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).     

Intranasally delivered bFGF enhances neurogenesis in adult rats following cerebral ischemia

Basic fibroblast growth factor (bFGF) is a very important mitogenic factor with proved neurogenesis effects in the central nervous system. Intranasal administration can bypass blood-brain barrier and deliver drugs into the brain directly. We investigated whether intranasal administration of bFGF at later time points after ischemia could promote adult neurogenesis and improve neurologic functions. Rats received bFGF or saline intranasally once daily for 6 consecutive days, starting at 1 day after transient middle cerebral artery occlusion (MCAO). Bromodeoxyuridine (BrdU) was injected at 5 and 6 days after MCAO. Rats were killed at 7 or 28 days after MCAO. Neurogenesis was assessed by immunostaining for BrdU and cell type-specific markers. Neurological functions were evaluated by the modified Neurological Severity Scores. Compared with the control animals, intranasal administration of bFGF improved behavioral recovery without affecting infarct size, and enhanced proliferation of progenitor cells in the subventricular zone and the subgranular zone of the dentate gyrus (DG). Furthermore, the new proliferated cells could differentiate into neurons (BrdU+NeuN+ cells) in the striatum and DG at 28 days after MCAO. Intranasal administration of bFGF offers a non-invasive alternative for the treatment of stroke.     

Hippocampal neurogenesis is reduced by sleep fragmentation in the adult rat

The adult hippocampal dentate gyrus (DG) is a site of continuing neurogenesis. This process is influenced by a variety of physiological and experiential stimuli including total sleep deprivation (TSD). In humans, sleep fragmentation (SF) is a more common sleep condition than TSD. SF is associated with several prevalent diseases. We assessed a hypothesis that SF would suppress adult neurogenesis in the DG of the adult rat. An intermittent treadmill system was used; the treadmill was on for 3 s and off for 30 s (SF). For sleep fragmentation control (SFC), the treadmill was on for 15 min and off for 150 min. SF was conducted for three durations: 1, 4 and 7 days. To label proliferating cells, the thymidine analog, 5-bromo-2-deoxyuridine (BrdU), was injected 2 h prior to the end of each experiment. Expression of the intrinsic proliferative marker, Ki67, was also studied. SF rats exhibited an increased number of non-rapid eye movement (NREM) sleep bouts with no change in the percent of time spent in this stage. The numbers of both BrdU-positive cells and Ki67-positive cells were reduced by approximately 70% (P<0.05) in the SF groups after 4 and 7 days of experimental conditions whereas no differences were observed after 1 day. In a second experiment, we found that the percentage of new cells expressing a neuronal phenotype 3 weeks after BrdU administration was lower in the SF in comparison with the SFC group for all three durations of SF. We also examined the effects of SF on proliferation in adrenalectomized (ADX) animals, with basal corticosterone replacement. ADX SF animals exhibited a 55% reduction in the number of BrdU-positive cells when compared with ADX SFC. Thus, elevated glucocorticoids do not account for most of the reduction in cell proliferation induced by the SF procedure, although a small contribution of stress is not excluded. The results show that sustained SF induced marked reduction in hippocampal neurogenesis.     

Sustained sleep fragmentation results in delayed changes in hippocampal-dependent cognitive function associated with reduced dentate gyrus neurogenesis

