Recent studies indicate the existence of progenitor cells and their potential for neurogenesis in the subventricular zone (SVZ) and the hippocampus of the normal adult mammalian brain. However, the proliferative response and the specific cell types generated following traumatic brain injury have not been examined. This cellular response to CNS injury was investigated using the fluid percussion injury (FPI) model, a widely accepted rat model that simulates moderate head injury sustained in humans. Forty-eight hours following moderate FPI, adult rats received intraperitoneal injections of the thymidine analogs, 5-bromodeoxyuridine (BrdU) or tritiated thymidine (3H-thymidine), which are markers for mitotic activity. Injured and control animals receiving BrdU were used to determine the total number of cells induced to proliferate. To determine the cellular identity of these proliferating cells, animals receiving 3H-thymidine were sacrificed and sections through the injured area were immunostained with markers for immature and mature astrocytes, activated microglia, neural precursors and mature neurons. These studies showed that the total number of proliferating cells was significantly increased in the injury group for both the SVZ and the hippocampus. However, the proliferating cells in the SVZ did not express any of the cellular markers used, suggesting that they have not yet begun to differentiate. In contrast, there was a significant increase in the number of immature astrocytes and activated microglia, but not neurons, at this early time point in the hippocampus. Taken together, these experiments demonstrate the compensatory capacity of the adult brain to injury and should lead to a new generation of studies aimed at enhancing the neuronal proliferative response.

Replication of prions is dependent on the presence of the host protein PrPc. During the course of disease, PrPc is converted into an abnormal isoform, PrPSc, which accumulates in the brain. Attempts to identify the cell type(s) in which prion replication and PrP conversion occur have reached conflicting results. Although PrP mRNA is present in high amounts in neurons throughout the life of the animal, PrPSc initially accumulates in astrocytes and possibly other glial cells and, later in the course of the disease, spreads diffusely in the tissue, often in white matter. We report here that PrP mRNA is expressed not only in neurons but also in astrocytes and oligodendrocytes throughout the brain of postnatal hamsters and rats. The level of glial Prp mRNA expression in neonatal animals was comparable to that of neurons and increased two-fold during postnatal development. A substantial portion of brain PrP mRNA is therefore contributed by glial cells. Our results provide an explanation for the accumulation of PrPSc in white matter tissue and in the cytoplasm of glial cells and argue for a direct involvement of glia in prion propagation.

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Several novel myelin-associated/oligodendrocytic basic protein (MOBP) isoforms were identified in this study by cDNA cloning. They are small, highly basic polypeptides comprising 69, 81, and 99 amino acids (8.2, 9.7, and 11.7 kDa, respectively) and show no significant homology with described proteins or domain structures. All (as yet) identified MOBP isoforms are identical in amino acids 1-68 but differ in the length and polarity of the C-terminal region. One isoform, designated MOBP81, was shown to be expressed abundantly during development. Interestingly, MOBP81 has a significant clustering of positively charged residues at positions 69-81, a feature that also has been observed for myelin basic protein (MBP) and Po. As demonstrated by in situ hybridization, MOBP gene expression occurs during development of the rat optic nerve later than that of MBP and proteolipid protein and coincides exactly with the beginning of myelin compaction. The 2.6 kb MOBP81-A transcript is localized in the processes of oligodendrocytes, whereas the 3.8 kb MOBP81-B transcript is restricted to the perinuclear region. Therefore, MOBP81-A and related mRNAs seem to be transported to the periphery of the oligodendrocytes, as is known for the transcripts of the MBP gene. The late developmental expression of the MOBP gene suggests that the MOBP proteins act at the late steps of myelin formation, possibly in myelin compaction and in the maintenance of the myelin sheath.

