Increased Neurogenesis in the Dentate Gyrus After Transient Global Ischemia in Gerbils

Abstract

Neurogenesis in the dentate gyrus of adult rodents is regulated by NMDA receptors, adrenal steroids, environmental stimuli, and seizures. To determine whether ischemia affects neurogenesis, newly divided cells in the dentate gyrus were examined after transient global ischemia in adult gerbils. 5-Bromo-2'-deoxyuridine-5'-monophosphate (BrdU) immunohistochemistry demonstrated a 12-fold increase in cell birth in the dentate subgranular zone 1-2 weeks after 10 min bilateral common carotid artery occlusions. Two minutes of ischemia did not significantly increase BrdU incorporation. Confocal microscopy demonstrated that BrdU immunoreactive cells in the granule cell layer colocalized with neuron-specific markers for neuronal nuclear antigen, microtubule-associated protein-2, and calbindin D28k, indicating that the newly divided cells migrated from the subgranular zone into the granule cell layer and matured into neurons. Newborn cells with a neuronal phenotype were first seen 26 d after ischemia, survived for at least 7 months, were located only in the granule cell layer, and comprised approximately 60% of BrdU-labeled cells in the granule cell layer 6 weeks after ischemia. The increased neurogenesis was not attributable to entorhinal cortical lesions, because no cell loss was detected in this region. Ischemic preconditioning for 2 min, which protects CA1 neurons against subsequent ischemic damage, did not prevent increased neurogenesis in the granule cell layer after a subsequent severe ischemic challenge. Thus, ischemia-induced dentate neurogenesis is not attributable to CA1 neuronal loss. Enhanced neurogenesis in the dentate gyrus may be a compensatory adaptive response to ischemia-associated injury and could promote functional recovery after ischemic hippocampal injury.

Reappearance of Hippocampal CA1 Neurons after Ischemia is Associated with Recovery of Learning and Memory

“…In contrast, at 90 DAI, BrdU was found in some of the CA1 neurons, supporting that these neurons indeed were formed subsequent to the ischemic injury ( Figure 2B). In agreement with previous studies (Choi et al, 2003;Liu et al, 1998;Sharp et al, 2002), the dentate gyrus showed BrdU-positive neurons at both 14 and 90 DAI (Figures 2C and 2D). In non-ischemic animals, we observed BrdU incorporation in the dentate gyrus, but not in CA1 neurons (not shown).…”

“…Ischemia is a powerful stimulus to enhance cell proliferation in the subgranular zone, leading to an increase of newborn granule cells in the dentate gyrus (Choi et al, 2003;Liu et al, 1998), although the enhancement is independent of the ischemic injury (Arvidsson et al, 2001;Liu et al, 1998). Ischemia also increases generation of neurons in the subventricular zone.…”

Combined Therapeutic Strategy Using Erythropoietin and Mesenchymal Stem Cells Potentiates Neurogenesis after Transient Focal Cerebral Ischemia in Rats

“…In the DG, cellular proliferation was unchanged after cerebral ischemia or administration of the different treatments. It seems that cellular proliferation in the DG is not dependent on ischemic hippocampal damage (Liu et al, 1998); nevertheless, published studies after focal cerebral ischemia described divergent results Arvidsson et al, 2001). Indeed, after focal cerebral ischemia in which hippocampus was not lesioned, Zhang et al (2001) showed that the number of BrdU-immunoreactive cells in the DG was unchanged, whereas Arvidsson et al (2001) observed an increase of cellular proliferation.…”

Mechanism of stem cells in the central nervous system

“…A second approach using electrophysiology to measure from GFP-retrovirally labeled cells showed that integrated neurons exhibited neuronal morphology and displayed passive membrane properties and action potentials (Song et al, 2002;van Praag et al, 2002). Furthermore, neurogenesis in the hippocampus can be induced by exogenous factors, including peripheral administration of insulin-like growth factor-I (IGF-I) (Aberg et al, 2000) or hormones like corticosteroids (Tanapat et al, 1999;Gass et al, 2000), enriched environment (Kempermann et al, 1997;Nilsson et al, 1999), exercise (van Praag et al, 1999a,b;Gould et al, 2000), or interestingly, by hypoxia (Liu et al, 1998). Unfortunately, none of these reports has demonstrated that these signals can be used as strategies for regeneration in humans.…”