Sleep fragmentation (SF) is prevalent in human sleep-related disorders. In rats, sustained SF has a potent suppressive effect on adult hippocampal dentate gyrus (DG) neurogenesis. Adult-generated DG neurons progressively mature over several weeks, and participate in certain hippocampal-dependent cognitive functions. We predicted that suppression of neurogenesis by sustained SF would affect hippocampal-dependent cognitive functions in the time window when new neurons would reach functional maturity. Sprague–Dawley rats were surgically-prepared with electroencephalogram (EEG) and electromyogram (EMG) electrodes for sleep state detection. We induced sleep-dependent SF for 12 days, and compared SF animals to yoked sleep fragmentation controls (SFC), treadmill controls (TC) and cage controls (CC). Rats were injected with bromodeoxyuridine on treatment days 4 and 5. Rats were returned to home cages for 14 days. Cognitive performance was assessed in a Barnes maze with 5 days at a constant escape position followed by 2 days at a rotated position. After Barnes maze testing rats were perfused and DG sections were immunolabeled for BrdU and neuronal nuclear antigen (NeuN), a marker of mature neurons.SF reduced BrdU-labeled cell counts by 32% compared to SFC and TC groups. SF reduced sleep epoch duration, but amounts of rapid eye movement (REM) sleep did not differ between SF and SFC rats, and non-rapid eye movement (NREM) was reduced only transiently. In the Barnes maze, SF rats exhibited a progressive decrease in escape time, but were slower than controls. SF animals used different search strategies. The use of a random, non-spatial search strategy was significantly elevated in SF compared to the SFC, TC and CC groups. The use of random search strategies was negatively correlated with NREM sleep bout length during SF. Sustained sleep fragmentation reduced DG neurogenesis and induced use of a non-spatial search strategy, which could be seen 2 weeks after terminating the SF treatment. The reduction in neurogenesis induced by sleep fragmentation is likely to underlie the delayed changes in cognitive function.     

Imipramine enhances cell proliferation and decreases neurodegeneration in the hippocampus after transient global cerebral ischemia in rats

This study was aimed to determine whether imipramine chronic treatment promotes neurogenesis in the dentate gyrus (DG) and interferes with neuronal death in the CA1 subfield of the hippocampus after transient global cerebral ischemia (TGCI) in rats. After TGCI, animals were treated with imipramine (20 mg/kg, i.p.) or saline during 14 days. 5-Bromo-2′-deoxyuridine-5′-monophosphate (BrdU) was injected 24 h after the last imipramine or saline injection to label proliferating cells. In order to confirm the effect of TGCI on neuronal death and cell proliferation, a group of animals was sacrificed 7 days after TGCI. Neurogenesis and neurodegeneration were evaluated by doublecortin (DCX)-immunohistochemistry and Fluoro-Jade C (FJC)-staining, respectively. The rate of cell proliferation increases 7 days but returns to basal levels 14 days after TGCI. There was a significant increase in the number of FJC-positive neurons in the CA1 of animals 7 and 14 days after TGCI. Chronic imipramine treatment increased cell proliferation in the SGZ of DG and reduced the neurodegeneration in the CA1 of the hippocampus 14 days after TGCI. Immunohistochemistry for DCX detected an increased number of newly generated neurons in the hippocampal DG 14 days after TGCI, which was not affected by imipramine treatment. Further studies are needed to evaluate whether imipramine treatment for longer time would be able to promote survival of newly generated neurons as well as to improve functional recovery after TGCI.     

Exposure to enriched environment restores the survival and differentiation of new born cells in the hippocampus and ameliorates depressive symptoms in chronically stressed rats

Chronic stress decreases neurogenesis in the adult brain, while exposure to enriched environment (EE) increases it. Recent studies demonstrate the ability of EE to ameliorate stress-induced behavioral deficits. Whether a restored neurogenesis contributes to these effects of EE is unknown. Recently, we demonstrated that EE following restraint stress restores cell proliferation in the dentate gyrus (DG), hippocampal volume and learning. In the current study, we examine the effects of EE following stress on survival and differentiation of the progenitor cells in the DG and behavioral depression using the forced swim test (FST) and sucrose consumption test (SCT). Adult male Wistar rats were subjected to 21 days of restraint stress followed by housing in either standard or enriched conditions (10 days, 6 h/day). Survival and differentiation of BrdU-labeled cells were evaluated 31 days post-BrdU administration. Stress decreased the survival and differentiation of progenitor cells, which was ameliorated by EE. Also the percentage of BrdU-ir cells that did not co-localize with NeuN or S100β was significantly greater in the stressed rats and was restored by EE. Stress increased immobility in FST and decreased sucrose preference in the SCT, and these behaviors were ameliorated by EE. Adult neurogenesis is thought to be linked to learning and memory and in mediating antidepressant effect. Taken together with our earlier report that EE restores stress-induced impairment in learning and cytogenesis, the current results indicate that the reversal of adult neurogenesis could be one of the mechanisms involved in the amelioration of stress-induced deficits.     

