretch (head moves back, trunk arches, arms lifted) 11 weeks: Yawning Cause and Function of Prenatal Movement Unable to inhibit movement; inhibition comes with the connection to higher brain centres Fetal movement is necessary for the physical systems to develop normally (stimulate development of muscles, tendons, ligaments); Breathing movement important for lung development Changes in position may promote better circulation & help prevent skins from sticking together Motor behaviour moves amniotic fluid structural growth of fetus Some behaviours (e.g., sucking) may be preparatory http://web.uvic.ca/psyc/coursematerial/psyc435a.f01/435A/Week%202%20Lecture%20Notes.pdf

Role of experience

Overview of brain growth Subcortical areas responsible for reflexes develop first E.g. spinal cord Followed by cortical areas in a specific progression What is most human develops last Most but not all neurons present at birth Synapses develop Myelin develops

At the same time - Myelination Fatty sheaths develop and insulate neurons Dramatically speeding up neural conduction Allowing neural control of body General increase in first 3 years is likely related to speedier motor and cognitive functioning allowing activities like standing and walking Endangered by prenatal lead exposure

“Promoting early brain development”? Re-discovery of importance of early experience “How brain connections grow and change as a result of stimuli from the environment. How early stress can be harmful to the developing brain. Principle of "use it or lose it" Seven ways to support brain development: http://www.pitc.org/

“Considerable misunderstanding of early brain development occurs when neurons and synapses are considered independently of the development of thinking, feeling, and relating to others.” Thompson, 2001, p. 29

Is it all over after 3? Is the course of development set in infancy? Early experience is important But, with some exceptions, human beings remain open to the positive effects of additional experience The same is true for the impact of experience on brain development How important is it to ‘stimulate your child’s brain’?

What kind of stimulation is best? Running rats … Adult neurogenesis …

Implications for practice It is important to provide a safe, warm, supportive, stimulating environment for infants But its never too late to improve developmental outcome for an individual At any point, current conditions are as important as past conditions No flashcards

Brain Overgrowth in the First Year of Life in Autism The clinical onset of autism appears to be preceded by 2 phases of brain growth abnormality: a reduced head size at birth and a sudden and excessive increase in head size between 1 to 2 months and 6 to 14 months. Abnormally accelerated rate of growth may serve as an early warning signal of risk for autism Courchesne, Carper, Akshoomoff, (2003) Why overgrowth?

Later developing processes more susceptible to the effects of experience Motor development more plastic than language development Sensitive periods Genetics and experience: Indissoluble

Synapse Rearrangement Active synapses likely take up neurotrophic factor that maintains the synapse Inactive synapses get too little trophic factor to remain stable

Synapse Rearrangement Time-lapse imaging of synapse elimination Two neuromuscular junctions (NM1 and NMJ2) were viewed in vivo on postnatal days 7, 8, and 9.

Myelination

MYELIN AND SALTATORY CONDUCTION Myelin is an electrical insulator sheath wrapped around axons Oligodendrocytes produce myelin on CNS axons Schwann cells produce myelin on PNS axons Short gaps in myelin along axons called nodes of Ranvier Myelin’s function is to speed action potential propagation down long axons

MYELIN SHEATH COMPOSED OF MANY LOOPS OF A GLIAL PROCESS Each oligodendrocyte has several processes, each of which produces a myelin sheath on a different axon Schwann cells each form only a single myelin sheath

MYELIN SHEATH GENERATED BY CONTINUED MIGRATION OF PROCESS LEADING EDGE AROUND AXON While the leading glial process continues to encircle the axon, the earlier-formed loops undergo compaction to form the contact myelin sheath

MYELINATED FIBERS VIEWED IN CROSS-SECTION Low magnification Light microscopy High magnification electron microsopy Electron microscopy at very high magnification reveals alternating major dense lines and intraperiod lines

ORGANIZATION OF THE MYELIN REPEAT PERIOD PLP is the most abundant protein in CNS myelin P0 is the most abundant protein in PNS myelin

THE PARANODE IS SITE OF TIGHT AXON-GLIAL ADHESIONS

ROLE OF MYELIN IN FAST ELECTRICAL TRANSMISSION Unmyelinated Axon (SLOW CONDUCTION) Myelinated Axon (FAST CONDUCTION) SODIUM CHANNELS ONLY AT NODES AT VERY HIGH DENSITY Action potential at one point along unmyelinated axon produces current that only propagates short distance along axon, since current is diverted through channels in axon membrane. So action potential can only next occur short distance away Myelin reduces effective conductance and capacitance of internodal axon membrane. Action potential at node of Ranvier produces current that propagates 0.5-5 mm to next node of Ranvier, generating next action potential

