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neurogenesis following conditional VEGF induction in the adult brain and showed that a short episode of VEGF exposure withdrawn shortly after the generation of durable new vessels (but not under conditions where newly made vessels failed to persist) is sufficient for neurogenesis to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.adult neurogenesis | VEGF | neurovascular | aging | neural stem cells T he reserve of neuronal stem cells (NSCs) in the hippocampal dentate gyrus (DG) continues to produce neuroblasts maturing into functional neurons after birth. Adult hippocampal neurogenesis, however, rapidly declines with age, and in the rodent brain, it is barely detected beyond 8 mo of age (1-4). Several factors, including BDNF, FGF, insulin-like growth factor, VEGF, and others, were shown to enhance the basal level of hippocampal neurogenesis (reviewed in ref. 5). However, there is no report of a factor capable of inducing sustained neurogenic enhancement lasting months after its withdrawal.It has been shown that age-related decrease in hippocampal neurogenesis is associated with progressive depletion of the finite NSC pool due to the fact that neuroblast-producing asymmetrical NSC divisions can only take place a limited number of times before their terminal differentiation to astrocytes (2). Supporting the notion of an exhaustible NSC reservoir is also a study showing that experimentally forced accelerated neurogenesis results in premature NSC depletion (6) and a study showing that experimentally induced epilepsy is associated with premature NSC exhaustion (7). Balancing this deterministic view, however, certain genetic manipulations [e.g., experimental phosphatase and tensin homolog (PTEN) deletion] were shown to increase NSC number by symmetrical divisions (8). It thus remains unclear whether there are means to enforce enhanced hippocampal neurogenesis for a long period without necessarily causing premature exhaustion of the NSC reservoir and a resultant accelerated age-related neurogenic decay.

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