Hippocampal CA field neurogenesis after pilocarpine insult: The hippocampal fissure as a neurogenic niche

Pilocarpine model for temporal lobe epilepsy has shown aberrant neurogenesis, but mainly restricted to the dentate gyrus (DG). Herein, by using a modified protocol, combining pilocarpine with ipratropium bromide, we unexpectedly observed a heretofore-unrecognized distinct cellular population expressing the neuroprogenitor marker doublecortin (DCX) on post insult days (PID) 10, 14 and 18, mainly located in the temporal segment of the hippocampal fissure (hf). Some of these DCX+ cells possessed high morphological complexity and seemed to disperse toward the CA fields. Next, we injected bromodeoxyuridine (BrdU) in early (PID 2–4) and delayed (PID 5–7) fashions and killed the rats 7–35 days later for immunohistochemical and anatomical analysis. Massive increase of BrdU labeling was found in the delayed group and the neural stem cell-specific marker nestin was highly expressed in the same narrow band on PID7, so was glial fibrillary acidic protein (GFAP). Using double labeling with BrdU and a mature neuron marker NeuN, we found discrete but clear BrdU+/NeuN+ double labeled cells in the Cornu Ammonis (CA) pyramidal cell layer on PID35. Based on immunohistochemical and anatomical observations, as well as time-course analysis of BrdU, nestin, GFAP, DCX and NeuN expressions in this population of cells located in/near hf, we wish to suggest that this structure harbors neurogenic niches, in addition of the possible dispersion of neuroprogenitors from subgranular niches to CA fields also revealed by this study. Our results support the few previous reports demonstrating hippocampal CA field neurogenesis in adult rats. Mechanistic basis of the phenomenon is discussed.     

Ischemic preconditioning enhances neurogenesis in the subventricular zone

Ischemic preconditioning (IPC) before subsequent prolonged ischemia is considered an emerging endogenous means of ischemic brain protection. We tested whether IPC induces endogenous neurogenesis in the subventricular zone (SVZ) and angiogenesis in the peri-ischemic area. Middle cerebral artery occlusion was administered to rats by filament insertion for 10 min (IPC) and/or 2 h (prolonged focal ischemia [PFI]). IPC alone increased 5'-bromo-2'-deoxyuridine (BrdU) (+) cells 2.5-fold in the SVZ compared with controls at 7 days. The numbers of BrdU/doublecortin (Dcx) or BrdU/neuronal nuclei (NeuN) double-labeled cells also increased, but extents of BrdU/glial fibrillary acidic protein (GFAP) double-labeling in the SVZ were not different. The IPC+PFI group showed about a 40% reduction in infarct volume. PFI increased BrdU (+) cells in the SVZ, and this was greatly enhanced by IPC treatment. The number of BrdU/Dcx double-labeled cells was strongly increased in ischemic brains administered IPC. Differentiation into mature neurons was also enhanced at 14 and 28 days. In addition, IPC significantly promoted angiogenesis in the ischemic penumbra as indicated by von Willebrand factor (vWF) staining. Our results indicate that IPC enhances neurogenesis in the SVZ even without subsequent PFI, and also enhances neurogenesis and angiogenesis after subsequent PFI. We conclude that IPC confers neuroprotection, and also promotes endogenous neurogenesis and angiogenesis.     

Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats

In adult hippocampus, neural progenitor cells give rise to neurons throughout life, and the neurogenesis is modulated by various intrinsic and extrinsic factors. Recent reports showed that lesion of septal cholinergic nuclei projecting to hippocampus suppressed the survival of newborn cells in the dentate gyrus (DG) of hippocampus. Here, we studied whether pharmacological treatment to activate or inhibit the cholinergic system could modulate adult hippocampal neurogenesis. 5'-Bromo-2'-deoxyuridine (BrdU) was injected to label dividing cells before the drug treatment. Immunohistochemical analysis was performed in normal rats chronically treated with an acetylcholinesterase inhibitor donepezil or a muscarinic acetylcholine receptor blocker scopolamine for four weeks. Donepezil increased, but scopolamine decreased, the number of BrdU-positive cells in the DG as compared with the control. Neither drug altered the percentage of BrdU-positive cells that were also positive for a neuronal marker neuronal nuclei, nor net population of proliferative cells labeled with proliferating cell nuclear antigen. We also found that donepezil enhanced, and scopolamine suppressed, the expression level of phosphorylated cAMP response element binding protein (CREB), which is related to cell survival, in the DG. These results indicate that donepezil enhances and scopolamine suppresses the survival of newborn cells in the DG via CREB signaling without affecting neural progenitor cell proliferation and the neuronal differentiation. This is the first evidence that pharmacological manipulation of the cholinergic system can modulate adult hippocampal neurogenesis.     

