Neuronal nitric oxide synthase-derived nitric oxide inhibits neurogenesis in the adult dentate gyrus by down-regulating cyclic AMP response element binding protein phosphorylation

Neuronal nitric oxide synthase, the major nitric oxide synthase isoform in the mammalian brain, is implicated in some developmental processes, including neuronal survival, precursor proliferation and differentiation. However, reports about the role of neuronal nitric oxide synthase in neurogenesis in the adult dentate gyrus are conflicting. Here we show that 5-bromodeoxyuridine-labeled dividing progenitor cells in the dentate gyrus were significantly increased in mice receiving 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor, and in null mutant mice lacking neuronal nitric oxide synthase gene (nNOS-/-) 6 h and 4 weeks after 5-bromodeoxyuridine incorporation. The increase in 5-bromodeoxyuridine positive cells in 7-nitroindazole-treated mice was accompanied by activation of cyclic AMP response element binding protein phosphorylation in the dentate gyrus. Pretreatment with N-methyl-D-aspartate receptor antagonist MK-801 fully abolished the effects of 7-nitroindazole on neurogenesis and cyclic AMP response element binding protein phosphorylation. Furthermore, neuronal nitric oxide synthase inhibition significantly enhanced the survival of newborn cells and the number of 5-bromodeoxyuridine positive/NeuN positive cells in the dentate gyrus. These results indicate that neuronal nitric oxide synthase-derived nitric oxide suppresses neurogenesis in the adult dentate gyrus, in which N-methyl-D-aspartate receptor functions and cyclic AMP response element binding protein phosphorylation may be involved.     

Behavioral recovery from unilateral photothrombotic infarcts of the forelimb sensorimotor cortex in rats: role of the contralateral cortex

During sensorimotor recovery following stroke ipsi- and contralesional alterations in brain function have been characterized in patients as well as animal models of focal ischemia, but the contribution of these bilateral processes to the functional improvement is only poorly understood. Here we examined the role of the homotopic contralateral cortex for sensorimotor recovery after focal ischemic infarcts at different time periods after the insult. One group of animals received a unilateral single photothrombotic infarct in the forelimb sensorimotor cortex, while four additional groups received a second lesion in the contralateral homotopic cortex either immediately or 2 days, 7 days, or 10 days after the first infarct. The time course of functional recovery of the impaired forelimbs was assessed using different sensorimotor scores: forelimb-activity during exploratory behavior and frequency of forelimb-sliding in the glass cylinder as well as forelimb misplacement during grid walking. Focal infarcts in the forelimb sensorimotor cortex area significantly impaired the function of the contralateral forelimb in these different behavioral tests. The subsequent damage of the contralateral homotopic forelimb sensorimotor cortex only affected the forelimb opposite to the new lesion but did not reinstate the original deficit. The time course of sensorimotor recovery after bilateral sequential cortical infarcts did not significantly differ from animals with unilateral single lesions. These data indicate that following small ischemic cortical infarcts in the forelimb sensorimotor cortex the contralateral cortex homotopic to the lesion plays only a minor role for functional recovery.     

局灶性脑缺血后鼠脑组织tPA基因表达及其与细胞凋亡

目的 探讨局灶性脑缺血后组织型纤溶酶原激活物（tＰＡ）基因的表达及其与细胞凋亡的 关系。方法 用原位杂交和免疫组织化学方法检测tＰＡ基因在大鼠局灶性脑缺血（大脑中 动脉阻塞）后的表达,用ＴＵＮＥＬ法检测缺血不同时间的细胞凋亡状况。结果 脑缺血６h缺血中心部位的胶质细胞和梗死灶周边缺血半影区的神经元均观察到tＰＡ免疫反应性信号,在大脑皮层后肢体区、顶皮层区、海马区和齿状回可见凋亡细胞,但缺血１８h缺血侧神     

Differential stroke-induced proliferative response of distinct precursor cell subpopulations in the young and aged dentate gyrus

