BRAIN DEVELOPMENT AND PLASTICTY

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BRAIN DEVELOPMENT AND PLASTICTY

• Dr. Nelly Amalia Risan, SpA(K)

Divisi Neuropediatri Departemen Ilmu Kesehatan
Anak Fakultas Kedokteran Universitas Padjadjaran
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Embryonic and Fetal Development of the Human Brain
Actual Size
Actual Size
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Photographs of Human Fetal Brain Development
Lateral view of the human brain shown at
one-third size at several stages of fetal
development. Note the gradual emergence of gyri
and sulci.
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Nervous System Development in the Human Embryo
(a) At 18 days after conception the embryo begins
to implant in the uterine wall. It consists of 3
layers of cells endoderm, mesoderm, and
ectoderm. Thickening of the ectoderm leads to the
development of the neural plate (inserts). (b)
The neural groove begins to develop at 20 days.
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Nervous System Development in the Human Embryo
(c) At 22 days the neural groove closes along the
length of the embryo making a tube. (d) A few
days later 4 major divisions of the brain are
observable the telencephalon, diencephalon,
mesencephalon, and rhombencephalon.
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Neuroplasticity

• The brain consists of nerve cells (or
  "neurons") and glial cell which are
  interconnected, and learning may happen through
  change in the strength of the connections, by
  adding or removing connections, and by the
  formation of new cells.

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• "Plasticity" relates to learning by adding or
  removing connections, or adding cells.

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Eight Phases in Embryonic and Fetal Development
at a Cellular Level

1. Mitosis/Proliferation
2. Migration
3. Differentiation
4. Aggregation
5. Synaptogenesis
6. Neuron Death
7. Synapse Rearrangement
8. Myelination

8 stages are sequential for a given neuron, but
all are occurring simultaneously throughout fetal
development
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Eight Phases in Embryonic and Fetal Development
at a Cellular Level
1. Mitosis 2. Migration 3.
Aggregation and
4. Differentiation
5. Synaptogenesis 6. Death 7. Rearrangement
8. Myelination
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1. Mitosis/Proliferation

• Occurs in ventricular zone
• Rate can be 250,000/min
• After mitosis daughter cells become fixed post
  mitotic

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1. Mitosis/Proliferation
Neurons and Glia
At early stages, a stem cell generates
neuroblasts. Later, it undergoes a specific
asymmetric division (the switch point) at which
it changes from making neurons to making glia
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2. Migration
Note that differentiation is going on as neurons
migrate.
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2. Migration
Radial Glia
Radial glial cells act as guide wires for the
migration of neurons
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2. Migration
Growth cones crawl forward as they elaborate the
axons training behind them. Their extension is
controlled by cues in their outside environment
that ultimately direct them toward their
appropriate targets.
Growth Cones
The fine threadlike extensions shown in red and
green are filopodia, which find adhesive surfaces
and pull the growth cone and therefore the
growing axon to the right.
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2. Migration
Growth Cones
Scanning electron micrograph of a growth cone in
culture. On a flat surface growth cones are very
thin. They have numerous filopodia
Ramon y Cajal drew these growth cones showing
their variable morphology
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2. Migration How Do Neurons Know Where to Go?
There are extrinsic and intrinsic determinants of
neurons fate.

• Extrinsic signals
• Different sources of extrinsic signals
• Generic signal transduction pathway
• Intrinsic determinants

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Migration
During development, each of the three cells arise
from different regions of the growing embryo.
The Schwann cells arise from the neural crest and
are led by the axons to their destination. Upon
reaching it, they form a loose, unmyelinated
covering over the innervating axons.
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Migration
The movement of the axons (and subsequently the
Schwann cells) is guided by the growth cone, a
filamentous projection of the axon that actively
searches for neurotrophins released by the
myotube
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3. Differentiation

• Neurons become fixed post mitotic and specialized
• They develop processes (axons and dendrites)
• They develop NT-making ability
• They develop electrical conduction

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3. Differentiation
Development of the cerebral cortex
The ventricular zone (VZ) contains progenitors of
neurons and glia. 1st neurons establish the
preplate (PP) their axons an ingrowing axons
from the thalamus establish the intermediate zone
(IZ). Later generated neurons establish layers
II-VI. After migration and differentiation there
are 6 cortical layers.
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Differentiation
At Pre-synaptic Differentiation, the changes
exhibited at the developing axon terminal are
well characterized. The pre-synaptic axon shows
an increase in synaptic volume and area, an
increase of synaptic vesicles, clustering of
vesicles at the active zone, and polarization of
the pre-synaptic membrane.
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Differentiation
The post-synaptic end plate grows deeper and
creates folds through invagination to increase
the surface area available for neurotransmitter
reception.
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Differentiation
At birth, Schwann cells form loose, unmyelinated
covers over groups of synapses, but as the
synapse matures, Schwann cells become dedicated
to a single synapse and form a myelinated cap
over the entire neuromuscular junction
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4. Aggregation
Like neurons move together and form layers
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5. Synaptogenesis
Axons (with growth cones on end) form a synapse
with other neurons or tissue (e.g. muscle)
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Synaptogenesis
Synaptogenesis is the formation of
synapses. Although it occurs throughout a healthy
person's lifespan, an explosion of synapse
formation occurs during early brain development.
Synaptogenesis is particularly important during
an individual's "critical period" of life,
during which there is a certain degree of
neuronal pruning due to competition for neural
growth factors by neurons and synapses.
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Synaptic plasticity
The underlying principle of synaptic plasticity
is that synapses undergo and activity-dependent
and selective strengthening or weakening so new
information can be stored
Synaptic plasticity depends on numerous factors
including the threshold of the presynaptic
stimulus in addition to the relative
concentrations of neurotransmitter molecules.
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5. Synaptogenesis Attraction to Target Cells
Target cells release a chemical that creates a
gradient (dots) around them. Growth cones orient
to and follow the gradient to the cells. The
extensions visible in c are growing out of a
sensory ganglion (left) toward their normal
target tissue. The chemorepellent protein Slit
(red) in an embryo of the fruit fly repels most
axons.
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6. Neuron Death

• Between 40 and 75 percent of all neurons born in
  embryonic and fetal development do not survive.
• They fail to make optimal synapses.

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Neuron Death Leads to Synapse Rearrangement
Release and uptake of neurotrophic factors
Neurons receiving insufficient neurotropic factor
die
Axonal processes complete for limited
neurotrophic factor
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7. Synapse Rearrangement

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

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7. 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.
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8. Myelination
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Myelination Lasts for up to 30 Years
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Brain Weight During Development and Aging
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Spontaneous Network Activity
During the early development of neural
connections, excitatory synapses undergo
spontaneous activation, resulting in elevated
intracellular calcium levels which signals the
onset of innumerable signaling cascades and
developmental processes.
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Critical Periods
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Teratogens
Greek teratos wonder or monster
genos - birth

1. Physical agents (e.g., x-rays)
2. Chemicals (e.g., drugs)
3. Microorganisms (e.g., rubella)