THIN AXO-GLIAL SPACE AT PARANODE LOOPS CREATES HIGH NODE-INTERNODE PERIAXONAL RESISTANCE WHICH ELECTRICALLY ISOLATES INTERNODAL MEMBRANE Tight junctions between mature loops Only 20 Angstrom gap between mature paranodal loop and axonal membrane SINCE Rparanode >>>> Raxial & Rleak CHARGING OF INTERNODAL MEMBRANE VERY SLOW AND CHANGE IN INTERNODE VM IS INSIGNIFICANT Rparanode Rparanode Raxial Raxial NODE PARANODE INTERNODE PARANODE NODE

MOST MATURE MYELINATED AXONS POTASSIUM CHANNEL SHUNT NOT REQUIRED IN MOST MATURE MYELINATED AXONS Myelinated axons conduct action potentials at ~ 50 mm/msec Total refractory period of nodal Na+ channels after inactivation is ~ 5 msec. Therefore, by the time Na+ channels return to rest after an action potential, the spike has propagated 25 cm away (which is terminated in most cases) K+ channel inhibition in mature myelinated fibers does not alter conduction or promote misfiring.

FORMATION OF NODAL, PARANODAL, AND JUXTANODAL PROTEIN CLUSTERS DURING MYELINATION Kv1 Kv1 Na+ channels cluster early at wide immature nodes. As nodes narrow and mature, Na+ channel density increases. K+ channels cluster later and shift their position. They first appear at nodes, But move to paranode and then juxtaparanode as structure matures. K+ CHANNELS ARE OF CONTINUED IMPORTANCE DURING MATURATION OF MYELIN, SINCE ONLY FULLY MATURE FIBERS CONDUCT FAST ENOUGH TO MAKE THEM UNNEEDED. PERSISTENCE OF K+ CHANNELS IN MATURE JUXTAPARANODES MAY FUNCTIONALLY PROTECT FIBERS IN CASE OF PARTIAL DE-MYELINATION

MUTATIONS CAN CAUSE MINOR OR MAJOR MYELIN LOSS “SHIVERER” mutant mouse has almost complete absence of myelination, due to a failure of precursor cells to differentiate into oligodendrocytes Other mutations which impair myelination are mutations in the major protein components of the myelin sheath

Similarly, structural mutations in PNS myelin protein genes MUTATIONS IN PLP GENE CAUSING HYPOMYELINATION IN CNS Similarly, structural mutations in PNS myelin protein genes cause defective myelination of the PNS

Myelination Lasts for up to 30 Years

Brain Weight During Development and Aging

Critical Periods

Sensitive Period Anatomy and physiology are especially sensitive to modulation by experience. Critical Period An extreme form of Sensitive Period. Appropriate expression is essential for the normal development of a pathway or set of connections (and after this period, it cannot be repaired). e.g., There was a critical period for the formation of ocular dominance columns, based on neuronal activity/input from both spontaneous firing and visual inputs from the eyes.

If appropriate information is not received during the critical period (from experience), this pathway never attains the ability to process information in a normal fashion, and as a result, perception or behavior can be permanently impaired. E.g., development of appropriate social and emotional responses to others. E.g., development of language skills in humans.

Models of Developmental Learning and the Importance of Early Experiences Sound localization in the owl. - a “map” of auditory space is developed in the midbrain of the barn owl. - This map integrates auditory and visual info so that movements of the eyes and head can be oriented towards auditory stimuli (and catch mice and rats!). To create a map of auditory space, the midbrain nucleus has to learn (of inferior colliculus) spatial cues based on auditory signals it receives from the 2 ears.

Auditory space map and its inputs

What are the cues? Differences in timing and in the level (and pitch) between the 2 ears. Why are these things not just genetically encoded? Individual differences in size, shape of head, sensations and speed of head movement, etc. In young animals, this plasticity allows the pathway to respond and adjust to change or disruptions (e.g., growth, damage to ear, etc.). Tuning of inferior colliculus neurons is adjusted in response to visual cues.

The location of plasticity is the ICX (external nucleus of the inferior colliculus). If a stable shift in visual field occurs during the critical period (i.e., owls raised with prisms over their eyes), the auditory receptor field of the icx will realign with the shifted visual field. Now, the owl will have (correctly coordinated visual/auditory stimuli with the prisms on). The sensitive period for the owl, during which large shifts can occur, is throughout juvenile life (until reaching sexual maturity).

The experience induces the growth and elaboration of axons into the icx to sites where they can support appropriate responses. This response depends upon activation of NMDA receptors (involved in plasticity). Note: in our example, the power of genetically programmed pattern is still great (though an adult owl cannot adjust to a large shift in visual field, one that has been shifted can return to normal in the adult (over a period of weeks) when the prisms are removed.

