Temporal lobe epilepsy (TLE) is a common and severe neurological disorder which is often intractable. It can not only damage the normal structure and function of hippocampus, but also affect the neurogenesis in dentate gyrus (DG). It is well documented from researches on the animal models of TLE that after a latent period of several days, prolonged seizure activity leads to a dramatic increase in mitotic activity in the hippocampal DG. However, cell proliferation returns to baseline levels within 3-4 weeks after status epilepticus (SE). Meanwhile, there are two major abnormalities of DG neurogenesis, including the formation of hilar basal dendrites and the ectopic migration of newborn granule cells into the polymorphic cell layer, which may affect epileptogenesis and seizure onset. However, the specific contribution of these abnormalities to seizures is still unknown. In other words, whether they are anti-epileptic or pro-epileptic is still under heated discussion. This article systematically reviews current knowledge on neurogenesis and epilepsy based on the results of studies in recent years and discusses the possible roles of neurogenesis in epileptogenesis and pathologic mechanisms, so as to provide information for the potential application of neurogenesis as a new clinical therapeutic target for temporal lobe epilepsy.
Animals ; Brain ; Cell Movement ; physiology ; Cell Proliferation ; physiology ; Dendrites ; pathology ; Dentate Gyrus ; growth & development ; pathology ; Epilepsy, Temporal Lobe ; etiology ; pathology ; physiopathology ; Hippocampus ; growth & development ; pathology ; Humans ; Mitosis ; physiology ; Neurogenesis ; physiology ; Neurons ; pathology ; Seizures ; etiology ; physiopathology ; Status Epilepticus ; physiopathology

In the adult mammalian brain, neural-lineage cells are continuously generated in the subventricular zone (SVZ) and dentate gyrus of the hippocampus. These cells in vivo arising from the adult SVZ may be regulated by environmental enrichment (EE). EE is a method of raising animals in a huge cage containing novel objects, running wheels and social interaction with a complex combination of physical, cognitive, and social stimulations. EE can affect neural plasticity via overexpression of growth factors such as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), fibroblast growth factor-2 (FGF-2), and synaptic activity-regulating genes. EE also have advanced effects on brain functions including the enhancement of motor and cognitive functions in normal and pathological states. Additionally, behavioral changes by EE are related with molecular changes including neurogenesis, gliogenesis, angiogenesis, axonal sprouting, and dendritic branching in the adult brain. In this review, we focus on brain plasticity and neurorestoration associated with molecular changes of neurotrophic growth factors such as BDNF, VEGF, IGF-1, FGF-2 and synaptic activity-regulating genes that occurs in interaction to EE.
Adult ; Animals ; Axons ; Brain* ; Brain-Derived Neurotrophic Factor ; Dentate Gyrus ; Fibroblast Growth Factor 2 ; Hippocampus ; Humans ; Insulin-Like Growth Factor I ; Intercellular Signaling Peptides and Proteins ; Interpersonal Relations ; Neurogenesis ; Plastics* ; Running ; Vascular Endothelial Growth Factor A

To investigate the beneficial effects of diosgenin (DG) on the multiple types of brain damage induced by Aβ-42 peptides and neurotoxicants, alterations in the specific aspects of brain functions were measured in trimethyltin (TMT)-injected transgenic 2576 (TG) mice that had been pretreated with DG for 21 days. Multiple types of damage were successfully induced by Aβ-42 accumulation and TMT injection into the brains of TG mice. However, DG treatment significantly reduced the number of Aβ-stained plaques and dead cells in the granule cells layer of the dentate gyrus. Significant suppression of acetylcholinesterase (AChE) activity and Bax/Bcl-2 expression was also observed in the DG treated TG mice (TG+DG group) when compared with those of the vehicle (VC) treated TG mice (TG+VC group). Additionally, the concentration of nerve growth factor (NGF) was dramatically enhanced in TG+DG group, although it was lower in the TG+VC group than the non-transgenic (nTG) group. Furthermore, the decreased phosphorylation of downstream members in the TrkA high affinity receptor signaling pathway in the TG+VC group was significantly recovered in the TG+DG group. A similar pattern was observed in p75NTR expression and JNK phosphorylation in the NGF low affinity receptor signaling pathway. Moreover, superoxide dismutase (SOD) activity was enhanced in the TG+DG group, while the level of malondialdehyde (MDA), a marker of lipid peroxidation, was lower in the TG+DG group than the TG+VC group. These results suggest that DG could exert a wide range of beneficial activities for multiple types of brain damage through stimulation of NGF biosynthesis.
Acetylcholinesterase ; Animals ; Brain* ; Dentate Gyrus ; Diosgenin* ; Lipid Peroxidation ; Malondialdehyde ; Mice ; Nerve Growth Factor* ; Neurodegenerative Diseases ; Neurons* ; Peptides ; Phosphorylation ; Superoxide Dismutase

