In the adult hippocampus, neuroprogenitor cells in the subgranular zone (SGZ) of the dentate gyrus give rise to newborn neuroblasts. However, only a small subset of these cells integrates into the hippocampal circuitry as mature neurons at the end of a 4 week period. Here, we show that the majority of the newborn cells undergo death by apoptosis in the first 1 to 4 days of their life, during the transition from amplifying neuroprogenitors to neuroblasts. These apoptotic newborn cells are rapidly cleared out through phagocytosis by unchallenged microglia present in the adult SGZ niche. Phagocytosis by the microglia is efficient and undeterred by increased age or inflammatory challenge. Our results suggest that the main critical period of newborn cell survival occurs within a few days of birth and reveal a new role for microglia in maintaining the homeostasis of the baseline neurogenic cascade.
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"Indeed, we found an increased level of Bdnf expression after running in both MC-and VPA-treated mice hippocampusFigure 6A). Voluntary running has also been shown to reduce the number of microglia and its activation (Gebara et al., 2013;Kohman et al., 2013), and previous reports showed that microglia can suppress the adult hippocampal neurogenesis (Sierra et al., 2010;Vukovic et al., 2012;Matsuda et al., 2015). Interestingly, we found that the number of IBA1-positive microglia and CD68-positive-activated microglia was also decreased by voluntary running in both MC-and VPA-treated mice (Figures 6B–6D). "
[Show abstract][Hide abstract] ABSTRACT: Prenatal exposure to valproic acid (VPA), an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running.
Full-text · Article · Nov 2015 · Stem Cell Reports
"The most critical survival period for adult-generated dentate granule cells occurs during the first few days post mitosis, as they differentiate from late intermediate progenitors to neuroblasts (Dayer et al., 2003; Kempermann, 2003; Sierra et al., 2010; Mandyam et al., 2007). In order to test the role of oxidative damage in this early phase of apoptosis, we used the hypoxia mimetic agent, Dimethyloxallyl glycine (DMOG) (Harten et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: The majority of adult hippocampal newborn cells die during early differentiation from intermediate progenitors (IPCs) to immature neurons. Neural stem cells in vivo are located in a relative hypoxic environment, and hypoxia enhances their survival, proliferation and stemness in vitro. Thus, we hypothesized that migration of IPCs away from hypoxic zones within the SGZ might result in oxidative damage, thus triggering cell death. Hypoxic niches were observed along the SGZ, composed of adult NSCs and early IPCs, and oxidative byproducts were present in adjacent late IPCs and neuroblasts. Stabilizing hypoxia inducible factor-1α with dimethyloxallyl glycine increased early survival, but not proliferation or differentiation, in neurospheres in vitro and in newly born SGZ cells in vivo. Rescue experiments in Bax(fl/fl) mutants supported these results. We propose that localized hypoxia within the SGZ contributes to the neurogenic microenvironment and determines the early, activity-independent survival of adult hippocampal newborn cells.
"n, number of spines. early critical period (1–4 days after cell birth) and a secondary, late critical period (1–3 weeks after cell birth) (Sierra et al., 2010). At the early stage the majority of adult-born cells undergo apoptosis as they develop from late proliferating amplifying neuroprogenitors to early neuroblasts. "