The capability of the adult brain to generate new hippocampal neurons after brain insults like stroke is decreasing during the aging process. Recent evidence further indicates that the proliferative properties of the precursor cells change in the aged brain. We therefore analyzed the early proliferative response of distinct precursor cell populations in the subgranular zone of the dentate gyrus in 3 and 16 months old transgenic nestin-green-fluorescent protein mice 4 days after ischemic cortical infarcts. A detailed immunocytochemical analysis of proliferating precursors revealed a significant infarct-induced activation of the earliest radial glia-like precursor cells (type 1 cells) and the more differentiated precursor cell subtypes (type 2b cells) in young mice. In contrast the proliferation of early neuronal precursor cells (type 2a cells) was stimulated in the aged brain. Additional long-term experiments further demonstrated that this differential proliferative response of distinct precursor cells is associated with an enhanced number of newborn neurons in the young DG after stroke whereas this increase in neurogenesis was absent in the aged brain. However, our study demonstrates that even precursor cells in the aged hippocampus possess the ability to respond to remote cortical infarcts.     

The effect of repetitive spreading depression on neuronal damage in juvenile rat brain

Spreading depression (SD) is pronounced depolarization of neurons and glia that travels slowly across brain tissue followed by massive redistribution of ions between intra- and extracellular compartments. There is a relationship between SD and some neurological disorders. In the present study the effects of repetitive SD on neuronal damage in cortical and subcortical regions of juvenile rat brain were investigated. The animals were anesthetized and the electrodes as well as cannula were implanted over the brain. SD-like event was induced by KCl injection. The brains were removed after 2 or 4 weeks after induction of 2 or 4 SD-like waves (with interval of 1 week), respectively. Normal saline was injected instead of KCl in sham group. For stereological study, paraffin-embedded brains were cut in 5 μm sections. The sections were stained with Toluidine Blue to measure the volume-weighted mean volume of normal neurons and the numerical density of dark neurons. The volume-weighted mean volume of normal neurons in the granular layer of the dentate gyrus and layer V of the temporal cortex in SD group were significantly decreased after four repetitive SD. Furthermore, densities of dark neurons in the granular layer of the dentate gyrus (after 2 weeks), the caudate–putamen, and layer V of the temporal cortex (after 4 weeks) were significantly increased in SD group. Repetitive cortical SD in juvenile rats may cause neuronal damage in cortical and subcortical areas of the brain. This may important in pathophysiology of SD-related neurological disorders.     

Ischemia induces cell proliferation and neurogenesis in the gerbil hippocampus in response to neuronal death

We studied hippocampal cellular proliferation and neurogenesis processes in a model of transient global cerebral ischemia in gerbils by labelling dividing cells with 5'-Bromo-2'-deoxyuridine (BrdU). Surrounding the region of selective neuronal death (CA1 pyramidal layer of the hippocampus), an important increase in reactive astrocytes and BrdU-labelled cells was detected 5 days after ischemia. A similar result was found in the dentate gyrus (DG) 12 days after ischemia. The differentiation of the BrdU+ cells was investigated 28 days after BrdU administration by analyzing the morphology, anatomic localization and cell phenotype by triple fluorescent labelling (BrdU, adult neural marker NeuN and DNA marker TOPRO-3) using confocal laser-scanning microscopy. This analysis showed increased neurogenesis in the DG in case of ischemia and triple positive labelling in some newborn cells in CA1. Seven brain hemispheres from gerbils subjected to ischemia did not develop CA1 neuronal death; hippocampus from these hemispheres did not show any of the above mentioned findings. Our results indicate that ischemia triggers proliferation in CA1 and neurogenesis in the DG in response to CA1 pyramidal neuronal death, independently of the reduced cerebral blood flow or the cell migration from subventricular zone (SVZ).     

Performance in an escape task induces fos-like immunoreactivity in a specific area of the motor cortex of the rat.