In this study, we determined how rosiglitazone (RSG) differentially affected hippocampal neurogenesis in mice fed a low-fat diet (LFD) or high-fat diet (HFD; 60% fat). LFD and HFD were given to the mice for 8 weeks. Four weeks after initiating the LFD and HFD feeding, vehicle or RSG was administered orally once a day to both groups of mice. We measured cell proliferation and neuroblast differentiation in the subgranular zone of the dentate gyrus using Ki67 and doublecortin (DCX), respectively, as markers. In addition, we monitored the effects of RSG on the levels of DCX and brain-derived neurotrophic factor (BDNF) in hippocampal homogenates. At 8 weeks after the LFD feeding, the numbers of Ki67- and DCX-positive cells as well as hippocampal levels of DCX and BDNF were significantly decreased in the RSG-treated group compared to the vehicle-treated animals. In contrast, the numbers of Ki67- and DCX-positive cells along with hippocampal levels of DCX and BDNF in the HFD fed mice were significantly increased in the RSG-treated mice compared to the vehicle-treated group. Our data demonstrate that RSG can modulate the levels of BDNF, which could play a pivotal role in cell proliferation and neuroblast differentiation in the hippocampal dentate gyrus.
Animals ; Blotting, Western ; Brain-Derived Neurotrophic Factor/metabolism ; Cell Differentiation/*drug effects ; Cell Proliferation/drug effects ; Dentate Gyrus/growth & development/physiology ; Diet, Fat-Restricted ; *Diet, High-Fat ; Hippocampus/growth & development/physiology ; Hypoglycemic Agents/*pharmacology ; Immunohistochemistry ; Ki-67 Antigen/metabolism ; Male ; Mice, Inbred C57BL ; Microtubule-Associated Proteins/metabolism ; Neurogenesis/*drug effects ; Neuropeptides/metabolism ; Thiazolidinediones/*pharmacology

Adult hippocampal neurogenesis plays important roles in learning, memory and mood regulation. External factors, such as physical exercise, have been found to modulate adult hippocampal neurogenesis. Voluntary running enhances cell proliferation in subgranular zone (SGZ) and increases the number of new born neurons in rodents, but underlying mechanisms are not fully understood. In this study, we used BrdU assay to identify proliferating cells in 2-month-old C57BL/6 mice after 15 days of voluntary wheel running test. mRNA and protein levels for several neural factors in dentate gyrus, Ammon's horn, and cortex were also analyzed by RT-qPCR and Western blot assay after 15 days of voluntary wheel running. Our data show that voluntary wheel running for 15 days elevated the number of proliferation cells in dentate gyrus and significantly up-regulated the mRNA levels of Bdnf, Igf1 and Wnt4. The protein levels of BDNF and IGF1 in dentate gyrus were also increased after voluntary wheel running. These results indicate that the increase of adult hippocampal neurogenesis caused by voluntary wheel running for 15 days might be through up-regulating BDNF, IGF1 and WNT4 in dentate gyrus.
Animals ; Brain-Derived Neurotrophic Factor ; metabolism ; Cell Proliferation ; Dentate Gyrus ; cytology ; metabolism ; Insulin-Like Growth Factor I ; metabolism ; Mice ; Mice, Inbred C57BL ; Motor Activity ; Neurogenesis ; Neurons ; cytology ; Wnt4 Protein ; metabolism

