The effect of Mash-1 gene overexpression on neural cell proliferation, differentiation and learning and memory ability in C57BL/6 adult male mice after brain trauma / 临床神经病学杂志

Objective To investigate the effects of Mash-1 gene overexpression on neural cell proliferation, differentiation and learning and memory ability in C57BL/6 adult male mice after brain trauma. Methods One hundred and sixty healthy adult male C57BL/6 mice were randomly divided into sham operation group, simple trauma group, negative control group and overexpression group. Gene transfection using recombinant adenovirus Ad5-mMash-1. Detection of Mash-1 mRNA level by RT-PCR at 1 d before TBI and 1 d, 3 d, 7 d, 14 d after traumatic brain injury (TBI). Western blotting was used to detect the expression of Mash-1 protein. The learning and memory ability was evaluated by means of water maze. The proliferation of nerve cells in dentate gyrus and cerebral cortex of hippocampus at 3 d and 7 d after TBI were detected by immunofluorescence. Results Compared with those in sham operation group, the relative expression of Mash-1 mRNA in simple trauma group and negative control group at 1 d, 3 d, 7 d, 14 d after TBI were significantly lower (P<0. 05-0. 01), and the relative expression of Mash-1 mRNA in overexpression group at 1 d, 3 d, 7 d, 14 d after TBI were significantly higher ( all P<0. 01 ). The relative expression of Mash-1 mRNA in overexpression group at 1 d , 3 d , 7 d , 1 4 d after TBI were significantly higher than those in simple trauma group and negative control group (all P<0. 05). Compared with those in sham operation group, expression of Mash-1 protein in simple trauma group at 1 d, 7 d, 14 d after TBI and negative control group and overexpression group at 1 d, 3 d, 7 d, 14 d after TBI (P<0. 05 -0. 01), expression of Mash-1 protein in simple trauma group at 3 d after TBI (P<0. 05). The expression of Mash-1 protein in overexpression group at 1 d, 3 d, 7 d, 14 d after TBI were significantly higher than those in simple trauma group and negative control group (all P<0. 05). Compared with those in sham operation group, the number of BrdU positive cells in simple trauma group at 3 d, 7 d after TBI and the number of DCX positive cells at 3 d after TBI were significantly decreased (P<0. 05-0. 01), and they were significantly increased in overexpression group (all P<0. 05). The number of BrdU positive cells at 3 d, 7 d after TBI and the number of DCX positive cells at 3 d after TBI in overexpression group were significantly increased than those in simple trauma group (all P<0. 05). There was no statistical difference of escape latency between simple trauma group, negative control group and overexpression group at 1 d, 3 d, 7 d, 14 d after TBI (all P>0. 05). Compared with those in sham operation group, escape latency in simple trauma group, negative control group and overexpression group at 1 d, 3 d, 7 d, 14 d after TBI were significantly increased (all P<0. 05). Conclusion Overexpression of Mash-1 gene increases neuronal proliferation and differentiation in dentate gyrus and cortex of adult C57BL/6 mice after traumatic brain injury, but it has no effect on learning and memory ability.

Repeated restraint stress promotes hippocampal neuronal cell ciliogenesis and proliferation in mice / 한국실험동물학회지

Stress severely disturbs physiological and mental homeostasis which includes adult neurogenesis in hippocampus. Neurogenesis in hippocampus is a key feature to adapt to environmental changes and highly regulated by multiple cellular signaling pathways. The primary cilium is a cellular organelle, which acts as a signaling center during development and neurogenesis in adult mice. However, it is not clear how the primary cilia are involved in the process of restraint (RST) stress response. Using a mouse model, we examined the role of primary cilia in repeated and acute RST stress response. Interestingly, RST stress increased the number of ciliated cells in the adult hippocampal dentate gyrus (DG). In our RST model, cell proliferation in the DG also increased in a time-dependent manner. Moreover, the analysis of ciliated cells in the hippocampal DG with cell type markers indicated that cells that were ciliated in response to acute RST stress are neurons. Taken together, these findings suggest that RST stress response is closely associated with an increase in the number of ciliated neurons and leads to an increase in cell proliferation.

Advance in the study of compounds with potential activities in promotion of adult hippocampal neurogenesis / 药学学报

With the increasing size of aging population all over the world, the incidence of Alzheimer's disease has reached to the highest level in many developed countries. However, the etiology of Alzheimer's disease remains largely unknown especially in the biological mechanism. Up to now, it is still a challenge that the disease can't be controlled by the approved clinical medicines. As a result, new therapeutic strategies are urgently needed to prevent and cure Alzheimer's disease. The hippocampus area is associated with learning, memory, cognitive regulation in the central nervous system, which is closely related to Alzheimer's disease. Adult neurogenesis in hippocampal area allows new neuronal cells to emerge in the central nervous system. The brain's plasticity is achieved in some sense. This review focuses on the progress in the study of variety of compounds in promotion of neurogenesis in adult hippocampal area in recent years. The potential of these compounds may shed a light on postponing the occurring of Alzheimer's disease or even curing it.

