Transcript Nervous System II: Development & Plasticity

Nervous
System II:
Development &
Plasticity
Arvin Gouw
Endocrinology Graduate
Program
Nervous System
Development
• Endoderm:
– Gastrointestinal System
– Endocrine System
– Respiratory Tract
• Mesoderm:
– Immune System
– Muscular System
• Ectoderm:
– Integument
– Nervous System
Nervous System
Components I
Astrocytes: star-shaped
glial cells with the
following functions:
– involved in the physical
structuring of the brain.
– provide neurons with
nutrients
– form part of the bloodbrain barrier.
– Reuptake & recycle
neurotransmitters
Nervous System Component
II
• Oligodendrocytes: few
tree cells. (Gk) type of
neuroglia which
myelinate axons in the
Central Nervous
System (CNS).
• Neurons: are nerve
cells electrically
excitable cells that
process and transmit
information.
Neuron Dogma
• Santiago Ramon y Cajal
Neurologist,1852-1934) wrote:
(Spanish
– neurons were discrete cells that communicated
with each other via specialized junctions, or
spaces, between cells
– No new neurons are produced in the adult
brain.
Thus neurogenesis was thought to happen only
during development and to stop in adulthood.
Neurogenesis in Adult Brain
• However Fred Gage of Salk Institute
discovered adult neurogenesis in mammalian
nervous system.
• In fact, neurogenesis in intact adult brain
occurs in:
– Hippocampus (related to memory and behavior)
– cells lining the ventricles and the spinal canal, then
migrating to olfactory bulb (OB)
• Ischemia (interruption of blood flow to a brain
region and loss of cells) leads to increased
neurogenesis
• Enriched environment and exercise may also
induce increased neurogenesis
Where do the new neurons
come from ?
• Adult neurogenesis phenomena leads one
to ask where the new neurons come from.
Studies have suggested:
–
–
–
–
Ependymal cells
Radial glia
Astrocytes
Oligodendrocytes
If so, then does it mean that transdifferentiation
from one type of cell to a different type of cell
is possible?
Tsonis, P.A., Stem Cells from Differentiated Cells, Mol.
Interven., 4, 81-83, 2004
• From newt amputated limb,
terminally differentiated cells
de-differentiate by losing their
original characteristics. This dedifferentiation produces blastema
cells that then re-differentiate to
reconstitute the lost limb.
• After lentectomy dedifferentiated cells lose pigment
and regenerate a perfect lens.
• De-differentiated myotubes
produce mesenchymal progenitor
cells that are able to differentiate
into adipocytes and osteoblasts.
How is transdifferentiation possible ?
Common ectodermic derivation of neurons and neuroglia
Neural Epithelium
Neuroblast
Neuron
Spongioblast
Migratory Spongioblast
Oligodendrocyte
Astrocyte
Astrocyte
Ependyma
Astrocyte
“Activated”
astrocyte
Proliferating
astrocytes
Neuroblast
migrate
From: Doetsch, F., et al., Neuron, 36:1021, 2002.
Why is transdifferentiation
important?
• If we can induce transdifferentiation
in the nervous system from neuroglia
into neurons, then we can possibly
relieve neurodegenerative diseases
such as:
– Alzheimer’s Disease
– Parkinson’s Disease
– Huntington’s Disease
– Any other neurodegenerative diseases
How should one induce
transdifferentiation?
• Since brain injuries have been known to
cause adult neurogenesis and
transdifferentiation of astrocytes into
neurons, we can study what happens in
vivo.
• In vivo, many chemicals are released
following trauma, including:
– Epidermal Growth Factor (EGF)
– Fibroblast Growth Factor (FGF)
– etc
EGF & FGF
• Epidermal Growth Factor (EGF)
– Mitogenic protein is involved in
mechanisms such as normal cell growth,
oncogenesis, and wound healing. Binds
to EGFR on cell surface eventually
stimulates DNA synthesis and cell
proliferation
• Fibroblast Growth Factor (FGF)
– Responsible for growth and
differentiation of numerous cell types
and stimulation of neuronal
proliferation.