The formation of neural synapses according to the development and growth of neurite were usually studied with various markers. Of these markers, synaptophysin is a kind of synaptic protein located in the synaptic vesicle of neuron or neuroendocrine cell known to be distributed consistently in all neural synapses. The purpose of this study was to investigate differential expression levels and patterns of synaptic marker (synaptophysin) in the mouse hippocampal region according to the developmental stages of embryonic, neonatal, and adulthood respectively. In the embryonic and neonatal groups, synaptophysin immunofluorescence was almost defined to cornu ammonis subfields (CA1 and CA3) of hippocampus and subiculum proper in the hippocampal region. However in dentate gyrus, synaptophysin immunoreactivities were insignificant or absent in all developmental stages. In embryonic and neonatal hippocampus, the intensities of immunofluorescence were significantly different between molecular and oriens layers. Furthermore, those intensities were decreased considerably in both layers of neonatal group compared to embryonic. The results from this study will contribute to characterizing synaptogenic activities in the central nervous system through developmental stages.
Animals ; Brain ; Central Nervous System ; Dentate Gyrus ; Fluorescent Antibody Technique ; Growth and Development ; Hippocampus ; Mice ; Neurites ; Neuroendocrine Cells ; Neurons ; Synapses ; Synaptic Vesicles ; Synaptophysin

The formation of neural synapses according to the development and growth of neurite were usually studied with various markers. Of these markers, synaptophysin is a kind of synaptic protein located in the synaptic vesicle of neuron or neuroendocrine cell known to be distributed consistently in all neural synapses. The purpose of this study was to investigate differential expression levels and patterns of synaptic marker (synaptophysin) in the mouse hippocampal region according to the developmental stages of embryonic, neonatal, and adulthood respectively. In the embryonic and neonatal groups, synaptophysin immunofluorescence was almost defined to cornu ammonis subfields (CA1 and CA3) of hippocampus and subiculum proper in the hippocampal region. However in dentate gyrus, synaptophysin immunoreactivities were insignificant or absent in all developmental stages. In embryonic and neonatal hippocampus, the intensities of immunofluorescence were significantly different between molecular and oriens layers. Furthermore, those intensities were decreased considerably in both layers of neonatal group compared to embryonic. The results from this study will contribute to characterizing synaptogenic activities in the central nervous system through developmental stages.
Animals ; Brain ; Central Nervous System ; Dentate Gyrus ; Fluorescent Antibody Technique ; Growth and Development ; Hippocampus ; Mice ; Neurites ; Neuroendocrine Cells ; Neurons ; Synapses ; Synaptic Vesicles ; Synaptophysin

PURPOSE: To investigate whether growth hormone (GH) has a protective effect on neurons in hippocampal slice cultures of neonatal rats exposed to oxygen-glucose deprivation (OGD). METHODS: Cultured hippocampal slices of 7-day-old rats were exposed to OGD for 60 min. Then, the slices were immediately treated with three doses of GH (5, 50, or 500 micrometer) in media. The relative fluorescent densities of propidium iodide (PI) uptake in the slices and relative lactate dehydrogenase (LDH) activities in the media were determined and compared between each GH-treated group of slices and untreated slices (control) at 12 and 24 h after OGD. Immunofluorescent staining for caspase-3 and TUNEL staining were performed to observe the effect of GH on apoptotic neuronal death. RESULTS: The relative fluorescent densities of PI uptake in CA1 and dentate gyrus (DG) of the hippocampal slices in each GH-treated group were not significantly different from those in the untreated slices at 12 and 24 h after OGD (P>0.05). Treatment with GH could reduce the relative LDH activities in the media of the GH-treated groups only at 12 h after OGD (P<0.05). Expression of caspase-3 and TUNEL positivity in CA1 and DG of the slices treated with 50-iM GH were not different from those of the untreated slices at 12 and 24 h after OGD. CONCLUSION: Treatment of hippocampal slice cultures with GH after OGD does not show a definitive protective effect on neuronal death but can reduce the LDH efflux of the slices in media at 12 h after OGD.
Animals ; Apoptosis ; Caspase 3 ; Dentate Gyrus ; Growth Hormone ; In Situ Nick-End Labeling ; L-Lactate Dehydrogenase ; Neurons ; Propidium ; Rats

