CELLS OF THE NERVOUS SYSTEM AND ELECTRICAL STIMULATION - Advanced Biomaterials: Fundamentals, Processing, and Applications - page 605

Limited laboratory techniques prevented successful investigations into specula-
tions of dividing cells in the postnatal CNS. Thus, Ramon y Cajal ' s work became
a dogma for about 90 years, despite evidence that began to prove otherwise
starting in 1961. For a detailed historical timeline see (Ming and Song 2005) and
(Gross 2000).
In 1982, Bromodeoxyuridine (5 - bromo - 2 - deoxyuridine, BrdU) was success-
fully used to detect neurogenesis in mice (Gratzner 1982) and later in humans
(Eriksson et al. 1998). BrdU labeling is still used to identify adult neurogenesis
and isolate NPCs from the brain. Once NPCs were cultured successfully in vitro ,
the functionality of differentiated neurons was electrophysiological tested to
established that NPCs were indeed capable of producing neurons.
Then, a very important study of the telencephalon (brain region) in song birds
related neurogenesis with learning (Alvarez-Borda et al. 2004). Furthermore,
synaptic activity and integration of new neurons into preexisting neural networks
has been shown in the CNS, specifi cally in the olfactory bulb (Saghatelyan et al.
2003; Belluzzi et al. 2003). Still, much is unknown. Future challenges lie in under-
standing why neurogenesis occurs only in certain areas of the brain; what func-
tions neurogenesis serves; and how neurogenesis is endogenously directed.
18.3.2 NPCs in the Brain
Within the brain, there are two zones that are most proliferative or neurogenic:
the sub ventricular zone (SVZ) of the lateral ventricles, and the subgranular zone
(SGZ) of the dentate gyrus in the hippocampus (Gage 2002; Ming and Song
2005). These two areas are being extensively investigated because of their ability
to maintain neurogenesis or neural progenitor cells throughout adult life (Doetsch
2003). It should also be noted that outside these areas, there are proliferating
progenitor cells that give rise to glial cells but not to neurons (Horner et al. 2000;
Gage 2000; Rakic 2002; Magavi et al. 2000).
Yet, purifi ed proliferating cells, dissected out of many regions in the adult
brain (Palmer et al. 1999), even non-neurogenic regions, such as the spinal cord
(Shihabuddin et al. 2000; Shihabuddin et al. 1997; Palmer et al. 1999), can produce
neurons in vitro , when cultured in the presence of FGF (Palmer et al. 1999), and
after grafting into neurogenic regions in vivo (Kondo and Raff 2000), such as the
dentate gyrus (Shihabuddin et al. 2000).
The exact phenotype or identity of the most primitive cells that are truly
adult stem cells (least differentiated with indefi nite self-renewal) in the adult
CNS, which terminally differentiate into glia and neurons, has not been clearly
established. Some evidence indicates that a subpopulation of ependymal cells in
the lining of the third ventricle are stem cells (Johansson et al. 1999). Yet other,
more convincing evidence points to a subset of cells in the SVZ that are astrocyte-
like (GFAP expressing) as being adult stem cells (Doetsch et al. 1999), as described
in a recent review by Alvarez-Buylla (Alvarez-Buylla et al. 2002). The resolution
of this issue is crucial in understanding neurogenesis and the development of cell-
based therapies for the nervous system (Alvarez-Buylla et al. 2002; Lindvall et al.