Lack of neurogenesis in the adult rat cerebellum after Purkinje cell degeneration and growth factor infusion

Abstract

Although constitutive neurogenesis exclusively occurs in restricted regions of the adult mammalian brain, resident progenitors can be isolated from many different CNS sites, and neuronal neogeneration can be stimulated in vivo by injury or infusion of growth factors. To ask whether latent compensatory mechanisms, which may be exploited to promote repair processes, are present throughout the CNS, we examined the neurogenic potentialities of the adult rat cerebellum in normal conditions, following injury, and after infusion of growth factors. Degeneration of Purkinje cells was induced by intracerebroventricular administration of the toxin saporin, conjugated to anti-p75 antibodies. In addition, epidermal growth factor and basic fibroblast growth factor, or FGF8, were infused for 2 weeks to either intact or injured animals. In all conditions, proliferating cells were identified from bromodeoxyuridine (BrdU) incorporation. In the unmanipulated cerebellum there were rare dividing cells, mainly represented by NG2-positive presumptive oligodendrocyte precursors. Mitotic activity was strongly enhanced in cortical areas with Purkinje cell degeneration, being mostly sustained by microglia, plus minor fractions of NG2-expressing cells, astrocytes and oligodendrocytes. In contrast, growth factor infusion had a weak effect on both intact and injured cerebella. In all experimental conditions, we never found any BrdU-positive cells coexpressing distinctive markers for immature or differentiated cerebellar neurons. Therefore, although some progenitor cells reside in the adult cerebellum, the local environment, either intact or injured, does not provide efficient cues to direct their differentiation towards neuronal phenotypes. In addition, neurogenic potentialities cannot be induced or boosted by the application of growth factors which are effective in other CNS regions.

Dynamic distribution and stem cell characteristics of Sox1-expressing cells in the cerebellar cortex

“…These observations suggest that the Bergmann glia are more plastic than initially thought. It is also possible that the culture protocol used to isolate and grow the cells in culture may be critical to revealing a stem cell phenotype, despite a more limited potential attributed to the cells in situ [25]. Our data show that the Sox1-positive cerebellar population is able to exhibit stem cell characteristics when subjected to standard NSC culture conditions.…”

“…It is also established that although expression of Nestin, another NSC marker, is not detected in adult cerebellum ( [29] and data not shown), it can be reversibly activated in Bergmann glia following disruption of the PCL [25,30,31]. Similarly, induced expression of PSA-NCAM and cd133 has recently been observed in a model of cerebellar damage [25]. These observations suggest that the Bergmann glia are more plastic than initially thought.…”

“…There are many reports in the literature describing the occurrence of Bergmann glia proliferation in response to damage in a range of models [25][26][27][28]. It is also established that although expression of Nestin, another NSC marker, is not detected in adult cerebellum ( [29] and data not shown), it can be reversibly activated in Bergmann glia following disruption of the PCL [25,30,31]. Similarly, induced expression of PSA-NCAM and cd133 has recently been observed in a model of cerebellar damage [25].…”

Different Types of Cerebellar GABAergic Interneurons Originate from a Common Pool of Multipotent Progenitor Cells

“…Their phenotypes were determined on the basis of several criteria, including (1) morphological features, (2) expression of type-specific markers, (3) morphometric parameters (e.g., cell body size), and (4) position in the host cortical layers or deep nuclei. The different types of GABAergic interneurons were identified according to the expression pattern of a set of distinctive markers and assigned to different categories: deep nuclei interneurons [NeuN/calretinin (Bastianelli, 2003;Weyer and Schilling, 2003)]; granular layer interneurons for Golgi [mGluR2/Pax-2 Grimaldi and Rossi, 2006)] and Lugaro cells [calretinin (Dino et al, 1999;Bastianelli, 2003)]; and molecular layer interneurons for basket and stellate cells [parvalbumin (Celio, 1990)]. Except for rare elements ectopically positioned in the white matter (see below and Fig.…”

Comparison of lifelong and late life exercise on oxidative stress in the cerebellum

“…Importantly, the extent of degeneration and loss of function is mitigated by lifelong exercise [25]. Interestingly, the cerebellum does not exhibit evidence of neurogenesis [13,24], therefore; we tested the hypothesis that exercise would reduce molecular indicators of oxidative damage in aged animals.…”