Nervous System Nervous System II: II:

Development & Development & PlasticityPlasticity

Arvin GouwArvin Gouw

Endocrinology Graduate Endocrinology Graduate ProgramProgram

Nervous System Nervous System DevelopmentDevelopment

• Endoderm: – Gastrointestinal System– Endocrine System– Respiratory Tract

• Mesoderm: – Immune System– Muscular System

• Ectoderm: – Integument – Nervous System

Nervous System Nervous System Components IComponents 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 blood-brain barrier.

– Reuptake & recycle neurotransmitters

Nervous System Nervous System Component IIComponent 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 DogmaNeuron Dogma• Santiago Ramon y Cajal (Spanish

Neurologist,1852-1934) wrote:– 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 BrainNeurogenesis 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 Where do the new neurons come from ?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?

• From newt amputated limb, terminally differentiated cells de-differentiate by losing their original characteristics. This de-differentiation produces blastema cells that then re-differentiate to reconstitute the lost limb.

• After lentectomy de-differentiated cells lose pigment and regenerate a perfect lens.

• De-differentiated myotubes produce mesenchymal progenitor cells that are able to differentiate into adipocytes and osteoblasts.

Tsonis, P.A., Stem Cells from Differentiated Cells, Tsonis, P.A., Stem Cells from Differentiated Cells, Mol. IntervenMol. Interven., 4, 81-83, 2004., 4, 81-83, 2004

Common ectodermic derivation of neurons and neuroglia

Neural Epithelium

Neuroblast Spongioblast

Neuron Migratory Spongioblast Astrocyte Ependyma

Oligodendrocyte Astrocyte

How is transdifferentiation possible ?

Astrocyte

“Activated”

astrocyte

Proliferating

astrocytes

Neuroblast

migrate

From: Doetsch, F., et al., Neuron, 36:1021, 2002.

Why is Why is transdifferentiation transdifferentiation

important?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 How should one induce transdifferentiation?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 & FGFEGF & 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.

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Growth Curve

2’3’-Cyclic Nucleotide 3’-Phosphohydrolase

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Glutamine Synthetase

Enzyme Activities in Astrocytes & Oligodendrocytes

• 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 Astrocytes: 14 Days of TreatmentTreatment

NeuN = Neuron Specific Nuclear Protein DAPI = stains the nuclei blue Untreated neuroglia lack NeuN, but EGF and FGF treated cells express the

neuronal protein.

Untreated neuroglia EGF (50ng/mL) FGF (80 ng/mL)

Oligodendrocytes: 14 Oligodendrocytes: 14 Days of TreatmentDays 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 Observation in Sisters of Notre Dameof 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 BlackMen Women Men Women

deaths per 1000

Education- yr CompletedSchool0-11 7.6 3.4 13.4 6.212 4.3 2.5 8.0 3.9College1-3 4.3 2.1 5.0 3.24 2.8 1.8 6.0 2.2

Income-$<9,000 16.0 6.5 19.5 7.6 9,000-14,999 10.2 3.4 10.8 4.5 15,000-18,999 5.7 3.3 9.8 3.7 19,000-24,999 4.6 3.0 4.7 2.8>25,000 2.4 1.6 3.6 2.3 ______________________________________________________________________________________

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 EffectsMechanisms of Education Effects

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

Better access to medical care

Anatomical Correlates of Educational Protective Effects*Educational Level Increasing levels from <12 to >12

grades

Anatomical Correlate total dendritic length

mean dendritic length

dendritic segment count

Location Pyramidal cells in layer 2,3 of Wernicke’s area

Variable Studied GenderHemisphereEducationPersonal history

Hormonal Correlate Thyroid Hormones dendritic number and length Glucocorticoids reactive synaptogenesis ______________* From Jacobs et al., J Comp. Nuerol., 327, 97, 1993

Neural PlasticityNeural 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.