The expression of the c-fos proto-oncogene was studied in two different areas of the motor cortex and in the hippocampus of the rat after performance in an escape task in a Skinner box. Performance in this task caused an increase in the number of cells showing fos-like immunoreactivity in layers V and VI of the forelimb motor-sensory cortex with respect to yoked animals which had received the same amount, frequency and duration of aversive stimulation and manipulation as the trained animals. Therefore, this increase is the specific effect of performing the behavioral task. In the hindlimb motor-sensory cortex there were no differences between the trained and the yoked animals in any of the cortical layers. No differences were observed in the dentate gyrus of the hippocampus between trained and yoked animals, while the control animals showed a much lower fos-like immunoreactivity. In conclusion, infragranular layers in the forelimb representation of the primary motor cortex become activated with respect to the expression of fos-like immunoreactivity after performance in an escape task in a Skinner box. This result is consistent with the idea that even in complex structures such as the cerebral cortex, specific trace systems become activated for the performance of complex behavioral tasks.     

Enhanced neurogenesis after transient global ischemia in the dentate gyrus of the rat

The dentate gyrus is one of the few areas of the mammalian brain where new neurons are continuously produced in adulthood. Certain insults such as epileptic seizures and ischemia are known to enhance the rate of neuronal production. We analyzed this phenomenon using the temporary occlusion of the two carotid arteries combined with arterial hypotension as a method to induce ischemia in rats. We measured the rate of cell production and their state of differentiation with a mitotic indicator, bromodeoxyuridine (BrdU), in combination with the immunohistochemical detection of neuronal markers. One week after the ischemic episode, the cell production in dentate gyrus was increased two- to threefold more than the basal level seen in control animals. Two weeks after ischemia, over 60% of these cells became young neurons as determined by colabeling with BrdU and a cytoplasmic protein (CRMP-4) involved in axonal guidance during development. Five weeks after the ischemia, over 60% of new neurons expressed calbindin, a calcium-binding protein normally expressed in mature granule neurons. In addition to more cells being generated, a greater proportion of all new cells remained in the differentiated but not fully mature state during the 2- to 5-week period after ischemia. The maturation rate of neurons as determined by the calbindin labeling and by the rate of migration from a proliferative zone into the granule cell layer was not changed when examined 5 weeks after ischemia. The results support the hypothesis that survival of dentate gyrus after ischemia is linked with enhanced neurogenesis. Additional physiological stimulation after ischemia may be exploited to stimulate maturation of new neurons and to offer new therapeutic strategies for promoting recovery of neuronal circuitry in the injured brain.     

Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia

Progenitor cells in the subventricular zone of the lateral ventricle and in the dentate gyrus of the hippocampus can proliferate throughout the life of the animal. To examine the proliferation and fate of progenitor cells in the subventricular zone and dentate gyrus after focal cerebral ischemia, we measured the temporal and spatial profiles of proliferation of cells and the phenotypic fate of proliferating cells in ischemic brain in a model of embolic middle cerebral artery occlusion in the adult rat. Proliferating cells were labeled by injection of bromodeoxyuridine (BrdU) in a pulse or a cumulative protocol. To determine the temporal profile of proliferating cells, ischemic rats were injected with BrdU every 4 h for 12 h on the day preceding death. Rats were killed 2-14 days after ischemia. We observed significant increases in numbers of proliferating cells in the ipsilateral cortex and subventricular zone 2-14 days with a peak at 7 days after ischemia compared with the control group. To maximize labeling of proliferating cells, a single daily injection of BrdU was administered over a 14-day period starting the day after ischemia. Rats were killed either 2 h or 28 days after the last injection of BrdU. A significant increase in numbers of BrdU immunoreactive cells in the subventricular zone was coincident with a significant increase in numbers of BrdU immunoreactive cells in the olfactory bulb 14 days after ischemia and numbers of BrdU immunoreactive cells did not significantly increase in the dentate gyrus. However, 28 days after the last labeling, the number of BrdU labeled cells decreased by 90% compared with number at 14 days. Clusters of BrdU labeled cells were present in the cortex distal to the infarction. Numerous cells immunostained for the polysialylated form of the neuronal cell adhesion molecule were detected in the ipsilateral subventricular zone. Only 6% of BrdU labeled cells exhibited glial fibrillary acidic protein immunoreactivity in the cortex and subcortex and no BrdU labeled cells expressed neuronal protein markers (neural nuclear protein and microtubule associated protein-2). From these data we suggest that focal cerebral ischemia induces transient and regional specific increases in cell proliferation in the ipsilateral hemisphere and that proliferating progenitor cells may exist in the adult cortex.     

Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis.

The dentate gyrus of the hippocampus is one of few regions in the adult mammalian brain characterized by ongoing neurogenesis. Significantly, recent studies indicate that the rate of neurogenesis in the hippocampus declines with age, perhaps contributing to age-related cognitive changes. Although a variety of factors may influence the addition of new neurons in the adult dentate gyrus, the mechanisms responsible for the age-related reduction remain to be established. Insulin-like growth factor-I (IGF-I) is one promising candidate to regulate neurogenesis in the adult and aging brain since it influences neuronal production during development and since, like the rate of neurogenesis, it decreases with age. In the current study, we used bromodeoxyuridine labeling and multilabel immunofluorescence to assess age-related changes in neuronal production in the dentate gyrus of adult Brown Norway x Fischer 344 rats. In addition, we investigated the relationship between changes in neurogenesis and the age-dependent reduction in IGF-I by evaluating the effect of i.c.v. infusion of IGF-I on neurogenesis in the senescent dentate gyrus. The analyses revealed an age-dependent reduction in the number of newly generated cells in the adult dentate subgranular proliferative zone and, in addition, a 60% reduction in the differentiation of newborn cells into neurons. Restoration of IGF-I levels in senescent rats significantly restored neurogenesis through an approximately three-fold increase in neuronal production.The results of this study suggest that IGF-I may be an important regulator of neurogenesis in the adult and aging hippocampus and that an age-related decline in IGF-I-dependent neurogenesis could contribute to age-related cognitive changes.     

Inhibitor of vascular endothelial growth factor receptor tyrosine kinase attenuates cellular proliferation and differentiation to mature neurons in the hippocampal dentate gyrus after transient forebrain ischemia in the adult rat

Neurogenesis in the adult hippocampal dentate gyrus is promoted by transient forebrain ischemia. The mechanism responsible for this ischemia-induced neurogenesis, however, remains to be determined. It has been suggested that there may be a close relationship between neurogenesis and the expression of vascular endothelial growth factor, an angiogenic factor. The purpose of the present study was to examine the relationship between vascular endothelial growth factor and cell proliferation in the dentate gyrus after transient forebrain ischemia. The mRNA expression of vascular endothelial growth factor was increased in the dentate gyrus on day 1 after ischemia. Immunohistochemical analysis on day 9 after ischemia, when a significant increase in cell proliferation was seen, showed that the cerebral vessel space in the subgranular zone of the dentate gyrus had not been affected by the ischemia. Neither were the vascular densities on days 1 and 3 after ischemia altered compared with those of non-operated naïve control rats. Furthermore, the distance from the center of the proliferative cells to the nearest cerebral vessel of ischemic rats was comparable to that of the sham-operated rats. We demonstrated that transient forebrain ischemia-induced cell proliferation and differentiation to mature neurons in the hippocampal dentate gyrus was attenuated by the i.c.v. administration of a vascular endothelial growth factor receptor tyrosine kinase inhibitor. These results suggest that vascular endothelial growth factor receptor at the early period of reperfusion may contribute to neurogenesis rather than to angiogenesis in the hippocampal dentate gyrus.     

Intracranial self-stimulation enhances neurogenesis in hippocampus of adult mice and rats

Running is known to promote neurogenesis. Besides being exercise, it results in a reward, and both of these factors might contribute to running-induced neurogenesis. However, little attention has been paid to how reward and exercise relate to neurogenesis. The present study is an attempt to determine whether a reward, in the form of intracranial self-stimulation (ICSS), influences neurogenesis in the hippocampus of adult rodents. We used bromodeoxyuridine labeling to quantify newly generated cells in mice and rats that experienced ICSS for 1 h per day for 3 days. ICSS increased the number of 5-bromodeoxyuridine (Brdu)-labeled cells in the hippocampal dentate gyrus (DG) of both species. The effect, when examined at 1 day, 1 week, and 4 weeks post-ICSS, was predominantly present in the side ipsilateral to the stimulation, although it was distributed to the contralateral side. We also found in rats that, 4 weeks after Brdu injection, surviving newborn cells in the hippocampal DG of the ICSS animals co-localized with a mature neuron marker, neuronal nuclei (NeuN), and these surviving cells in rats were double-labeled with Fos, a marker of neuronal activation, after the rats had been trained to perform a spatial task. The results demonstrate that ICSS can increase newborn neurons in the hippocampal DG that endure into maturity.     

