Dr. Bambang Retnoaji, M.Sc.

2015
 Stages of Development
Phase Approximate Age Highlight

Prenatal Conception - birth Rapid physical

growth
Infancy Birth - 2 yrs Motor development
Childhood 2 - 12 yrs Abstract reasoning
Adolescence 13 - 20 yrs Identity creation,
Judgement

Directly related to maturation of

the Prefrontal Cortex
 Organogenesis Begins With
Development of the Nervous System
The nervous system is the first
organ system to develop.
The notochord grows and
induces overlying ectoderm to
form the neural plate.

Cells of the neural plate fold to

form the neural groove and
the surrounding neural folds
fuse to form the neural tube.

The anterior portion forms the

brain; the rest forms the spinal
cord.
 Neurulation

Chordates Only

formation of a dorsal, hollow neural tube:

ectodermal cells flatten into neural plate
the center of the plate sinks forming neural groove
edge of plate is elevated to form neural folds
neural folds fuse and form neural tube
anterior end develops into brain
posterior end develops into spinal cord
Neuralation in a frog embryo

Neural folds Eye Somites Tail bud

Neural Neural plate
fold

SEM 1 mm
1 mm
Neural tube Neural
Neural Neural crest
fold plate Notochord
cells
Neural Coelom
crest cells

Notochord
Ectoderm Somite
Mesoderm Outer layer Archenteron
of ectoderm (digestive
Endoderm Neural
crest cells cavity)
(c) Somites
Archenteron
(a) Neural plate formation
Neural
tube
(b) Neural tube formation
 E-Chaderin to N-Chaderin
cadherin switch accompanies the gradual
partition and final commitment of the
neurectoderm into three distinct populations,
the ectoderm, neural crest, and neural tube,
characterized by different cadherin repertoires
under the control of specific sets of
transcriptional regulators
 Organogenisis in a chick

Neural tube Eye

Notochord
Forebrain
Archenteron Somite
Coelom Heart
Lateral
fold Endoderm
Mesoderm Blood
Ectoderm vessels

Somites
Yolk stalk

These layers Yolk sac

form extraembryonic
Neural
membranes. YOLK tube
(a) Early organogenesis (b) Late organogenesis
 Ectoderm

Morpho-genesis results
from cells changing
shape
Figure 47.15-2
Ectoderm

Neural
plate

Microtubules
Figure 47.15-3
Ectoderm

Neural
plate

Microtubules

Actin
filaments
Figure 47.15-4
Ectoderm

Neural
plate

Microtubules

Actin
filaments
Figure 47.15-5
Ectoderm

Neural
plate

Microtubules

Actin
filaments

Neural tube
Elongation of tissue by convergent extension
Neurulation
 The Neural Crest
The neural crest is a
critical structure that
guides formation of several
organ systems
The neural crest forms on
either side of the point of
fusion
Its cells migrate to form the
dorsal root ganglia, the
postganglionic sympathetic
neurons, many sense organs
and all pigment-forming
cells
Figure 47.11 Organogenesis in a frog embryo
 Neural crest
Although derived from the ectoderm, the
neural crest has sometimes been called the
fourth germ layer because of its importance. It
has even been said, perhaps hyperbolically,
that the only interesting thing about
vertebrates is the neural crest
The neural crest cells originate at the
dorsalmost region of the neural tube.
 Tipe neural crest
The cranial (cephalic) neural crest,
whose cells migrate dorsolaterally to produce the
craniofacial mesenchyme that differentiates into the
cartilage, bone, cranial neurons, glia, and connective
tissues of the face. These cells enter the pharyngeal
arches and pouches to give rise to thymic cells,
odontoblasts of the tooth primordia, and the bones of
middle ear and jaw.
 Tipe neural crest
The trunk neural crest,
whose cells take one of two major pathways. Neural
crest cells that become the pigment-synthesizing
melanocytes migrate dorsolaterally into the
ectoderm and continue on their way toward the
ventral midline of the belly.
The second migratory pathway takes the trunk neural
crest cells ventrolaterally through the anterior half of
each sclerotome.
 Tipe neural crest
The vagal and sacral neural crest,
whose cells generate the parasympathetic (enteric)
ganglia of the gut (Le Douarin and Teillet 1973;
Pomeranz et al. 1991).
The vagal (neck) neural crest lies opposite chick
somites 17, while the sacral neural crest lies posterior
to somite 28. Failure of neural crest cell migration from
these regions to the colon results in the absence of
enteric ganglia and thus to the absence of peristaltic
movement in the bowels.
 Tipe neural crest
The cardiac neural crest is located between the
cranial and trunk neural crests.
The cardiac neural crest cells can develop into
melanocytes, neurons, cartilage, and connective
tissue (of the third, fourth, and sixth pharyngeal
arches). In addition, this region of the neural crest
produces the entire musculoconnective tissue wall of
the large arteries as they arise from the heart, as well
as contributing to the septum that separates the
pulmonary circulation from the aorta (Le Livre and
Le Douarin 1975).
Table 13.1 Some derivatives of the neural crest

