Neuroscience: Exploring
the Brain, 3e
Chapter 23: Wiring the Brain
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Introduction
• Operation of the brain
– Precise interconnections among 100 billion neurons
• Brain development
– Begins as a tube
– Neurogenesis, synaptogenesis, pathway formation,
connections formed and modified
• Wiring in brain
– Establishing correct pathways and targets
– Fine tuning based on experience
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The Genesis of Neurons
• Example: Mammalian retinogeniculocortical pathway
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Activity-dependent Synaptic
Rearrangement
• Synaptic rearrangement
– Change from one pattern to another
– Consequence of neural activity/synaptic transmission
before and after birth
– Critical Period
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The Elimination of Cells and Synapses
• Changes in Synaptic Capacity
– Synapse elimination modeled in the neuromuscular
junction
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The Lateral
Geniculate
Nucleus (LGN)
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Activity-dependent Synaptic
Rearrangement
• Synaptic segregation
– Refinement of synaptic connections
• Segregation of Retinal Inputs to the LGN
• Retinal waves (in utero) (Carla Shatz)
• Activity of the two eyes not correlated ->
segregation in LGN
• Process of synaptic stabilization
• Hebbian modifications (Donald Hebb)
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Activity-dependent Synaptic
Rearrangement
• Segregation of Retinal
Inputs to the LGN
(Cont’d)
– Plasticity at
‘Hebb’ synapses
– “Winner-takesall”
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Activity-dependent Synaptic
Rearrangement
• Segregation of LGN Inputs in the Striate Cortex
– Visual cortex has ocular dominance columns
(cat, monkey) - segregated input from each
eye
– Synaptic rearrangement is activity-dependent
– Plastic during critical period
– Effects of congenital cataracts (if not removed
early)
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Activity-dependent Synaptic
Rearrangement
• Synaptic Convergence
– Anatomical basis of binocular vision and binocular
receptive fields
– Monocular deprivation:
• Ocular dominance shift
• Plasticity of binocular connections
• Synaptic competition
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Activity-dependent Synaptic
Rearrangement
• Critical period for plasticity of binocular connections
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Activity-dependent Synaptic
Rearrangement
• Effect of strabismus on cortical binocularity
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Activity-dependent Synaptic
Rearrangement
• Modulatory Influences
– Increasing age
– Before and after birth
– Enabling factors
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Elementary Mechanisms of Cortical
Synaptic Plasticity
• Two rules for synaptic modification
– Wire together fire together (Hebbian modifications)
– Out of sync lose their link
– Correlation: heard and validated
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Elementary Mechanisms of Cortical
Synaptic Plasticity
• Excitatory Synaptic Transmission in the Immature Visual System
–
Focus on 2 glutamate receptors (Rs):
• AMPARs: glutamate-gated ion channels
• NMDARs: Unique properties
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Elementary Mechanisms of
Cortical Synaptic Plasticity
• Excitatory Synaptic Transmission
– NMDA receptors have two
unique properties
• Voltage-gated owing to
Mg2+
• Conducts Ca2+
• Magnitude of Ca2+ flux
signals level of pre- and
postsynaptic activation
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Elementary Mechanisms of Cortical
Synaptic Plasticity
• Long-Term Synaptic Potentiation
– Monitor synaptic strength before and after episodes
of strong NMDA activation
– Accounting for LTP
• AMPA insertion (“AMPAfication”)
• Splitting synapses (doubling)
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Elementary Mechanisms of Cortical
Synaptic Plasticity
• Lasting synaptic effects of strong NMDA receptor activation
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Elementary Mechanisms of Cortical
Synaptic Plasticity
• Long-Term Synaptic Depression (LTD)
– Neurons fire out of sync
– Synaptic plasticity mechanism opposite of LTP
• Loss of synaptic AMPARs
• Loss of synapses? (unknown)
– Mechanism for consequences of monocular
deprivation
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Elementary Mechanisms of Cortical
Synaptic Plasticity
• Brief monocular deprivation leads to reduced visual
responsiveness
–
Depends on retinal activity, NMDA activation, postsynaptic
calcium
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Why Critical Periods End
• Why do critical periods end?