Electrophysiological neurodifferentiation of subventricular zone-derived precursor cells following stroke

Stroke in rodents is associated with increased neurogenesis and the migration of newborn neurons to sites of brain ischemia, where they may participate in repair and recovery. To determine if neurogenesis following stroke yields functional new neurons, we labeled neuronal precursors in the mouse subventricular zone (SVZ) with a lentivirus-green fluorescent protein vector, produced stroke by occluding the middle cerebral artery, and detected newborn neurons 8 weeks later by fluorescence microscopy. Patch-clamp studies on fluorescent neurons in the cortical region surrounding infarction showed tetrodotoxin-sensitive Na⁺ action potentials and spontaneous excitatory post-synaptic currents, suggesting that ischemia led to functional neurogenesis with synaptic integration. These findings support the hypothesis that enhancing endogenous neurogenesis after stroke might have therapeutic benefit.     

Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice

Age-related changes in neurogenesis and its modulation by caloric restriction (CR) were studied in C57BL/6 mice. To this end, bromodeoxyuridine (BrdU) labeling was used to assess neuronal and glial precursor proliferation and survival in the granular cell layer (GCL) and the hilus of the dentate gyrus of 2-, 12-, 18-, and 24-month-old mice. For both regions, we found an age-dependent decrease in proliferation but not in survival of newborn cells. Interestingly, the reduction in proliferation occurred between 2 and 18 months of age with no additional decline between 18- and 24-month-old mice. Phenotyping of the newborn cells revealed a decrease in the neuron fraction in the GCL between 2 and 12 months of age but not thereafter. The majority of BrdU cells in the hilus colocalized with astrocytic but none with neuronal markers. CR from 3 to 11 months of age had no effect on neurogenesis in the GCL, but had a survival-promoting effect on newly generated glial cells in the hilus of the dentate gyrus. In conclusion, C57BL/6 mice reveal a substantial reduction in neurogenesis in the dentate gyrus until late adulthood with no further decline with aging. Long-term CR does not counteract this age-related decline in neurogenesis but promotes survival of hilar glial cells.     

Integration of cerebral and peripheral inputs by interpositus neurons in monkey

Summary The patterns of convergence of cerebral and peripheral nerve inputs onto interpositus neurons were studied in cebus monkeys. The strongest inputs to interpositus neurons are from motor and somatosensory cortex, with weaker inputs from peripheral nerves and cerebral area 6. The neurons in the anterior portion of interpositus receive cerebral and peripheral inputs primarily representing the hindlimb, while inputs to neurons in the posterior division represent forelimb or mixed forelimb and hindlimb. The hindlimb neurons integrate signals principally from motor cortex, somatosensory cortex, nerves, supplementary motor and medial premotor areas, while forelimb neurons receive inputs from motor, somatosensory, lateral premotor cortical areas and nerves. The results from this study are compared with those from studies of interpositus and dentate neurons in cat and monkey in order to determine the role of n. interpositus in movement. It is suggested that the inputs integrated by interpositus neurons are consistent with a role in up-dating skilled movements.     

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

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 age-related 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.     

Convergence of cerebral inputs onto dentate neurons in monkey

Summary The patterns of convergence of inputs from different areas of the cerebral cortex and the peripheral nerves onto single dentate neurons was studied in cebus monkeys. Dentate neurons receive their strongest and most numerous inputs from the premotor and supplementary motor regions of area 6. The sensorimotor and frontal cortices have weaker projections to the dentate nucleus, while peripheral nerves and many other association cortical areas were found to be ineffective in influencing cells of the lateral cerebellum. Dentate cells that respond to stimulation of hindlimb regions of the sensorimotor cortex tend to receive their principal input from the supplementary motor area and medial premotor regions, while neurons responding to forelimb sensorimotor cortex tend to receive lateral premotor inputs. In addition there is a topographical organization within the ventral pole of dentate with the hindlimb represented in the anterior regions and the forelimb in the posterior regions. These results are compared with those of similar studies of interpositus and dentate neurons in cat and monkey. The differences between the afferent inputs to dentate and interpositus are consistent with the suggestion that the lateral cerebellum is involved in programming movement parameters before movement initiation while the intermediate zone is involved in up-dating the evolving movement.     

