Reduced neuronal nitric oxide synthase is involved in ischemia‐induced hippocampal neurogenesis by up‐regulating inducible nitric oxide synthase expression
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Abstract Nitric oxide (NO), a free radical with signaling functions in the CNS, is implicated in some developmental processes, including neuronal survival, precursor proliferation, and differentiation. However, neuronal nitric oxide synthase (nNOS) ‐derived NO and inducible nitric oxide synthase (iNOS) ‐derived NO play opposite role in regulating neurogenesis in the dentate gyrus after cerebral ischemia. In this study, we show that focal cerebral ischemia reduced nNOS expression and enzymatic activity in the hippocampus. Ischemia‐induced cell proliferation in the dentate gyrus was augmented in the null mutant mice lacking nNOS gene (nNOS−/−) and in the rats receiving 7‐nitroindazole, a selective nNOS inhibitor, after stroke. Inhibition of nNOS ameliorated ischemic injury, up‐regulated iNOS expression, and enzymatic activity in the ischemic hippocampus. Inhibition of nNOS increased and iNOS inhibitor decreased cAMP response element‐binding protein phosphorylation in the ipsilateral hippocampus in the late stage of stroke. Moreover, the effects of 7‐nitroindazole on neurogenesis after ischemia disappeared in the null mutant mice lacking iNOS gene (iNOS−/−). These results suggest that reduced nNOS is involved in ischemia‐induced hippocampal neurogenesis by up‐regulating iNOS expression and cAMP response element‐binding protein phosphorylation.Although the existence of adult neurogenesis in the dentate gyrus is now almost universally accepted, it is not widely established that the new neurons perform any necessary function. However, evidence indicates that the number of new neurons that are generated and form functional synapses is clearly large enough to impact the circuitry of the hippocampus. Additionally, several treatments show parallel effects on neurogenesis and hippocampus-dependent behaviors, suggesting a possible causal relationship between new neurons and hippocampal function. Most importantly, several recent studies have found that killing or inhibiting proliferation of granule cell precursors impairs performance on several hippocampus-dependent tasks. Control experiments showing no impairment on slightly different behavioral tests suggest that the deficits are highly specific and unlikely to result from side effects of the neurogenesis-inhibiting treatments. In summary, the evidence to date strongly suggests that adult neurogenesis in the dentate gyrus plays a vital role in hippocampal function.
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Voluntary physical exercise (wheel running, RUN) and environmental enrichment (ENR) both stimulate adult hippocampal neurogenesis but do so by different mechanisms. RUN induces precursor cell proliferation, whereas ENR exerts a survival-promoting effect on newborn cells. In addition, continued RUN prevented the physiologically occurring age-related decline in precursor cell in the dentate gyrus but did not lead to a corresponding increase in net neurogenesis. We hypothesized that in the absence of appropriate cognitive stimuli the potential for neurogenesis could not be realized but that an increased potential by proliferating precursor cells due to RUN could actually lead to more adult neurogenesis if an appropriate survival-promoting stimulus follows the exercise. We thus asked whether a sequential combination of RUN and ENR (RUNENR) would show additive effects that are distinct from the application of either paradigm alone. We found that the effects of 10 days of RUN followed by 35 days of ENR were additive in that the combined stimulation yielded an approximately 30% greater increase in new neurons than either stimulus alone, which also increased neurogenesis. Surprisingly, this result indicates that although overall the amount of proliferating cells in the dentate gyrus is poorly predictive of net adult neurogenesis, an increased neurogenic potential nevertheless provides the basis for a greater efficiency of the same survival-promoting stimulus. We thus propose that physical activity can "prime" the neurogenic region of the dentate gyrus for increased neurogenesis in the case the animal is exposed to an additional cognitive stimulus, here represented by the enrichment paradigm.
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Abstract The dentate gyrus continues to produce new neurons in adult rodents. The possibility of differential regulation of neurogenesis within regions of the dentate gyrus is largely unexplored, despite several other aspects of this phenomenon being well characterized in a large number of studies. In this report, we describe an area located at the anterior pole of the dentate gyrus that consistently lacks neurogenesis. This neurogenically quiescent zone invariably lacks expression of the neuroblast marker doublecortin (DCX), bromodeoxyuridine and Ki‐67, though DCX expression can be elicited in response to a combined paradigm of environmental enrichment and wheel running. We propose that this region may provide a valuable model system to discern the factors that regulate the process of neurogenesis.