Percent Growth of Cells
Growth Curve
160%
140%
Control
120%
100%
FGF - 80
ng/mL
80%
60%
EGF - 50
ng/mL
40%
20%
0%
0
2
4
6
8
10
12
14
16
18
20
Time (Days)
Enzyme Activities in Astrocytes &
Oligodendrocytes
2’3’-Cyclic Nucleotide
3’-Phosphohydrolase
120%
Control
100%
80%
60%
40%
20%
0%
8
Time (Days)
14
Control
Percent Activity Based on
Control
Glutamine Synthetase
FGF - 80 ng/mL
120%
100%
80%
60%
40%
20%
0%
8
EGF - 50 ng/mL
14
Time (Days)
• Looking at both the data from cell
counts and enzymatic activity, a
general trend can be seen in which
the neuroglia are shifting:
From:
•
Proliferation
•Maturation
To:
•
Proliferation
•De-differentiation
Astrocytes: 14 Days of
Treatment
Untreated neuroglia
EGF (50ng/mL)
FGF (80 ng/mL)
 NeuN = Neuron Specific Nuclear Protein
 DAPI = stains the nuclei blue
 Untreated neuroglia lack NeuN, but EGF and FGF treated cells express the
neuronal protein.
Oligodendrocytes: 14 Days
of Treatment
Untreated neuroglia
EGF (50ng/mL)
FGF (80 ng/mL)
 Nestin = Intermediate filament protein in neurons
 Presence of Nestin in EGF and FGF treated cells and lack of neuronal protein
in untreated neuroglia.
Learning at all Ages Induces
Successful Aging
Observation in Sisters of
Notre Dame
• The nuns were highly involved in
teaching and studying well till old
age, and they have been shown to
live longer (75-104 yrs old), avoiding
the Alzheimer’s Disease.
• “Aging With Grace: What the Nun Study Teaches
Us About Leading Longer, Healthier, and More
Meaningful Lives” (paperback). By David
Snowdon. Bantam 2002.
Death Rates in 1986 among Persons 25- 64 Years Old in Selected
Education and Income Groups According to Race and Sex.
________________________________________________________
Group
White
Men
Black
Women
Men
Women
deaths per 1000
Education- yr
Completed
School
0-11
12
College
1-3
4
7.6
4.3
3.4
2.5
4.3
2.8
2.1
1.8
5.0
6.0
3.2
2.2
Income-$
<9,000
9,000-14,999
15,000-18,999
19,000-24,999
>25,000
16.0
10.2
5.7
4.6
2.4
6.5
3.4
3.3
3.0
1.6
19.5
10.8
9.8
4.7
3.6
7.6
4.5
3.7
2.8
2.3
13.4
8.0
6.2
3.9
______________________________________________________________________________________
Pappas, G., Queen, S., Hadden, W., and Fisher, G. The increasing disparity in mortality between socioeconomic groups in the United
States, 1960 and 1986. N. Engl. J Med. 329, 103-109, 1993.
Mechanisms of Education Effects
Better access to medical care
Better access to recreational activity
Better nutrition
Higher income
Responsibility to health behaviors
No alcohol intake
No smoking
Increased brain reserve capacity?
More dendritic branching, cortical synapses?;
Better cerebral blood flow?;
Better neural cell efficiency, adaptability, redundancy, survival and growth
Anatomical Correlates of Educational Protective Effects*
Educational Level
Anatomical Correlate
Increasing levels from <12 to >12
grades
total dendritic length
mean dendritic length
dendritic segment count
Location
Pyramidal cells in layer 2,3 of
Wernicke’s area
Variable Studied
Gender
Hemisphere
Education
Personal history
Hormonal Correlate
Thyroid Hormones
Glucocorticoids
______________
* From Jacobs et al., J Comp. Nuerol., 327, 97, 1993
dendritic number and length
reactive synaptogenesis
Neural Plasticity
• Thus the nervous system is much
more plastic than previously thought.
• Better knowledge of factors
regulating prenatal brain
development may be useful in
understanding post-natal potential
plasticity and neurogenesis.