期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：48
页码：E7828-E7836
DOI：10.1073/pnas.1609592113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceGeneration of new neurons is maintained in the adult hippocampus throughout life. The process, which is driven by an exhaustible reservoir of neuronal stem cells (NSCs), greatly declines with age, however. We show that even a short, episodic exposure to the angiogenic factor VEGF and a resultant ramification/rejuvenation of the vasculature within the stem cell microenvironment ("niche") is sufficient for neurogenesis to proceed at a markedly elevated rate for months later without accelerating the rate of NSC depletion. Importantly, this manipulation culminates in marked attenuation of age-dependent neurogenic decline. Long-term neurogenic enhancement via VEGF preconditioning was found to be associated with extensive NSC morphological remodeling resembling a "juvenile" pattern of NSC and blood vessel engagements. Several factors are known to enhance adult hippocampal neurogenesis but a factor capable of inducing a long-lasting neurogenic enhancement that attenuates age-related neurogenic decay has not been described. Here, we studied hippocampal neurogenesis following conditional VEGF induction in the adult brain and showed that a short episode of VEGF exposure withdrawn shortly after the generation of durable new vessels (but not under conditions where newly made vessels failed to persist) is sufficient for neurogenesis to proceed at a markedly elevated level for many months later. Continual neurogenic increase over several months was not accompanied by accelerated exhaustion of the neuronal stem cell (NSC) reserve, thereby allowing neurogenesis to proceed at a markedly elevated rate also in old mice. Neurogenic enhancement by VEGF preconditioning was, in part, attributed to rescue of age-related NSC quiescence. Remarkably, VEGF caused extensive NSC remodelling manifested in transition of the enigmatic NSC terminal arbor onto long cytoplasmic processes engaging with and spreading over even remote blood vessels, a configuration reminiscent of early postnatal "juvenile" NSCs. Together, these findings suggest that VEGF preconditioning might be harnessed for long-term neurogenic enhancement despite continued exposure to an "aged" systemic milieu.