Astrogliosis is temporally correlated with enhanced neurogenesis in adult rat hippocampus following a glucoprivic insult

2-Deoxy-d-glucose (2-DG) administration causes transient depletion of glucose derivates and ATP. Hence, it can be used in a model system to study the effects of a mild glycoprivic brain insult mimicking transient hypoglycemia, which often occurs when insulin or oral hypoglycemic agents are administered for diabetes control. In the present study, the effect of a single 2-DG application (500 mg/kg, a clinically applicable dose) on glial reactivity and neurogenesis in adult rat hippocampus was examined, as well as a possible temporal correlation between these two phenomena. Post-insult (PI) glial reactivity time course was assessed by immunoreaction against glial-fibrillary acidic protein (GFAP) during the following 5 consecutive days. A clear increase of GFAP immunoreactivity in hilus was observed from 48 to 96 h PI. Moreover, enhanced labeling of long radial processes in the granule cell layer adjacent to hilus was evidenced. On the other hand, a transient increase of progenitor cell proliferation was detected in the subgranular zone, prominently at 48 h PI, coinciding with the temporal peak of glial activation. This increase resulted in an augment of neuroblasts double labeled with 5-bromo-deoxyuridine (BrdU) and with double cortin (DCX) at day 7 PI. Around half of these cells survived 28 days showing matured neuronal phenotype double labeled by BrdU and a neuronal specific nuclear protein marker (NeuN). These findings suggest that a transient neuroglycoprivic state exerts a short-term effect on glial activation that possibly triggers a long-term effect on neurogenesis in hippocampus.     

Neurogenesis in the dentate gyrus of the rat hippocampus enhanced by tickling stimulation with positive emotion

Hippocampal neurogenesis is influenced by many factors. In this study, we examined the effect of tactile stimulation (tickling), which induced positive emotion, on neurogenesis in the dentate gyrus (DG) of the hippocampus. Four week-old rats were tickled for 5 min/day on 5 consecutive days and received 5-bromo-2′-deoxyuridine (BrdU) administration for 4 days from the second tickling day. Then they were allowed to survive for 18 h or 3 weeks after the end of BrdU treatment. Neurogenesis in the DG was compared between the tickled and untickled rats by using immunohistochemistry with anti-BrdU antibody. The result showed that the number of BrdU- and NeuN (neural cell marker)-double positive neurons on 18 h as well as 3 weeks of the survival periods was significantly increased in the tickled group as compared with the untickled group. The expression of mRNA of brain-derived neurotrophic factor (BDNF) in the hippocampus of the tickled rats was not altered when compared with the control rats. In conclusion, tickling stimulation which induces positive emotion may affect the generation and survival of new neurons of the DG through the BDNF-independent pathway.     