Changes in the expression of Hes5 and Mash1 mRNA in the adult rat dentate gyrus after transient forebrain ischemia

Accumulating evidence indicates that neurogenesis in the adult brain occurs in restricted brain regions, including the hippocampal dentate gyrus and is promoted by ischemia. The mechanism responsible for ischemia-induced neurogenesis in the adult brain, however, remains unclear. Notch pathway plays a pivotal role in the regulation of the timing for differentiation and determination of the fate of neural progenitor cells in the developing nervous system. To elucidate the mechanism underlying ischemia-induced neurogenesis, we investigated changes in the expression of mRNAs of Hes5, which is a downstream target of Notch, and Mash1, a neurogenic basic helix-loop-helix factor, which is negatively regulated by Hes5, in the adult hippocampal dentate gyrus after transient forebrain ischemia. Transient forebrain ischemia was produced by four-vessel occlusion procedure in rats. The levels of Hes5 mRNA decreased on days 1 and 3 after the start of reperfusion and the decreased levels of the mRNA returned to the basal level by 5 days after ischemia. In contrast, the level of Mash1 mRNA increased on day 1 and then returned to the basal level by 3 days after ischemia. These results suggest that an inhibition of Notch activity and subsequent expression of neurogenic basic helix-loop-helix factors, including Mash1, may, at least in part, contribute to ischemia-induced neurogenesis in the adult dentate gyrus.     

Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb

Neurogenesis in the subgranular zone of the hippocampal dentate gyrus and olfactory bulbs continues into adulthood and has been implicated in the cognitive function of the adult brain. The basal forebrain cholinergic system has been suggested to play a role in regulating neurogenesis as well as learning and memory in these regions. Herein, we report that highly polysialylated neural cell adhesion molecule (PSA-NCAM)-positive immature cells as well as neuronal nuclei (NeuN)-positive mature neurons in the dentate gyrus and olfactory bulb express multiple acetylcholine receptor subunits and make contact with cholinergic fibers. To examine the function of acetylcholine in neurogenesis, we used donepezil (Aricept), a potent and selective acetylcholinesterase inhibitor that improves cognitive impairment in Alzheimer's disease. Intraperitoneal administrations of donepezil significantly enhanced the survival of newborn neurons, but not proliferation of neural progenitor cells in the subgranular zone or the subventricular zone of normal mice. Moreover, donepezil treatment reversed the chronic stress-induced decrease in neurogenesis. Taken together, these results suggest that activation of the cholinergic system promotes survival of newborn neurons in the adult dentate gyrus and olfactory bulb under both normal and stressed conditions.     

Pneumococcal cell wall-induced meningitis impairs adult hippocampal neurogenesis

Bacterial meningitis is a major infectious cause of neuronal degeneration in the hippocampus. Neurogenesis, a continuous process in the adult hippocampus, could ameliorate such loss. Yet the high rate of sequelae from meningitis suggests that this repair mechanism is inefficient. Here we used a mouse model of nonreplicative bacterial meningitis to determine the impact of transient intracranial inflammation on adult neurogenesis. Experimental meningitis resulted in a net loss of neurons, diminished volume, and impaired neurogenesis in the dentate gyrus for weeks following recovery from the insult. Inducible nitric oxide synthase (iNOS) immunoreactivity was prominent in microglia in nonproliferating areas of the dentate gyrus and hilus region after meningitis induction. Treatment with the specific iNOS inhibitor N6-(1-iminoethyl)-L-lysine restored neurogenesis in experimental meningitis. These data suggest that local central nervous system inflammation in and of itself suppresses adult neurogenesis by affecting both proliferation and neuronal differentiation. Repair of cognitive dysfunction following meningitis could be improved by intervention to interrupt these actively suppressive effects.