Chap 22' Wiring the brain

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Chap 22. Wiring the brain
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Eriksson PS and Gage FH. Neurogenesis in the
adult human hippocampus. Nat Med 1998
Nov4(11)1313-7 Human brain tissue was obtained
postmortem from patients who had been treated
with the thymidine analog, bromodeoxyuridine
(BrdU), that labels DNA during the S phase.
Using immunofluorescent labeling for BrdU and
for one of the neuronal markers, NeuN, calbindin
or neuron specific enolase (NSE), we demonstrate
that new neurons, as defined by these markers,
are generated from dividing progenitor cells in
the dentate gyrus of adult humans. Our results
further indicate that the human hippocampus
retains its ability to generate neurons
throughout life.
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• van Praag H, Kempermann G, Gage FH.Running
  increases cell proliferation and neurogenesis in
  the adult mouse dentate gyrus.Nat Neurosci 1999
  Mar2(3)266-70
• -Exposure to an enriched environment increases
  neurogenesis in the dentate gyrus of adult
  rodents. Environmental enrichment, however,
  typically consists of many components, such as
  expanded learning opportunities, increased social
  interaction, more physical activity and larger
  housing.
• Attempted to separate components water-maze
  learning (learner), swim-time-yoked control
  (swimmer), voluntary wheel running (runner), and
  enriched (enriched) and standard housing
  (control) groups.
• Running, not maze training or yoked swimming,
  doubled the number of surviving newborn cells
• Voluntary exercise is sufficient for enhanced
  neurogenesis in the adult mouse dentate gyrus.

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Neurogenesis in the adult neocortex Macaque
monkey To association and temporal cortexes
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Inside-out development of the cortex
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1. Pathway selection 2. Target selection 3.
Address selection
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The growth cone
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Fasciculation
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Axon guidance chemoattraction and
chemorepulsion Contact-mediated.
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Establishing retinotopy in the frog retinotectal
projection Roger Sperry Frog eye rotation
exp. Tectal memb strip exp. Contact mediated.
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Tessier-Lavigne M and Goodman CS. The molecular
biology of axon guidance.Science. 1996
2741123-33
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Why dont axons regenerate in our CNS?

• a-motor axons regenerate in the periphery
• DRG neurons stop growing in the dorsal horn
• Axon regeneration in the damaged human brain and
  spinal cord

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Wallerian degeneration degradation of the axonal
cytoskeleton
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Strittmatter SM at Yale Univ. Repulsive factors
and axon regeneration in the CNS.Curr Opin
Neurobiol. 2001 Feb11(1)89-94. Review.
Inhibitory influences at the site of axonal
damage -Astrocyte-rich glial scar that contains
inhibitory molecules such as tenascin-R, keratin,
and CSPGs. -Intact and damaged oligodendrocytes
that express Nogo, MAG and CSPGs.
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-MAG, CSPGs and Nogo, signal through unidentified
receptors (?) on the axonal growth cone. -
Intracellular signaling cascades may converge at
a common downstream target, such as Rho, to
destabilize the actin cytoskeleton and prevent
axonal outgrowth.
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Molecular cloning of Nogo Nogo protein
released by damaged oligodendrocytes, not by
Schwann cells or fish. Nogo antibodies enabled
5 of axons to regenerate Chen M.S., Schwab M.E.
(2000) Nature, 403434-439. Nogo-A is a
myelin-associated neurite outgrowth inhibitor and
an antigen for monoclonal antibody
IN-1. GrandPre T., Strittmatter S.M. (2000)
Nature, 403439-444. Identification of the Nogo
inhibitor of axon regeneration as a Reticulon
protein. Prinjha R., Walsh F.S. (2000) Nature,
403383-384 Inhibitor of neurite outgrowth in
humans.
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Fournier AE, GrandPre T, Strittmatter
SM. Identification of a receptor mediating
Nogo-66 inhibition of axonal regeneration. Nature.
2001 Jan 18409(6818)341-6.
Flanagan J. Neuron 2001 30 11-14.
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• GrandPre T and Strittmatter SM
• Nogo-66 receptor antagonist peptide promotes
  axonal regeneration.Nature. 2002 May
  30417(6888)547-51.
• -The IN-1 monoclonal antibody recognizes Nogo-A
  and promotes corticospinal tract regeneration and
  locomotor recovery however, the undefined nature
  of the IN-1 epitope in Nogo, the limited
  specificity of IN-1 for Nogo, and nonspecific
  anti-myelin effects have prevented a firm
  conclusion about the role of Nogo-66 or NgR.
• Competitive antagonists of NgR derived from
  amino-terminal peptide fragments of Nogo-66.
• The Nogo-66(1 40) antagonist peptide (NEP1 40)
  blocks Nogo-66 or CNS myelin inhibition of axonal
  outgrowth in vitro
• Intrathecal administration of NEP1 40 to rats
  with mid-thoracic spinal cord hemisection results
  in significant axon growth of the corticospinal
  tract, and improves functional recovery.

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• MUSK and rapsyn
• Neuregulin (or ARIA, acetylcholine
  receptor-inducing activity)?
• Regulate expression of AchR

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Synaptic capacity Each neurons receive on its
dendrites and soma a finite Number of
synapses Constant throughout infancy and
puberty Dramatic decrease during
adolescence (50 decrease in just two years.
5000/sec) No wonder adolescence is such a
trying time!
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Synaptic elimination
Receptor loss precedes axon withdrawal. Activity
is important Complete silencing of the activity
of muscle leads to a retention of polyneuronal
innervation Competition!
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Synaptic rearrangement
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Plasticity at Hebb synapses
LGN
Activity required TTX prevents the
segregation Winner-takes-all segregation
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Modification of ocular dominance stripes after
monocular deprivation
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Ocular dominance shift
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Strabismus and cortical binocularity Conclusion
Disconnection from one eye occurs as the
results of competition rather than
disuse Winner takes all Supports the concept
of Hebbian synapse
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Modulatory inputs and binocularity
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Cortical plasticity 1. Neurons that fire
together wire together 2. Neuron that fire out
of sync lose their link
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The lasting effects of strong NMDA receptor
activation Long-term potentiation (LTP) and
depression (LTD)
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Silent synapses and their maturation
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• Why do critical periods ends?
• Diminished axon growth
• Mature synaptic transmission (Rc
  profile/downstream signaling/LTP and LTD
  characteristics)
• Diminished cortical activation (eg. Diminished
  Ach or NE-mediated enhancement