In vivo neurogenesis in the dorsal vagal complex of the adult rat brainstem

The dorsal vagal complex (DVC) encompasses the nucleus tractus solitarii (NTS), the dorsal motor nucleus of the vagus nerve (DMX) and the area postrema (AP), that altogether provide the major integrative center for the mammalian autonomic nervous system. The adult rat DVC has been reported to contain afferent-dependent concentration of the plasticity-promoting polysialylated form of neural cell adhesion molecule [J Neurosci 21 (2001) 4721; Eur J Neurosci 14 (2001) 1194]. This prompted us to assess the occurrence of neurogenesis in the DVC of adult rats. Cumulative in vivo labeling of cell proliferation with i.p. bromodeoxyuridine (BrdU) injections was combined with phenotypic markers and confocal microscopy on serial brainstem sections throughout the DVC extent. In basal condition, sparse BrdU+ nuclei were selectively detected in the DVC according to a discrete and reproducible pattern. Some of them were found to colocalize with the neuronal markers doublecortin, HuC/D, or neuronal-specific antigen (NeuN), demonstrating that neurogenesis does occur within the DVC of adult rat. In the NTS, 10% of the BrdU+ nuclei were also NeuN+. A comparable proportion of astrogliogenesis was found in the DVC. Nestin immunohistochemistry yielded a highly specific labeling pattern at the border between AP and NTS. These data may relate to the neural stem cells that have been reported in the floor of the IVth ventricle [J Neurosci 16 (1996) 7599]. In order to assess a possible modulation of neurogenesis by afferent input in vivo, unilateral vagotomy was performed prior to cumulative BrdU treatment. Such DVC deafferentation triggered a large increase of BrdU incorporation in the ipsilateral DVC, which was associated with microglial proliferation in the DMX and with increased genesis of neurons and astrocytes in the NTS. These findings establish DVC as a novel model of adult neurogenesis that is reactive to deafferentation.     

Repeated estradiol administration alters different aspects of neurogenesis and cell death in the hippocampus of female, but not male, rats

Estradiol has been shown to have neuroprotective effects, and acute estradiol treatment enhances hippocampal neurogenesis in the female brain. However, little is known about the effects of repeated administration of estradiol on the female brain, or about the effects of estradiol on the male brain. Gonadectomized male and female adult rats were injected with 5-bromo-2-deoxyuridine (BrdU) (200 mg/kg), and then 24 h later were given subcutaneous injections of either estradiol benzoate (33 mug/kg) or vehicle daily for 15 days. On day 16, animals were perfused and the brains processed to examine cells expressing Ki-67 (cell proliferation), BrdU (cell survival), doublecortin (young neuron production), pyknotic morphology (cell death), activated caspase-3 (apoptosis), and Fluoro-Jade B (degenerating neurons) in the dentate gyrus. In female rats, repeated administration of estradiol decreased the survival of new neurons (independent of any effects on initial cell proliferation), slightly increased cell proliferation, and decreased overall cell death in the dentate gyrus. In male rats, repeated administration of estradiol had no significant effect on neurogenesis or cell death. We therefore demonstrate a clear sex difference in the response to estradiol of hippocampal neurogenesis and apoptosis in adult rats, with adult females being more responsive to the effects of estradiol than males.     

The effects of Fabp7 and Fabp5 on postnatal hippocampal neurogenesis in the mouse

New neurons are continually produced after birth from neural stem/progenitor cells (NSCs/NPCs) in the hippocampal dentate gyrus (DG). Recent studies have reported that fatty acid binding protein 7 (Fabp7/brain lipid binding protein (BLBP)) is required for the maintenance of embryonic NSCs/NPCs and have identified an association between the Fabp7 gene and behavioral paradigms that correlate with hippocampal functions. However, the specific roles of Fabps in postnatal neurogenesis remain unknown. Herein, we demonstrate the effects of Fabp7, and another Fabp, Fabp5, on postnatal neurogenesis. Fabp7 and Fabp5 were detected in the subgranular zone (SGZ) of the DG, and Fabp7+ cells were less differentiated than Fabp5+ cells. We analyzed the differentiation state of NSCs/NPCs in the SGZ of 4-week-old (4w) Fabp7 knockout (7KO), Fabp5 KO (5KO), and Fabp7/Fabp5 double KO (7/5KO) mice and found that the number of NSCs/NPCs was dramatically reduced compared with wild-type mice. Although the uptake of BrdU 1 day after injection was decreased in all KO mice, the survival of BrdU+ cells 1 month after injection was increased in the 7/5KO mice compared to other three genotypes. We also observed an enhancement of neuronal differentiation in all Fabp KO mice. In addition, the proliferation and survival of NSCs/NPCs differed along the anterior-posterior axis (A-P axis). A greater number of newborn cells in the posterior region became extinct, but this tendency was not apparent in the Fabps KO mice. These data suggest that Fabp7 and Fabp5 have differential roles for proliferation and survival of the NSCs/NPCs during postnatal DG neurogenesis.     