Derivative Cell type or structure derived

Peripheral nervous Neurons, including sensory ganglia, sympathetic and parasympathetic ganglia, and
system (PNS) plexuses Neuroglial cells Schwann cells
Neuroglial cells
Schwann cells
Endocrine and Adrenal medulla
paraendocrine
derivatives
Calcitonin-secreting cells
Carotid body type I cells
Pigment cells Epidermal pigment cells
Facial cartilage and Facial and anterior ventral skull cartilage and bones
bone
Connective tissue Corneal endothelium and stroma
Tooth papillae
Dermis, smooth muscle, and adipose tissue of skin of head and neck
Connective tissue of salivary, lachrymal, thymus, thyroid, and pituitary glands
Connective tissue of salivary, lachrymal, thymus, thyroid, and pituitary glandsConnective
tissue and smooth muscle in arteries of aortic arch origin

Source: After Jacobson 1991, based on multiple sources.

Development of the Central Nervous System

an ongoing process, through adolescence and

maybe even adult hood ?
the nervous system is plastic

Experience plays a key role

Dire consequences when something goes wrong
- teratogens
- Drugs of abuse, industrial chemicals, caffeine?,
household chemicals
 Phases of Prenatal Development
Ovum + sperm
zygote

Once zygote implants

in uterus
embryo

Week 8 until birth

fetus
The University of South Wales, Dr. Mark Hill
 Development of the Brain.
The human central nervous system begins to
form when the embryo is approximately 2
weeks old.
The dorsal surface thickens forming a neural tube
surrounding a fluid filled cavity.
The forward end enlarges and differentiates into
the hindbrain, midbrain and forebrain.
The rest of the neural tube becomes the spinal
cord.
Fig. 5-3, p. 123
Prenatal Brain Development is primarily structural
3-4 Weeks
3-4 Weeks
Neural Groove
3-4 Weeks
Neural Groove

Neural Tube
3-4 Weeks
Neural Groove

Neural Tube

Brain

Spinal Chord
 Brain Sculpting
Embryonic brain development occurs rapidly
Within the first month, the brain is emerging
and the embryo is forming the separations of
its parts from the spinal cord to the brain,
with the brain beginning to separate into
forebrain, midbrain, and hindbrain
5 to 6 Weeks
5 to 6 Weeks
Forebrain

Midbrain

Hindbrain
 Neurons forming rapidly
1000s per minute

7 Weeks
 Division of the halves of the brain visible

14 Weeks
7 Weeks
 Nerve cell generation complete
Cortex beginning to wrinkle
Myelinization

6 Months
14 Weeks
7 Weeks
9 Months
9 Months
 Axon Pathfinding - chemotropism http://web.sfn.org/content/Publications/BrainBriefings/axo
n.html#fullsize

Blue - attractant molecules

Orange - repellent molecules

Axons locate their target tissues by using chemical attractants (blue)

and repellants (orange)
Either diffusable substances released by cells or molecules
embedded in the plasmalemma

Surfaces of target tissue cells can also display attractant or repellent

molecules.