– Plasticity diminishes:
• When axon growth ceases
• When synaptic transmission matures
• When cortical activation is constrained
– Intrinsic inhibitory circuitry late to mature
– Understanding developmental regulation of plasticity
may help recovery from CNS damage
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Enriched environment:
structure.
More complex brain
•Increased dendritic branching and synaptic density
•Increased transmitter levels, total protein
•Better at solving maze problems
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Concluding Remarks
• Generation of brain development circuitry
– Placement of wires before birth
– Refinement of synaptic infancy
• Developmental critical periods
– Visual system and other sensory and motor systems
• Environment influences brain modification throughout life
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End of Presentation
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The Genesis of Neurons
• Cell Proliferation
– Neural stem cells give rise to neurons and glia
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The Genesis of Neurons
• Cell Proliferation (Cont’d)
– Cleavage plane during cell division determines fate of
daughter cells
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The Genesis of Neurons
• Cell Migration
– Pyramidal cells and
astrocytes migrate
vertically from ventricular
zone by moving along thin
radial glial fibers
– Inhibitory interneurons
and oligodendroglia
generate from a different
site and migrate laterally
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The Genesis of Neurons
• Cell Migration
– First cells to migrate take
up residence in “subplate”
layer which eventually
disappears
– Next cells to divide
migrate to the cortical
plate
– The first to arrive become
layer VI, followed V, IV,
and so on: “inside out”
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The Genesis of Neurons
• Cell Differentiation
– Cell takes the appearance and characteristics of a
neuron after reaching its destination but
programming occurs much earlier
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The Genesis of Neurons
• Differentiation of Cortical Areas
– Adult cortical sheet is a “patchwork quilt
– Cortical “protomap” in the ventricular zone replicated
by radial glial guides
– But some neurons migrate laterally
– Thalamic input contributes to cortical differentiation
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The Genesis of Connections
• The three phases of pathway formation:
– (1) pathway, (2) target, (3) address
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The Genesis of Connections
• The Growing Axon
– Growth cone: Growing tip of a neurite
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The Genesis of Connections
• Axon Guidance
– Challenge in wiring the brain
• Distances between connected structures
• But in early stages nervous system is a few
centimeters long
– Pioneer axons stretch as nervous system expands
• Guide neighbor axons to same targets
– Pioneer neurons grow in the correct direction by
“connecting the dots”
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The Genesis of Connections
• Axon Guidance
– Guidance Cues: Chemoattractant (e.g., netrin),
Chemorepellent (e.g., slit)
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The Genesis of Connections
• Axon Guidance
– Establishing Topographic Maps
• Choice point; Retinal axons innervate targets of
LGN and superior colliculus
• Sperry (1940s): Chemoaffinity hypothesis
• CNS axons regenerate in amphibians, not in
mammals
• Factors guiding retinal axons to tectum
• Ephrins/eph (repulsive signal)
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The Genesis of Connections
• Axon Guidance
– Establishing Topographic Maps
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The Genesis of Connections
• Synapse Formation
– Modeled in the neuromuscular junction
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The Genesis of Connections
• Synapse Formation
– Steps in the formation of a
CNS synapse:
– Dendritic filopodium contacts
axon
– Synaptic vesicles and active
zone proteins recruited to
presynaptic membrane
– Receptors accumulate on
postsynaptic membrane
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The Elimination of Cells and Synapses
• The mechanisms of pathway formation
– Large-scale reduction in neurons
and synapses
• Development of brain function
– Balance between genesis &
elimination of cells and synapses
• Apoptosis: Programmed Cell Death
– Importance of trophic factors, e.g.,
nerve growth factor
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