NMDA receptors

Plasticity of axons in the ICX

Development of Birdsong. A special form of communication developed by birds to i.d. their own, defend territories, or attract mates. Birdsong is complex and has a periodic structure (like music). “Dialects” or varieties of song can specify a geographic area, where the basic song structure is common to a species. Song is developed by a combination of genetic instructions and learning (early experiences). The latter often takes place during a critical period.

Characteristics of song learning. *How can the extent of the critical period be determined in a species? [raise birds in acoustic isolation and expose them to song for brief periods at different points of development] “Isolate song”: a flat, species-specific pattern with complexity that a bird can develop if raised in isolation during the critical period. “Developmental song”: abnormal pattern developed in a bird that is unable to hear itself and get auditory feedback during critical period.

2 major pathways for birdsong learning

Birdsong characteristics

2) Shows importance of a critical period during song memorization (learning songs of conspecifics: 2-8 weeks). 3) Illustrates importance of critical period during vocal learning (bird hears and evaluates his own song so that it matches the memorized song pattern). [auditory feedback is essential for shaping the pattern of connectivity in the song-production pathway]

Importance of genetic background for the types of patterns that can develop: - note isolate song (earlier) - what does a baby bird develop when raised with an alien (other species) birdsong during the critical period for memorization? [genetically detrimental “filters” within pathway are responsible for song memorization]. If too distinct from normal, isolate song develops. Regarding song memorization, the critical period is closed after the appropriate stimuli have been received. After 8 weeks plasticity decreases; So, stimulus must be prolonged and rich (i.e., live bird and not a recording) for any memorization to occur.

Closure of critical period and decreased plasticity are also related to sexual maturity. *What happens if a bird receives testosterone early? (song is fixed in “immature” state). *What happens if bird is castrated prior to learning to sing? [song production inconsistencies and unstable for rest of life – critical period never closes?] Neural Pathway for Song Learning Still an active area of research We know a little regarding song production in species when only males sing (*how is this studied?)

[Sexual dimorphism] Song System – 2 groups of nuclei: Motor – posterior forebrain: song production Feedback – anterior forebrain: oral learning Posterior pathway: - necessary for products of learned sounds. Higher visual center (HVC)  RA arhistriatum  hypoglossal nucleus: motor neurons centrally vocal muscles. Anterior pathway: neurons respond maximally to bird’s own song. HVC  “area X”  DCM (a thalamic nucleus)  LMAN (lateral magnocellular nuc of ant striatum)

Sexual dimorphism-song nuclei

Sexual Dimorphism In Mammals:

A lesion in LMAN during critical learning period “freezes” song much like early testosterone. However, lesions in adult birds after learning is complete have zero effect. LMAN then sends input to RA  hypoglossal n.  muscles mediated by NMDA receptors. These synapses will compete selectively and several will be eliminated just prior to closure of critical period (as sex hormones rise).

3. Imprinting Learning of cues through i. d 3. Imprinting Learning of cues through i.d. a parent – important for survival involves learning multiple sensory cues that i.d. the parent (visual, auditory, olfactory, etc.) during brief critical periods. Recall the classic experiment by Konrad Lorenz (“mother goose”). Critical periods can be brief and can begin shortly before birth in some species.

What happens if baby is in isolation during critical period What happens if baby is in isolation during critical period? [never responds appropriately to social signals from members of its own species]. What happens when raised by another species? What is the genetic filter here? During the (critical) imprinting period, a duck will choose a duck over another species, or the closest equivalent (i.e., goose > human). One Neural Path Auditory stem  nucleus of anti forebrain activated as in previous examples of selective elimination of inputs occurs during late critical period in response to experience.

Binocular Vision Ability to “fuse” the image from 2 eyes to create a 3-D image with depth. The consequence of visual inputs onto neurons of the visual cortex is guided by early experience. A critical period exists, during which monocular deprivation can prevent the development of stereoscopic vision. Review the development of the ocular dominance columns for the projection of LGN to Layer IV of visual ctx.

Critical period for binocular vision development

Equal input from both eyes  equally wide columns with competition based on neural activity: If 1 eye is occluded, open eyes inputs are pruned and activity of majority of visual ctx is driven by LGN afferents from normal eye. *Competition is driven by: amount of neural activity degree of synchrony Therefore, the stimulation of both optic nerves with equal but asynchronous stimuli  one dominating , and impaired binocular vision.

Amount and synchrony of synaptic activation shapes the synaptic function and architecture by adjustments in synaptic strength through a process depending on activation of NMDA receptors: LTP. *Rats: This dual process is not as rapid and plastic as the other examples we have reviewed. Disruption are not completely universal during critical period and patterns are not as ‘pre-set’.