Illustration by Lydia Kibiuk, Copyright 1995 Lydia Kibiuk.

At about 18 days after conception the embryo begins to implant in the
uterine wall.

a. Consists of 3 layers of
cells: endoderm,
mesoderm, and ectoderm.
Thickening of the
ectoderm leads to the
development of the
neural plate

b. The neural groove

begins to develop at 20
days.
c. At 22 days the
neural groove closes
along the length of the
embryo making the
neural tube.

d. A few days later 4

major divisions of the
brain are observable
the telencephalon,
diencephalon,
mesencephalon, and
rhombencephalon.
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.
 Phases of brain development

Neural plate induction

Neural proliferation
Migration & Aggregation
Axon growth & Synapse formation
Cell death & Synapse rearrangement
 Induction of the Neural Plate
2-3 weeks after conception

A patch of tissue on the dorsal surface of

the embryo that will become the nervous
system

Development induced by chemical signals

growth factors: several chemicals produced

in developing and mature brain that stimulate
neuron development and help neurons respond
to injury
 Neural Plate
Totipotent (zygote)
Fertilized ovum has ability to divide and produce all cells of
the body (brain, kidney, liver, skin, bone etc.)
Can produce a whole animal

Pluripotent: 5 days after fertilization = blastocyst forms, some of

these cells are embryonicstem cells. Can be taken and
differentiated into any organ ?

With the development of the neural tube, cells become

multipotent
able to develop into any type of mature nervous system cell
 Phases of brain development

Neural plate induction

Neural proliferation
Migration & Aggregation
Axon growth & Synapse formation
Cell death & Synapse rearrangement
2. Mitosis/Proliferation

Proliferation
Generation of new cells

3 swellings at the anterior end

in humans will become the
forebrain, midbrain, and
hindbrain

Occurs in ventricular zone

Rate can be 250,000/min
After mitosis daughter
cells become fixed post
mitotic
3. Migration: slow movement to the right place

Only a soma and immature

axon at this point
-undifferentiated at
start of migration.
But, differentiation begins as
neurons migrate.
They develop
neurotransmitter making
ability, action potential
3. Migration
Radial Glia

Radial glial cells act as

guide wires for the
migration of neurons
Migrating cells are
immature, lacking
dendrites
Cells that are done
migrating align
themselves with others
cells and form structures
(Aggregation)
Growth Cones: tips of axons on migrating, immature neurons

Growth cones crawl forward as they

elaborate the axons training behind
them. Their extension is controlled by
chemical cues in their outside
environment that ultimately direct
them toward their appropriate targets.
Chemoattractants
Vs
Chemorepellants
5 Phases of Neurodevelopment

Neural plate induction

Neural proliferation
Migration & Aggregation
Axon growth & Synapse formation
Cell death & Synapse rearrangement
 4. Axon Growth/Synaptogenesis
Once migration is complete and structures have
formed (aggregation), axons and dendrites begin
to grow to their mature size/shape.

Axons (with growth cones on end)

and dendrites form a synapse with
other neurons or tissue (e.g. muscle)

Growth cones and chemo-attractants

are critical for this.
 Synaptogenesis

Formation of new synapses

Depends on the presence of glial cells especially

astrocytes

Chemical signal exchange between pre- and

postsynaptic neurons is needed
5 Phases of Neurodevelopment

Neural plate induction

Neural proliferation
Migration & Aggregation
Axon growth & Synapse formation
Cell death & Synapse rearrangement
 5. Neuronal Death

Between 40-75% neurons made, will die

after
migration death is normal and necessary !!
Neurons die due to failure to compete for
chemicals provided by targets

