MCB 135K: Discussion March 9, 2005 GSI: Jason Lowry

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: Progenitor “precursor” neurons lining the cerebral ventricules Neurons in the hippocampus Neurons usually “dormant” with potential for neuron and glia proliferation Astrocytes and oligodentrocytes 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 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

Mechanisms 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

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.

Common ectodermic derivation of neurons and neuroglia Astrocytes: –Star shaped cells –Support neurons metabolically –Assist in neuronal transmission Oligodendrocytes: myelinate neurons Neural Epithelium NeuroblastSpongioblast NeuronMigratory Spongioblast Astrocyte Ependyma Oligodendrocyte Astrocyte Neural Cells

Growth Curves Measuring Cell Proliferation EGF FGF * 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

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,

Aging of the Visual System

Structural Changes (See handout) –Tear Film: Dry eyes or tearing –Sclera: Fat deposits – yellowing Thinning – blueing –Cornea Diameter does not change after age 1 Shape changes –Retina Photoreceptor density decreases; other layers become disordered Illuminance decreases with age –Lens Increased size and thickness Becomes more yellow

Aging of the Visual System Function –Corneal and Lens Decreased accommodation power Increased accommodation reflex latency Refractive error becomes more hyperopic with age Corneal sensitivity decreases Scatter increases –Retinal Decreased critical flicker frequency Visual acuity declines Visual Field decreases Color vision changes Darkness adaptation is slowed Increased glare problems Decreased light reaches retina

Aging of the Visual System Recommendation to Accommodate Problems: –Wear appropriate optical correction –Increase ambient light –Make lighting even and reduce glare –Improve contrast in critical areas –Avoid rapid changes in light level –Avoid Pastel –Allow more time

Aging of Cardiovascular System Atherosclerosis –Characteristics –Disease Results –Arterial Changes –Atherogenesis –Contributing Factors –Age Changes in Vascular Endothelium

Atherosclerosis Characteristics –Universal –Progressive –Deleterious –Irreversible …but (?)

Atherosclerosis Disease Manifestation –Myocardial Infarct –Stroke –Aneurysm –Gangrene

Arterial Changes Morphological Characteristics of the Arterial Wall –Intima – inner most layer of endothelial cells –Media Elastica interna – formed by elastin fibers Smooth Muscle cells Vasa vasorum (penetrates media) Elastica externa –Adventitia – outer most layer of collagen bundles Vasa vasorum – provide blood Read Pages

Atherogenesis Fatty Streak (Intima) –Increased LDL and oxidized LDL –Accumulation of LDL in endothelial space –Alter and breakdown of Elastic fiber –Alerts immune system –Monocytes  macrophages –Phagocytose LDL and elastic fibers –Macrophages become full of LDL and appear as foam cells after staining

Atherogenesis Fibrous Plaque (Intima and Media) –Damaged smooth muscle cells take up LDL –Increase foam cells –Defense mechanism create scar tissue –Problem for metabolic exchange later

Atherogenesis Atheroma –Alteration of endothelial cells –Decreased number of cell –Platelets seal off area where there was a loss of cells Increased growth factors Increased RBC Results in thrombus