Regeneration of Neurons in the Mammalian Brain

There is evidence that injured mammalian brain tissue can respond to injury by a low-level increase in neurogenesis. Although Magavi et al. (2000) found no evidence of maintenance neurogenesis in the mouse cortex, they did observe neurogenesis after destruction of a subset of pyramidal neurons in the lower layer (VI) of the cortex that projects to the thalamus. Thalamic neurons were injected with chromophore-conjugated chlorin e6 nanospheres, which were retrogradely transported to layer VI cortical neurons. The layer VI neurons were then killed by activating the chromophore with laser light at a wavelength of 674 nm. Subsequent proliferation of BrdU-labeled lateral ventricle cells was no greater than in uninjured animals, but cells labeled with BrdU and expressing doublecortin were observed along a path to the cortex. One to two percent of the BrdU-labeled cells within the cortex expressed the mature neuron marker NeuN. Retrograde labeling showed that the regenerated neurons were pyramidal neurons that projected to the thalamus; i.e., the neurons that were destroyed were selectively regenerated and functionally integrated into the normal circuitry of the brain. Other studies have shown increased production of granule cells in the dentate gyrus of the hippocampus in rats and gerbils after neuronal degeneration induced by focal or global ischemia (Gould and Tanapat, 1997; Jin et al., 2001; Liu et al., 1998). Thus, it would appear that injury signals can diffuse (or be carried by the circulation) far enough to activate and "home" NSCs to the injury site, and are sufficient to increase

FIGURE 5.19 Effect on hair cell division of knocking out the Rb gene in mouse utricles. Utricles from mice transgenic for a Rb gene carrying lox P (P) sites flanking exon 19 (hatched) were cultured in vitro. (A) The utricles were transfected with an adenovirus (AV) constitutively expressing the Cre gene. (B) The Cre enzyme excised exon 19 at the lox P sites, creating a defective Rb gene whose product could no longer block entry into the cell cycle. (C, D) The result was mitosis of the hair cells.

FIGURE 5.19 Effect on hair cell division of knocking out the Rb gene in mouse utricles. Utricles from mice transgenic for a Rb gene carrying lox P (P) sites flanking exon 19 (hatched) were cultured in vitro. (A) The utricles were transfected with an adenovirus (AV) constitutively expressing the Cre gene. (B) The Cre enzyme excised exon 19 at the lox P sites, creating a defective Rb gene whose product could no longer block entry into the cell cycle. (C, D) The result was mitosis of the hair cells.

the number of NSCs that differentiate into neurons. However, only a small fraction of the degenerated neurons are replaced, not enough for functional recovery.

The small increase in the frequency of ischemia-induced differentiation of hippocampal NSCs into pyramidal neurons can be markedly enhanced by exogenous FGF-2 and EGF (Nakatomi et al., 2002). Intraventricular injection of FGF-2 and EGF together boosted the number of regenerated neurons to 40% of the number that were lost. The neurons were functionally integrated into the normal hippocampal circuitry as determined by microscopy, the electrophysiological properties of synapses, and the performance of the rats on behavioral tasks. These findings are consistent with the fact that FGF-2 expression is upregulated after CNS injury in mammals by fibrous astrocytes (Fawcett and Asher, 1999) and helps to keep NSCs dividing and undifferentiated in vitro (Temple, 2001).

Neonatal astroglia induce the proliferation and differentiation of adult hippocampal NSCs into neurons in vitro, whereas the effect of adult astrocytes is only half that of neonatal cells (Song et al., 2002). Furthermore, the effect seems specific to hippocampal astrocytes, since spinal cord astrocytes do not support hippocampal neurogenesis. These results suggest that astrocytes are involved in generation of the hippocam-pal NSC niche, but that the low level of increase in neurogenesis in the injured adult hippocampus is due to deficient FGF-2 and EGF signaling from astrocytes to NSCs.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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