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Regeneration, Repair, and Plasticity. Chapters 6, 7, 8, 10 P.S. Timiras. Brain Plasticity and CNS Regenerative Potential. From the beginning of the 20th Century until the 1990s, it was stated that neurons DID NOT proliferate.

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slide1
Regeneration, Repair, and Plasticity

Chapters 6, 7, 8, 10

P.S. Timiras

brain plasticity and cns regenerative potential
Brain Plasticity and CNS Regenerative Potential
  • From the beginning of the 20th Century until the 1990s, it was stated that neurons DID NOT proliferate.
  • The fact that they COULD NOT proliferate did not exclude the possibility of proliferation under “specific conditions.”
  • In fact, the CNS has a considerable regenerative potential depending on the special conditions of the neuronal environment.
neurons that may proliferate into adulthood include
Neurons that may proliferate into adulthood include:
  • Progenitor “precursor” neurons lining the cerebral ventricules
  • Neurons in the hippocampus
  • Neurons usually “dormant” with potential for neuron and glia proliferation
  • Neuroglia (astrocytes, oligodentrocytes) and microglia (immune cells) with the ability to perpetually self renew and produce the three types of neural cells
regenerative potential depends on changes in whole body and neural microenvironment
Regenerative potential depends on changes in whole body and neural microenvironment
  • Whole body changes:
    • Physical exercise
    • Appropriate nutrition
    • Good circulation
    • Education
    • Stress
    • others
  • Neural microenvironment
  • changes:
    • Brain metabolism (oxygen consumption, free radicals, circulatory changes)
    • Hormonal changes (estrogens, growth factors, others)
    • others
slide5
Death Rates in 1986 among Persons 25- 64 Years Old in Selected Education and Income Groups According to Race and Sex.

________________________________________________________

GroupWhite Black

Men Women Men Women

deaths per 1000

Education- yr

Completed

School

0-11 7.6 3.4 13.4 6.2

12 4.3 2.5 8.0 3.9

College

1-3 4.3 2.1 5.0 3.2

4 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.

slide6
Proportion of Remaining Life Expected to be Lived with a Disability in Activities of Daily Living and Death Rates

________________________________________________________

At Age At Age At Age Death Rates

65 75 85 per 1,000

White men

Low education .11 .21 .45 7.6

Higher education .10 .19 .37 2.8

White women

Low education .15 .24 .45 3.4

Higher education .14 .23 .40 1.8

Black men

Low education .13 .22 .36 13.4

Higher education .11 .18 .31 6.0

Black women

Low education .15 .22 .36 6.2

Higher education .14 .21 .31 2.2

________________________________________________________________________

From: Guralink, J.M., et al., Educational status and active life expectancy among older blacks and whites, N Engl. J Med., July 8, 1993, Vol. 29:110-116

slide7
Better access to medical care

Better access to recreational activity

Better nutrition

Higher income

Responsibility to health behaviors

No alcohol intake

Increased brain reserve capacity?

More dendritic branching, cortical synapses?;

Better cerebral blood flow?;

Better neural cell efficiency, adaptability, redundancy, survival and growth

Mechanisms of Education Effects

No smoking

slide8
Fig. 7-4: “Denudation” of the neurons. Changes in pyramidal neurons of the aging human cerebral cortex
slide9
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 Gender

Hemisphere

Education

Personal history

Hormonal Correlate

Thyroid Hormones dendritic number and length

Glucocorticoids reactive synaptogenesis

______________

* From Jacobs et al., J Comp. Nuerol., 327, 97, 1993

slide11
Perceived Functioning of Medicare Beneficiaries, by Gender and Age, 2002

100

Perform with difficulty

65-74 years

75-84 years

85 years and over

80

60

40

20

0

Women

Men

Women

Men

Women

Men

Mobility Limitation

ADL

IADL

Source: Health & Health Care of the Medicare Population: Data from the 2002 Medicare Current Beneficiary Survey. Rockville, MD: Westat, February 2006

slide12
Evidence from several laboratories show:

That in the brain there are neural cells which can divide

These are cells located in:

olfactory bulbs

hippocampus

ependymal cells

(in proximity of the ventricles)

glial cells

(astrocytes which can de-differentiate & differentiate into neurons)

From Wong, R.J., Thung, E., et al., Keeping Cells Young: The role of growth factors in restricting cell differentiation in cultured neuroglia, FASEB Journal, 17(5): A967, 2003.

slide13
Neural Cells
  • Common ectodermic derivation of neurons and neuroglia
  • Astrocytes:
    • Star shaped cells
    • Support neurons metabolically
    • Assist in neuronal transmission
  • Oligodendrocytes: myelinate neurons

Neural Epithelium

Neuroblast Spongioblast

Neuron Migratory Spongioblast Astrocyte Ependyma

Oligodendrocyte Astrocyte

slide14
Growth Curves Measuring Neuroglial Cell Proliferation

FGF

EGF

* Proliferation increased most effectively with the 50 ng/ml dose (193% over control cells) for EGF, reaching a peak at day 10

* Proliferation increased most effectively with the 80 ng/ml dose (269% over control cells) for FGF, reaching a peak at day 8

slide15
Assays of enzymatic activity

(e.g. glutamine synthetase--a marker of astrocytes)

show decreased activity

suggesting a loss of astrocytic specificity

  • From:
  • Proliferation
  • Maturation
  • To:
  • Proliferation
  • De-differentiation
slide16
“Activated” astrocyte

Proliferating astrocytes

Astrocyte

Neuroblast

migrate

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

slide17
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 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 in adipocytes and osteoblasts.

Also refer to: Brawley, C. and Matunis, E., Regeneration of male germ line stem cells by spermatogonial de-differentiation in vivo. Science 304, 1331-1334. 2004

slide19
The brain regulates motor function

and, reciprocally,

Motor function influences brain activity

Throughout life,

One’s behavior can change the structure of the brain

And these changes

Can affect how we behave in our environment

Get Up and Move:

A Call to Action

for Older Men & Women

slide20
Additional Studies
  • To promote regeneration/repair responses in aging muscle:
    • Injection of growth hormone in aging cardiac muscle
    • Implantation of stem cells into infarcted cardiac muscle
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