Neurotrophins
promote growth and survival
guide axons
stimulate synaptogenesis
 Synaptic rearrangment

Release and Neurons receiving Axonal processes

uptake of insufficient complete for
neurotrophic neurotropic factor limited
factors die neurotrophic factor
Synaptic rearrangment, contd: Myelination

Time after synaptogenesis

 Postnatal Cerebral Development Human
Infants
Postnatal growth is a consequence of
Synaptogenesis
Increased dendritic branches
Myelination (prefrontal cortex continues into
adolescence)
Overproduction of synapses may underlie the
greater plasticity of the young brain
Young brain more able to recover function after injury,
as compared to older brain
Early Studies of Experience and Brain
Development

Early visual deprivation

fewer synapses and dendritic spines in visual
cortex
deficits in depth and pattern vision

Enriched environment
thicker cortices
greater dendritic development
more synapses per neuron
Development of the Prefrontal Cortex

Believed to underlie age-related changes in

cognitive function, judgement, decision-making

No single theory explains the function of this

area

Prefrontal cortex plays a role in working

memory, planning and carrying out sequences
of actions, and inhibiting inappropriate
responses
Where is your Prefrontal Cortex ?
 Postnatal Cerebral Development:
Adolescence
The prefrontal lobe is the last to fully develop

http://www.youtube.com/watch?v=4-
9sjvitKWA
 Neuroplasticity in Adults ?

Mature brain changes and adapts

Neurogenesis (birth of new neurons)

seen only in olfactory bulb and hippocampus of
adult mammals

Not clear if this is critical for normal adult

behavior
 Effects of Experience on the
Reorganization of the Adult Cortex
Skill training leads to reorganization of motor
cortex

Adult musicians who play instruments have an

enlarged representation of the hand in
somatosensory cortex

Reorganization is synaptogenesis or pruning of

unused synapses
 Neurodevelopmental Disorders
Autism Spectrum Disorders
1/91 live births in U.S.)

Fetal Alcohol Spectrum Disorders

(1/100 live births in North America ?)
 Autism
http://health.yahoo.com/nervous-videos/what-is-autism/healthination--
HNB10051_autism_1.html

3 core symptoms:
Reduced ability to communicate
Reduced capacity for social interaction
Preoccupation with a single subject or activity

Heterogenous level of brain damage and

dysfunction varies (Autism Spectrum Disorder)
Probably no single cause
 Autism
Most have some abilities preserved

Savants intellectually
handicapped individuals who
display specific cognitive or
artistic abilities
~1/10 autistic individuals
display savant abilities
 Neural Basis of Autism
Genetic basis
Siblings of the autistic have a 5% chance of being autistic
60% concordance rate for monozygotic twins

Several genes interacting with the environment

 Fetal Alcohol Spectrum Disorders
50+% of women who could become
pregnant are drinking

2% of women drink significantly during

pregnancy, 10% drink some
Glass of wine, bottle of beer, shot of liquor are equal
approximately 0.5 oz absolute alcohol

Fetal brain damage occurs at regular doses of 1-2 oz/day (2-4 drinks)

Source: National Institute on Alcohol

Abuse and Alcoholism
Symptoms of FASD
Infant: Problems with sleep, feeding, milestones, muscle tone,
sensory information processing

Child: Hyperactive, poorly coordinated, learning delays

Adolescent/Adult: poor judgment, attention, problems with arithmetic,

memory, abstraction, frustration/anger
Neural Basis of Fetal Alcohol Spectrum
Disorders
When is alcohol exposure most dangerous ???
 Neural Basis of Fetal Alcohol Spectrum
Disorders
Alcohol inhibits all stages of brain development, except
neuronal death, which it promotes.
Brain damage resulting from prenatal alcohol

Brain of baby with Brain of baby with heavy no exposure to

alcohol prenatal exposure to alcohol

Photo courtesy of Sterling Clarren, MD