Nitric oxide generated by muscle corrects defects in hippocampal neurogenesis and neural differentiation caused by muscular dystrophy

Duchenne muscular dystrophy (DMD) results from null mutation of dystrophin, a membrane-associated structural protein that is expressed in skeletal muscle. Dystrophin deficiency causes muscle membrane lesions, muscle degeneration and eventually death in afflicted individuals. However, dystrophin deficiency also causes cognitive defects that are difficult to relate to the loss of dystrophin. We assayed neurogenesis in the dentate gyrus (DG) in the mdx mouse model of DMD, using bromodeoxyuridine incorporation as a marker of proliferation and NeuN expression as a marker of differentiation. Our findings show that dystrophin mutation disrupts adult neurogenesis by promoting cell proliferation in the DG and suppressing neuronal differentiation. Because loss of dystrophin from muscle results in the secondary loss of neuronal nitric oxide synthase (nNOS), and NO is able to modulate neurogenesis, we assayed whether the genetic restoration of nNOS to mdx muscles corrected defects in adult, hippocampal neurogenesis. Assays of NO in the sera of active mice showed significant reductions in NO caused by the dystrophin mutation. However, over-expression of nNOS in the muscles of mdx mice increased serum NO and normalized cell proliferation and neuronal differentiation in the DG. These findings indicate that muscle-derived NO regulates adult neurogenesis in the brain and loss of muscle nNOS may underlie defects in the central nervous system in DMD.     

Increased neurogenesis in brains of scrapie-infected mice

Persistent neurogenesis occurs in the adult brain throughout the life of all mammals. Recent studies have shown that neurogenesis was increased in adult gerbil and rat brains after ischemia. Neurogenesis has not been examined during neurodegenerative diseases such as scrapie. To investigate the regeneration of neurons after scrapie-infection, we infused 5-bromo-2'-deoxyuridine (BrdU), a DNA replication indicator, into both control and scrapie-infected mice. Mice were sacrificed at 150 days post-infection, i.e., at the start of clinical disease and a time when PrP(Sc) was readily detected in brain by both immunostaining and Western blot. We investigated expression of BrdU in each region of brain and observed cellular localization of BrdU using various cell markers such as neuronal nuclear (NeuN), microtubule-associated protein 2 (MAP2) and glial fibrillary acidic protein (GFAP). Immunohistochemically, BrdU-labeled cells were observed in the striatum, hippocampus, and brain stem of scrapie-infected brains. BrdU-labeled cells were much more prevalent in the hippocampus of scrapie-infected mice compared to hippocampus of control brains. In scrapie mice, there was more staining in hippocampus than in other brain regions. We also found that BrdU-positive cells colocalized with the neuronal markers NeuN and MAP2, whereas BrdU staining was not merged with GFAP, an astrocytic marker. Taken together, our results suggest that scrapie-infection induces region-specific increases in neuron regeneration.     

Increased BrdU incorporation reflecting DNA repair, neuronal de-differentiation or possible neurogenesis in the adult cochlear nucleus following bilateral cochlear lesions in the rat

Neurogenesis is known to occur in response to injury in the brain, for example, as a result of neurodegenerative diseases. However, there have been few investigations into how the brain responds to damage to peripheral sensory nerves, in other areas such as the brainstem. Here, we report that bilateral surgical lesions of the cochlea result in increased incorporation of the DNA replication marker, bromodeoxyuridine (BrdU), in cells of the brainstem cochlear nucleus (CN) of the adult rat, suggesting either cell proliferation or DNA repair. Some of the BrdU-labelled cells colabelled for the mature neuron marker, NeuN and the GABAergic enzyme GAD-65, suggesting the possibility that neurogenesis might have occurred and resulted in the generation of new neurons with a GABAergic phenotype. However, some of the mature neurons also re-expressed immature neuronal intermediate filament and microtuble-associated proteins, without apoptotic neuronal death, which suggests that the colabelling of BrdU with NeuN and GAD-65 may not be a true reflection of neurogenesis, but injury-stimulated neuronal dedifferentiation. These results suggest the possibility that DNA repair, neuronal de-differentiation or possible neurogenesis occurs in the cochlear nucleus, in response to damage to the peripheral auditory system.     