PURPOSE: To investigate whether growth hormone (GH) has a protective effect on neurons in hippocampal slice cultures of neonatal rats exposed to oxygen-glucose deprivation (OGD). METHODS: Cultured hippocampal slices of 7-day-old rats were exposed to OGD for 60 min. Then, the slices were immediately treated with three doses of GH (5, 50, or 500 micrometer) in media. The relative fluorescent densities of propidium iodide (PI) uptake in the slices and relative lactate dehydrogenase (LDH) activities in the media were determined and compared between each GH-treated group of slices and untreated slices (control) at 12 and 24 h after OGD. Immunofluorescent staining for caspase-3 and TUNEL staining were performed to observe the effect of GH on apoptotic neuronal death. RESULTS: The relative fluorescent densities of PI uptake in CA1 and dentate gyrus (DG) of the hippocampal slices in each GH-treated group were not significantly different from those in the untreated slices at 12 and 24 h after OGD (P>0.05). Treatment with GH could reduce the relative LDH activities in the media of the GH-treated groups only at 12 h after OGD (P<0.05). Expression of caspase-3 and TUNEL positivity in CA1 and DG of the slices treated with 50-iM GH were not different from those of the untreated slices at 12 and 24 h after OGD. CONCLUSION: Treatment of hippocampal slice cultures with GH after OGD does not show a definitive protective effect on neuronal death but can reduce the LDH efflux of the slices in media at 12 h after OGD.
Animals ; Apoptosis ; Caspase 3 ; Dentate Gyrus ; Growth Hormone ; In Situ Nick-End Labeling ; L-Lactate Dehydrogenase ; Neurons ; Propidium ; Rats

OBJECTIVEIt is well documented that epilepsy can increase neurogenesis in certain brain regions and cause behavioral alternations in patients and different epileptic animal models. A series of experimental studies have demonstrated that neurogenesis is regulated by various factors including glucocorticoid (CORT), which can reduce neurogenesis. Most of studies in animal have been focused on adulthood stage, while the effect of recurrent seizures to immature brain in neonatal period has not been well established. This study was designed to investigate how the recurrent seizures occurred in the neonatal period affected the immature brain and how CORT regulated neurogenesis in immature animals.

METHODSNeonatal rats were subjected to 3 pilocarpine-induced seizures from postnatal day 1 to day 7. Then neurogenesis at different postnatal ages (i.e. P8, P12, P22, P50) was observed. Behavioral performance was tested when the rats were mature (P40), and plasma CORT levels following recurrent seizures were simultaneously monitored.

RESULTSRats with neonatal seizures had a significant reduction in the number of Bromodeoxyuridine (BrdU) labeled cells in the dentate gyrus compared with the control groups when the animals were euthanized on P8 or P12 (P<0.05); whereas there was no difference between the two groups on P22. Until P50, rats with neonatal seizures had increased number of BrdU-labeled cells compared with the control group (P<0.05). In Morris water maze task, pilocarpine-treated rats were significantly slower than the control rats at the first and second day, and there were no differences at other days. In probe trial, there was no significant difference in time spent in the goal quadrant between the two groups. Endocrine studies showed a correlation between the number of BrdU positive cells and the CORT level. Sustained increase in circulating CORT levels was observed following neonatal seizures on P8 and P12.

CONCLUSIONNeonatal recurrent seizures can biphasely modulate neurogenesis over different time windows with a down-regulation at early time and up-regulation afterwards, cause persistent deficits in cognitive functions of adults, and increase the circulating CORT levels. CORT levels are related with the morphological and behavioral consequences of recurrent seizures.

Age Factors ; Animals ; Animals, Newborn ; Critical Period (Psychology) ; Dentate Gyrus ; cytology ; growth & development ; metabolism ; Glucocorticoids ; blood ; Male ; Maze Learning ; physiology ; Neurons ; cytology ; metabolism ; Random Allocation ; Rats ; Rats, Wistar ; Seizures ; metabolism ; pathology ; physiopathology ; Stem Cells ; cytology ; metabolism