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AIM To investigate the tempo spatial characteristics of neurogenesis in dentate gyrus (DG) of rats after global ischemia reperfusion and to explore the possible mechanisms of neurogenesis. METHODS Male mature Spraque Dawley rats were subjected to a 4 vessel occlusion (4 VO) model. Bromodeoxyuridine (BrdU) labelling method was used to observe the neurogenesis in the DG of rats and double immunostaining with laser confocal microscopy was used to determine the cell phenotype. RESULTS Ischemia enhanced cell proliferation in DG of adult rats. The number of BrdU immunoreactive cells in DG did not significantly increase during the first 3 days after the global ischemia. Thereafter, cell proliferation increased markedly and reached the peak on the 14th day after ischemia. Compared with the control rats, the quantity of BrdU immunoreactive cells in the DG of rats after global ischemia had a 7 fold increase. The result obtained by observing the differentiation of newborn cells showed that many of the BrdU immunoreactive cells in DG had become neurons. CONCLUSION Neurogenesis in DG could be induced to increase at a certain time window after global ischemia reperfusion. The accommodational mechanisms of neurogenesis were possibly related to the changes of hormones, neurotransmitters, neurotrophic factors and the micro circumstances of the dentate gyrus after ischemia.
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Abstract Background Adult neurogenesis continuously adds new neurons to the dentate gyrus and the olfactory bulb. It involves the proliferation and subsequent differentiation of neuronal progenitors, and is thus closely linked to the cell cycle machinery. Cell cycle progression is governed by the successive expression, activation and degradation of regulatory proteins. Among them, D-type cyclins control the exit from the G 1 phase of the cell cycle. Cyclin D2 (cD2) has been shown to be required for the generation of new neurons in the neurogenic niches of the adult brain. It is differentially expressed during hippocampal development, and adult cD2 knock out (cD2KO) mice virtually lack neurogenesis in the dentate gyrus and olfactory bulb. In the present study we examined the dynamics of postnatal and adult neurogenesis in the dentate gyrus (DG) of cD2KO mice. Animals were injected with bromodeoxyuridine at seven time points during the first 10 months of life and brains were immunohistochemically analyzed for their potential to generate new neurons. Results Compared to their WT litters, cD2KO mice had considerably reduced numbers of newly born granule cells during the postnatal period, with neurogenesis becoming virtually absent around postnatal day 28. This was paralleled by a reduction in granule cell numbers, in the volume of the granule cell layer as well as in apoptotic cell death. CD2KO mice did not show any of the age-related changes in neurogenesis and granule cell numbers that were seen in WT litters. Conclusions The present study suggests that hippocampal neurogenesis becomes increasingly dependent on cD2 during early postnatal development. In cD2KO mice, hippocampal neurogenesis ceases at a time point at which the tertiary germinative matrix stops proliferating, indicating that cD2 becomes an essential requirement for ongoing neurogenesis with the transition from developmental to adult neurogenesis. Our data further support the notion that adult neurogenesis continuously adds new neurons to the hippocampal network, hence increasing cell density of the DG.
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Abstract Several neuronal populations in the mammalian central nervous system (CNS) continue to be generated from dividing precursor cells well into adulthood. A large number of factors regulating adult neurogenesis have now been identified, including specific experiences, as well as hormones, neurotransmitters, and growth factors. Distinct factors control neuronal precursor proliferation and survival of the young neurons, and distinct, though somewhat overlapping, factors control these processes in the dentate gyrus and olfactory bulb. Although no coherent picture has emerged to connect all of the regulatory factors, there appears to be a direct relationship between the ability to increase neurogenesis in the dentate gyrus and anti‐depressant properties, either in humans or animal models. This review discusses the large number of factors currently known to regulate cell proliferation and survival of young neurons in the dentate gyrus and olfactory bulb.
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