Postischemic exercise decreases neurogenesis in the adult rat dentate gyrus

Running exercise enhances neurogenesis in the normal adult and aged hippocampus. However, the effect of exercise on neurogenesis in the ischemic hippocampus is unclear. Here, we show that running exercise has different effects on ischemic and non-ischemic brain. Young (3-4-month-old) normotensive Wistar rats were used for this study. We administered bromodeoxyuridine (BrdU) to rats 7 days after the induction of transient forebrain ischemia or sham operation. BrdU-labeled cells were increased in the ischemic subgranular zone (SGZ) and granule cell layer (GCL) and double immunofluoresence showed approximately 80% of BrdU-labeled cells expressed neuronal markers. To assess the effect of running exercise on neurogenesis, BrdU-labeled cells in these regions were quantified after 1 day and 14 days. In sham-operated rats, the numbers of BrdU-labeled cells were significantly increased (2.2-fold) in the SGZ and GCL in response to running exercise. The numbers of BrdU-labeled cells were increased in response to ischemia, however, they were decreased 14 days after BrdU administration and running exercise accelerated the reduction in BrdU-labeled cells in ischemic rats. These findings suggest that running exercise has a negative effect on neurogenesis in the ischemic hippocampus. This may be important with respect to assessment of therapeutic approaches for functional recovery after stroke.     

营养不良可增加幼鼠齿状回颗粒下层的细胞增殖和神经生发(英文)

为了观察营养不良对幼鼠海马齿状回 (DG)和脑室下层 (SVZ)的细胞增殖和神经发生的影响 ,采用 5 -溴 -2 -脱氧尿苷(Brd U)标记结合免疫组织化学方法对脑切片分别进行 Brd U、Tu J1(β tubulin,β微管蛋白 )及 GFAP(胶质纤维酸性蛋白 )反应或双重反应。结果表明 ,营养不良幼鼠齿状回的细胞增殖和神经生发明显高于营养良好的幼鼠而脑室下层的细胞增殖数量在两者却无明显差异。在齿状回 ,新生的细胞中大约有 5 0 %为新生的神经元 ,10～ 2 0 %为神经胶质细胞。本文结果提示 ,幼鼠海马齿状回的细胞增殖和神经生发可能因营养不良而增加 ,这些新生的细胞可能对日后某些海马依赖性行为产生一定的影响     

Glatiramer acetate could be a potential antidepressant through its neuroprotective and anti-inflammatory effects

Antidepressants that act by increasing the activity of central serotonergic or noradrenergic systems are the main biological treatments for major depressive disorder (MDD). Although these agents are generally safe and effective, they are far from ideal due to their slow onset and a substantial proportion of MDD patients do not clinically improve, despite maximal dosing. Thus, the development of new antidepressants based on novel theories may help to develop faster and more effective antidepressant agents. Over the last decade, there has been an impressive accumulation of data about non-monoamine systems that might mediate the pathogenesis of, and therapeutic mechanisms in, MDD. For example, MDD has been associated with a decreased central brain-derived neurotrophic factor (BDNF) state and activating the BDNF-signaling pathway may play an important role in the mechanisms of antidepressant therapeutic action. Glatiramer acetate (GA) is a collection of synthetic polypeptides indicated as therapy for relapsing-remitting multiple sclerosis. Both preclinical and clinical studies have demonstrated that peripheral GA administration can enhance central BDNF activity or increase serum BDNF levels. Furthermore, MDD has been associated with an inflammatory process in the brain. Animal studies have demonstrated that GA administration has a central anti-inflammatory effect through the release of interleukin-10. Finally, recent animal studies have suggested that psychosocial stress reduces neurogenesis, whereas antidepressant treatment increases neurogenesis and blocks the effects of stress. Peripheral administration of GA was found to augment neurogenesis, including cell proliferation, migration, and differentiation in rodent brain. From the above evidence, GA could have antidepressant effects by increasing central BDNF, stimulating neurogenesis or through its anti-inflammatory effect. It is also suggested that immediate GA treatment after stress may prevent the development of stress-related psychiatric disorders such as MDD and post-traumatic stress disorder.