Effect of neural precursor proliferation level on neurogenesis in rat brain during aging and after focal ischemia

Abstract

The observed age-related decline in neurogenesis may result from reduced proliferation or increased death rate of neuronal precursor cells (NPCs). We found that caspase-3, but not caspase-6, -7, or -9, was activated in NPCs in neurogenic regions of young, young-adult, middle-aged and aged rat brains. The number of capase-3-immunoreactive cells was highest in young and lowest in aged rats. Surprisingly, intraventricular administration of a caspase-3 inhibitor failed to restore the number of BrdU-positive cells in the aged dentate gyrus, suggesting that the age-related decline in neurogenesis may be attributable primarily to reduced proliferation. Additionally, we also found that NPCs in the subventricular zone of young-adult and aged rat brain were increased after focal cerebral ischemia, suggesting that the increase in neurogenesis induced by ischemia may result from an increase in the rate of NPC proliferation, but not from a decrease in NPC death. Thus, our results suggest that agerelated and injury-induced changes in the rate of neurogenesis are controlled at the level of NPC proliferation. Furthermore, our results may imply that the mechanisms that maintain a stable population of NPCs in the normal adult and in the ischemic brain, which account for the observed age-dependent reduction or injury-induced increases in neurogenesis, impinge on the regulation of cell division at the NPC level.

Adult Neurogenesis Is Regulated by Endogenous Factors Produced During Neurodegeneration

“…The evidence for this enhancement comes from the finding that transient global ischemia in the brain increases the number of mitotic cells labeled with bromodeoxyuridine (BrdU) or expressing Ki67 in the hippocampal SGZ (3) and SVZ (4). BrdU-positive cells in the SGZ successfully migrate to the dentate granular cell layer, whereas those in the SVZ migrate to the olfactory bulb, cortex, and striatum.…”

Comparison of Neurogenesis in the Dentate Gyrus Between the Adult and Aged Gerbil Following Transient Global Cerebral Ischemia

“…Neurogenesis in the brain is influenced by various environmental stimuli including aging and ischemic injury [5][6][7][8][9][10][11][12]. Neurogenesis decreases in intact brain including the DG [13][14][15], and the subventricular zone of the lateral ventricle during the normal aging process [8,9].…”

“…On the other hand, neurogenesis is enhanced by following an ischemic damage, and it could contribute to functional recovery through the generation of new neurons to replace those neurons lost by injury in the adult brain [7,[16][17][18][19]. There are some studies on the comparison of neurogenesis with ischemic condition between adult and aged rat and mouse brains using middle cerebral artery occlusion for focal ischemia [5][6][7]10]. However, there is no any comparative study on neurogenesis combined with time dependent alteration of cell proliferation and neuroblast differentiation in the DG between the adult and aged gerbil after transient global cerebral ischemia.…”

Plasticity of hippocampal stem/progenitor cells to enhance neurogenesis in response to kainate‐induced injury is lost by middle age

“…However, it is unknown whether aging alters the response of NSCs in the DG to brain injury, as most studies on changes in dentate neurogenesis following injury were performed using young animals. Studies on neurogenesis during normal aging demonstrate that the number of NSCs remains stable during the course of aging but NSCs in the middle-aged and aged hippocampus exhibit dramatically diminished proliferation (Rao et al ., 2006a;Tang et al ., 2007;Hattiangady & Shetty, 2008). This is likely because of changes in their microenvironment such as the reduced concentration of NSC mitogenic factors BDNF, FGF-2, IGF-1, and VEGF Shetty et al ., 2005a), changes in the relationship between vascular niches and NSCs (Hattiangady & Shetty, 2008) and alterations in receptors mediating the actions of mitogenic factors (Chadashvili & Peterson, 2006).…”