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Activity-Dependent Development Plasticity

1. Development of OD columns

2. Effects of visual deprivation

3. The critical period

4. Hebb’s hypothesis

5. Hebb’s mechanism for OD plasticity

6. The neurotrophin hypothesis

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Transneuronal dye to study the structure of OD columns

Areas which get inputs from the injected eye are labeled

left right radioactive

amino acid

2CI

II

C

C

layer 4

R L R LL

LGN

V1

eye

65

43

21

3

4

OD distribution in V1 after monocular deprivation

MD V1 --

Ocular dominance shifts to the non-deprived eye.

Animal blind in the sutured eye.

monocular deprivation (MD) -- suture one eye of the newborn animal (monkey) for several months, reopen.

Num

ber

of c

ells

V1 after monocularly depriving the contralateral eye

Equal

OD groups

contralateral ipsilateral

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Segregation of LGN afferents

- MD animals

1. axon terminals from the closed eye retract more

2. axon terminals from the open eye take over more areas

- normal adults

1. selective elimination of axon branches

2. local outgrowth of new axon branches

L R

layer 4

- new borns

1. single LGN afferent has lots of branches, covers a big area

2. axon terminals from the two eyes overlap extensively

L R

layer 4

layer 4

deprived eyeopen eye

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Development of Ocular Dominance Column:

Radioactive amino acid injected into one eye resulted in diffuse distribution of activity in layer 4 of V1 in 2 wk-old cat, but discrete bands in 13 wk-old cat.

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8

Compare OD columns in newborns, adults and MD animals

normal adults - labeled and unlabeled alternate

new borns - no OD column, all areas are labeled

MD animals - deprived eye columns shrink, non-deprived eye columns expand

layer 4

layer 4

layer 4

deprived eye non-deprived eye

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OD column formation is an activity-dependent, competitive process

Experiments:

1. Binocular injection of TTX, blocks segregation of OD columns - segregation is activity dependent

2. If both eyes are deprived (binocular deprivation), OD columns are normal!

- segregation depends NOT on the absolute level of activity, but on the balance between the input

from the two eyes, thus there is a competitive process.

Interpretations:

1. Normal development

- initially the axon terminals from the two eyes overlap

- at local region, inputs from one eye happen to be stronger

2. Monocular deprivation

- open eye more active, take over more territory

- deprived eye less active, lose most of the territory

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Critical Period

-Postnatal period during which nerve connections

are shaped by activity (sensitive to perturbation).

- Different among various brain regions, species, functions

1. Monocular deprivation (MD) causes a shift of OD in V1 toward the non-deprived eye. This is effective only before certain age. MD has no effect on adult animals.

monkey: first 6 months

human: 1st year most important, but may extend to 5 years

2. MD within the critical period, the effect is permanent and irreversible.

- implication for treatment of congenital cataracts in children

3. MD within the most sensitive part of the critical period (e.g., first 6 wk for monkey), a few day’s MD results in a complete loss of vision in the sutured eye.

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Critical period varies among different brain functions

• Visual System

- OD cat: 3rd week ~ 3 months

monkey: first 6 months

human: 1-5 year?

- More complex visual functions (e.g., contour integration) have longer critical period

• Human Language

- 2-7 years of age

- Phoneme recognition during the first year, an ability lost later

• Social Interaction

- Newborn monkeys reared in isolation for 6-12 months, behaviorally abnormal

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Donald Hebb

When an axon of cell 1 is near enough to excite a cell 2 and repeatedly and persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that 1's efficacy, as one of the cells firing 2, is increased. (Hebb, 1949)

“Cells that fire together wire together”

“neurons out of synch lose the link”

Hebb’s hypothesis provides a synaptic basis for learning and memory, and has been the guiding principle for neurophysiological studies for the past several decades.

Hebb’s Hypothesis for Learning

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A property of Hebbian synapse

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Hebb’s rule and OD development

A. Normal OD development

- Small differences in either the activity level or the initial strength causes the postsynaptic cell activity to be more similar (correlated) to the activity of the more active/strong input. This input will be strengthened and will win the competition.

-Inputs from the same eye are likely to be more correlated, thus are stabilized together, whereas the inputs from the opposite eyes are weakened and driven away, leading to segregated zones of inputs from opposite eyes.

B. Monocular deprivation

- Deprived eye input is uncorrelated with cortical cell activity, and will lose the competition.

C. Binocular deprivation

-Similar to normal development. The outcome of competition is determined by small differences in initial input strengths or spontaneous activity levels of the two inputs. Relatively normal OD columns.

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Further tests of Hebb’s rule in OD development

If you force inputs from the two eyes to be correlated (synchronous stimulation), you can prevent competition and OD segregation

If you make the inputs from the two eyes even less correlated (asynchronous stimulation or strabismus), you enhance competition and OD segregation (there will be very few binocular cells in V1)

L

R

L

R

L R

% c

ells

L R

% c

ells

MP Stryker (1986)

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Development of retinotopic mapping

• Initial development of the map is activity-independent, require guidance of matching molecular gradients in the retina and tectum (ephrin – Eph receptor interaction)

• Refinement of the map requires activity:

- nearby retinal ganglion cell fire in a correlated manner, leading to stabilization of their connections to the tectal cell which is triggered to fire synchronously by these inputs, while distant cells fire in an uncorrelated manner, leading to elimination of their connection.

Retina Tectum

EphA3 Ephrin-A2

N T R C

ganglioncell tectal

cell

development

Topographic Mapping

of Retinotectal Projections

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Latest Findings (L. Katz) : OD exists to some extent before eye opening

• Normal visual input may not be necessary for the initial formation, but required for fine tuning and maintenance of visual circuit

• Initial OD development may depend on spontaneous activity (e.g., retinal waves, correlated between neighboring RGC, but uncorrelated between the two eyes)

Different colors represent activity of RGCs at different times sequentially (C. Shatz & R. Wong)

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--Synaptic competition between co-innervating nerve terminals is determined by activity-dependent competition for the neurotrophin secreted by the postsynaptic cell.

Criteria for neurotrophins to function as molecular signals in synaptic competition:

1) expressed in the right place and at the right time

2) secretion is activity-dependent

3) regulate synaptic functions

4) the amount and distribution are limited

The Neurotrophin Hypothesis

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from L eye from R eye

pre-

post-

Development of OD at the level of cortical neurons:

- Axons from R eye relatively stronger, trigger the firing of postsynaptic cell

- Postsynaptic depolarization triggers release of neurotrophins

- Active presynaptic nerve terminals from R eyes take up the released neurotrophin, whereas the inactive (non-correlated) terminals inputs from the L eye do not receive the neurotrophin

- Stabilization and growth of R eye inputs and regression and elimination of the L eye inputs

Neurotrophin hypothesis for activity-dependent competition

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2. Neurotrophins

- infusion of BDNF or NT-4/5, prevent formation of OD columns

Molecular mechanism of cortical plasticity

BDNF

NT-4/5

Disrupt formation of OD column

NT-3no effect

NGF

A Normal

Layer 4

C NT-4/5 or BDNF administration

Layer 4

B NGF or NT-3 administration

Layer 4