Transcript layer 4 - Molecular and Cell Biology

Activity-Dependent
Development Plasticity
1.
2.
3.
4.
5.
Development of OD columns
Effects of visual deprivation
The critical period
Hebb’s hypothesis
Hebb’s mechanism for OD
plasticity
6. The neurotrophin hypothesis
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Transneuronal dye to study the structure
of OD columns
left
radioactive
right
amino acid
eye
LGN
V1
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5
4
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2
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C
I
C
I
I
C
L
R
2
L
R
L
layer 4
Areas which get inputs from the injected eye are labeled
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OD distribution in V1 after monocular deprivation
monocular deprivation (MD) -- suture one eye of the
newborn animal (monkey) for several months, reopen.
Number of cells
V1 after monocularly depriving the contralateral eye
Equal
contralateral
ipsilateral
OD groups
MD V1 -Ocular dominance shifts to the non-deprived eye.
Animal blind in the sutured eye.
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Segregation of LGN afferents
- new borns
1. single LGN afferent has lots of
branches, covers a big area
layer 4
2. axon terminals from the two
eyes overlap extensively
L
R
- normal adults
1. selective elimination of axon
branches
layer 4
2. local outgrowth of new axon
branches
L
R
- MD animals
1. axon terminals from the closed
eye retract more
layer 4
2. axon terminals from the open
eye take over more areas
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open eye
deprived eye
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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Compare OD columns in newborns,
adults and MD animals
normal adults - labeled and unlabeled alternate
layer 4
new borns - no OD column, all areas are labeled
layer 4
MD animals - deprived eye columns shrink, non-deprived eye
columns expand
layer 4
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deprived eye
non-deprived eye
OD column formation is an activitydependent, 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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Hebb’s Hypothesis for Learning
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)
Donald Hebb
“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.
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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)
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Development of retinotopic mapping
Tectum
Retina
Topographic Mapping
of Retinotectal Projections
T
N
EphA3
C
R
Ephrin-A2
development
ganglion
cell
tectal
cell
• 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,
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while distant cells fire in an uncorrelated manner, leading
to
elimination of their connection.
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 17
different times sequentially (C. Shatz & R. Wong)
The Neurotrophin Hypothesis
--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
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Neurotrophin hypothesis for activitydependent competition
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 (noncorrelated) 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
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Molecular mechanism of cortical plasticity
2. Neurotrophins
- infusion of BDNF or NT-4/5, prevent formation of OD columns
A Normal
Layer 4
B NGF or NT-3 administration
NGF
no effect
NT-3
Layer 4
C NT-4/5 or BDNF administration
BDNF
NT-4/5
Layer 4
Disrupt
formation of
OD column
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