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Stem/progenitor cells reside throughout the adult CNS and are actively dividing in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. This neurogenic capacity of the SVZ and DG is enhanced following traumatic brain injury (TBI) suggesting that the adult brain has the inherent potential to restore populations lost to injury. This raises the possibility of developing strategies aimed at harnessing the neurogenic capacity of these regions to repair the damaged brain. One strategy is to enhance neurogenesis with mitogenic factors. As basic fibroblast growth factor (bFGF) is a potent stem cell mitogen, we set out to determine if an intraventricular administration of bFGF following TBI could affect the levels of injury-induced neurogenesis in the SVZ and DG, and the degree to which this is associated with cognitive recovery. Specifically, adult rats received a bFGF intraventricular infusion for 7 days immediately following TBI. BrdU was administered to animals daily at 2–7 days post-injury to label cell proliferation. At 1 or 4 weeks post-injury, brain sections were immunostained for BrdU and neuronal or astrocytic markers. We found that injured animals infused with bFGF exhibited significantly enhanced cell proliferation in the SVZ and the DG at 1 week post-TBI as compared to vehicle-infused animals. Moreover, following bFGF infusion, a greater number of the newly generated cells survived to 4 weeks post-injury, with the majority being neurons. Additionally, animals infused with bFGF showed significant cognitive improvement. Collectively, the current findings suggest that bFGF-enhanced neurogenesis contributes to cognitive recovery following TBI.

Evidence of injury-induced neurogenesis in the adult hippocampus suggests that an endogenous repair mechanism exists for cognitive dysfunction following traumatic brain injury (TBI). One factor that may be associated with this restoration is S100B, a neurotrophic/mitogenic protein produced by astrocytes, which has been shown to improve memory function. Therefore, we examined whether an intraventricular S100B infusion enhances neurogenesis within the hippocampus following experimental TBI and whether the biological response can be associated with a measurable cognitive improvement. Following lateral fluid percussion or sham injury in male rats (n = 60), we infused S100B (50 ng/h) or vehicle into the lateral ventricle for 7 days using an osmotic micro-pump. Cell proliferation was assessed by injecting the mitotic marker bromodeoxyuridine (BrdU) on day 2 postinjury. Quantification of BrdU-immunoreactive cells in the dentate gyrus revealed an S100B-enhanced proliferation as assessed on day 5 post-injury (p < 0.05), persisting up to 5 weeks (p < 0.05). Using cell-specific markers, we determined the relative numbers of these progenitor cells that became neurons or glia and found that S100B profoundly increased hippocampal neurogenesis 5 weeks after TBI (p < 0.05). Furthermore, spatial learning ability, as assessed by the Morris water maze on day 30-34 post-injury, revealed an improved cognitive performance after S100B infusion (p < 0.05). Collectively, our findings indicate that an intraventricular S100B infusion induces neurogenesis within the hippocampus, which can be associated with an enhanced cognitive function following experimental TBI. These observations provide compelling evidence for the therapeutic potential of S100B in improving functional recovery following TBI.

It is well known that the cognitive functions of juveniles recover to a greater extent than adult patients following traumatic brain injury (TBI). The exact mechanisms underlying this age-related disparity are unknown; however, we speculate that this improved recovery in juveniles following TBI may be associated with an endogenous neurogenic response in the hippocampus. We, therefore, examined the effects of TBI on cellular proliferation and differentiation in the dentate gyrus (DG) of the hippocampus in juvenile and adult rats following lateral fluid percussion injury (FPI). The temporal profile of the injury-induced proliferative response was determined using BrdU labeling at varying survival times. The differentiation of these newly generated cells was investigated using cell-type specific markers. We found that, following injury, there was a significant increase in cell proliferation in the DG in both injured juveniles and adults at 2 days post injury when compared to shams. When comparing the extent of cell proliferation between juveniles and adults following TBI, the absolute number of cells generated in the subgranular zone (SGZ) was far greater in the juveniles. Moreover, the percentage of newly generated cells in the SGZ that differentiated into neurons was nearly two times higher in the juveniles as compared to adults. Conversely, more glial differentiation was observed in the DG of adult rats. These findings provide compelling evidence that age-related differences in the neurogenic response to injury may underlie the differences observed in cognitive recovery in juvenile mammals as compared to adults following TBI.