Neurogenesis in Adult Central Neurogenesis in Adult Central

Nervous System: Death of a Nervous System: Death of a

DogmaDogma

Anton B. Tonchev

Division of Cell Biology,

Varna University of Medicine, Bulgaria

Department of Restorative Neurosurgery

Kanazawa University, Japan

Aristotle University of Thessaloniki, Greece, Nov. 2007

NeuroplasticityNeuroplasticity is a continuous

process in reaction to neuronal

activity and neuron injury, which

involves modulation of structural

and functional processes of

axons, dendrites, and synapses.

• Synapses (electrical, biochemical, structural)

• Neurite (axon, dendrite)

• Neuron cell bodies

• Transport (anterograde and retrograde)

• Cell interactions (neuron - glia)

• Neural networks

Processes that manifest plasticity

• Synaptic� efficacy

� LTP

� remodeling

� genesis

• Neurite extension

� axonal sprouting

� dendritic remodeling

• Neurogenesis and recruitment

SStructural elementstructural elements of plasticity

presynaptic terminal

postsynaptic terminal

Synaptic efficacy

& remodeling

neurite

extension

Cell division & neurogenesis

SStructural elementstructural elements of plasticity

Synaptogenesis

“Once development was ended, the founts of growth and

regeneration of the axons and dendrites dried up

irrevocably. In the adult centers the nerve paths are

something fixed, ended and immutable. Everything must

die, nothing may be regenerated. It is for the science of

the future to change, if possible, this harsh decree.”

Ramon y Cajal (1928):

•Undifferentiated

•Proliferate

•Self-renew

•Generate descendants

•Regenerate tissue?

(Okano H, Keio Med J, 2002)

Neural Stem Cells

Generation of neurons from stem/progenitor cells

Neurogenesis

SVZ – Cellular architecture

Doetsch F. 2003. The glial identity of neural stem cells. Nat Neurosci 6:1127-1134.

Stem

cell

Transit

amplify

ing cell

Neuronal

progenitor

2 / 1 / 3

Migration to Olfactory Bulb

O’Rourke NA. 1996. Neuron 16:1061-1064

Human SVZ

Neural Progenitor Cells in Adult BrainNeural Progenitor Cells in Adult Brain

Dennis A Steindler, David W Pincus

Lancet 2002; 359: 1047–54

Gould et al., Proc Natl Acad Sci

USA 1998; 95: 3168–3171

Anatomy of Primate Hippocampus

CA1

CA2

CA3

CA4

Gyrus dentatus

Entorhinal cortex

Dentate Gyrus Dentate Gyrus -- NeurogenesisNeurogenesis

Progenitor Immature neuron Mature neuron

Becker S, Wojtowicz JM, Trends Cogn Sci. 2007 Feb;11(2):70-6

Gradual Maturation of New Neurons in DGGradual Maturation of New Neurons in DG

1d

7d

21d

Functional NeurogenesisDentate Gyrus

(vanPraag et al, Nature, 2002)

Levels of Functional Analysis in Adult Neurogenesis

Kempermann, Wiskott, Gage. Curr Opin Neurobiol 2004, 14:186–191.

• Increased proliferation� environmental enrichment, learning

� physical exercise

• Decreased proliferation� ageing

� maternal separation

Physiological Conditions Affecting Neurogenesis

(Gyrus dentatus)

Drugs Affecting Neurogenesis(Gyrus dentatus)

• Increased proliferation� antidepressants (TCA & SSRI); ECT

� haloperidol

� lithium

� estrogen, aldosterone

� inhibitory amino acids (GABA)

• Decreased proliferation� corticosteroids

� opiates (morphine)

� excitatory amino acids (GLU)

• Increased proliferation� ischemia

� seizures

� trauma

� degeneration (dementia)

• Decreased proliferation� stress (depression)

� irradiation

� inflammation (meningitis)

� chronic alcoholism

Clinical Conditions Affecting Neurogenesis(Gyrus dentatus)

Multipotent progenitor

Proliferating progenitors

Astrocyte Oligodendrocyte Neuron

FGF-2, EGF

VEGF

Shh

IGF-I

GDNF

LIF

BMP IGF-IBDNFBDNF

TGFαααα

Epo

SCF

HB-EGF

Evolution of the view of adult neurogenesis

Gould E. Nat Rev Neurosci. 2007;

8:481-8.

NeurogenesisNeurogenesis

??

Rodent = MonkeyRodent = Monkey

Clinical Applications of

Neural Progenitors

• Cerebral ischemic injury

• Neurodegenerative diseases

• Multiple sclerosis

• Brain tumors

• Congenital malformations

Dennis A Steindler, David W Pincus

Lancet 2002; 359: 1047–54

Sources of Stem Cells for Transplantation

Jakel et al,

Conclusions

• Endogenous progenitor cells reside in adult

mammalian brain including that of primates

• Progenitor cells in respond to various

environmental stimuli

• Progenitor cells are located in specific

cellular niches

• Neurogenesis takes place in an angiogenic

environment

Varna, BulgariaVarna, Bulgaria

Medical University - Varna