Effects of aluminum on the reduction of neural stem cells, proliferating cells, and differentiating neuroblasts in the dentate gyrus of D-galactose-treated mice via increasing oxidative stress

Aluminum (Al) accumulation increases with aging, and long-term exposure to Al is regarded as a risk factor for Alzheimer's disease. In this study, we investigated the effects of Al and/or D-galactose on neural stem cells, proliferating cells, differentiating neuroblasts, and mature neurons in the hippocampal dentate gyrus. AlCl3 (40 mg/kg/day) was intraperitoneally administered to C57BL/6J mice for 4 weeks. In addition, vehicle (physiological saline) or D-galactose (100 mg/kg) was subcutaneously injected to these mice immediately after AlCl3 treatment. Neural stem cells, proliferating cells, differentiating neuroblasts, and mature neurons were detected using the relevant marker for each cell type, including nestin, Ki67, doublecortin, and NeuN, respectively, via immunohistochemistry. Subchronic (4 weeks) exposure to Al in mice reduced neural stem cells, proliferating cells, and differentiating neuroblasts without causing any changes to mature neurons. This Al-induced reduction effect was exacerbated in D-galactose-treated mice compared to vehicle-treated adult mice. Moreover, exposure to Al enhanced lipid peroxidation in the hippocampus and expression of antioxidants such as Cu, Zn- and Mn-superoxide dismutase in D-galactose-treated mice. These results suggest that Al accelerates the reduction of neural stem cells, proliferating cells, and differentiating neuroblasts in D-galactose-treated mice via oxidative stress, without inducing loss in mature neurons.

Neural Stem Cells and Ischemic Brain / 대한뇌졸중학회지

Stroke activates neural stem cells in the ventricular-subventricular zone (V/SVZ) of the lateral ventricle, which increases neuroblasts and oligodendrocyte progenitor cells (OPCs). Within the ischemic brain, neural stem cells, neuroblasts and OPCs appear to actively communicate with cerebral endothelial cells and other brain parenchymal cells to mediate ischemic brain repair; however, stroke-induced neurogenesis unlikely plays any significant roles in neuronal replacement. In this mini-review, we will discuss recent findings how intercellular communications between stroke-induced neurogenesis and oligodendrogenesis and brain parenchymal cells could potentially facilitate brain repair processes.

Epigallocatechin-3-gallate rescues LPS-impaired adult hippocampal neurogenesis through suppressing the TLR4-NF-kappaB signaling pathway in mice

Adult hippocampal dentate granule neurons are generated from neural stem cells (NSCs) in the mammalian brain, and the fate specification of adult NSCs is precisely controlled by the local niches and environment, such as the subventricular zone (SVZ), dentate gyrus (DG), and Toll-like receptors (TLRs). Epigallocatechin-3-gallate (EGCG) is the main polyphenolic flavonoid in green tea that has neuroprotective activities, but there is no clear understanding of the role of EGCG in adult neurogenesis in the DG after neuroinflammation. Here, we investigate the effect and the mechanism of EGCG on adult neurogenesis impaired by lipopolysaccharides (LPS). LPS-induced neuroinflammation inhibited adult neurogenesis by suppressing the proliferation and differentiation of neural stem cells in the DG, which was indicated by the decreased number of Bromodeoxyuridine (BrdU)-, Doublecortin (DCX)- and Neuronal Nuclei (NeuN)-positive cells. In addition, microglia were recruited with activatingTLR4-NF-kappaB signaling in the adult hippocampus by LPS injection. Treating LPS-injured mice with EGCG restored the proliferation and differentiation of NSCs in the DG, which were decreased by LPS, and EGCG treatment also ameliorated the apoptosis of NSCs. Moreover, pro-inflammatory cytokine production induced by LPS was attenuated by EGCG treatment through modulating the TLR4-NF-kappaB pathway. These results illustrate that EGCG has a beneficial effect on impaired adult neurogenesis caused by LPSinduced neuroinflammation, and it may be applicable as a therapeutic agent against neurodegenerative disorders caused by inflammation.

Influence of acrylamide on adult neurogenesis and expression of GSK3βin mouse / 中国免疫学杂志

Objective:To investigate the influence of acrylamide ( ACR) on adult neurogenesis and expression of GSK 3βin mouse.Methods:Method Adult male Kunming mice were used and divided into two groups:control group and experimental poisoning groups,that were exposured to acrylamide by intraperitoneal injection.Brdu labeling and immunohistochemistry were used to investigate the proliferation of adult neural stem cells in the subgranular zone ( SGZ).BrdU/NeuN/GFAP triple labeling to investigate the survival and differentiation of newly generated cells.Detecting GSK3βexpression and distribution in Neuro-2a cells,the expression of GSK3βwas examined by using Western blot.Results:Compared with control mice ,lower number of BrdU-positive cells and less differentiated into neurons in ACR mice.Less neural stem cells survived ,but more glia cells were generated in the subgranular zone of acrylamide mice.Moreover,higher phosphorylated GSK 3β( Ser9 ) were detected in Neuro-2a cells and mouse dentate gyrus in ACR mice respectively .Conclusion:These results suggested that acrylamide inhibits neural stem cells proliferation and influences the survival and differentiation of newly generated cells.Acrylamide inhibits neurogenesis maybe through GSK 3βsignaling pathway.

Regulación de la neurogénesis hipocámpica por los estrógenos: su relación con la depresión / Regulation of adult hippocampal neurogenesis by estrogens: relationship to depression

Estrogens produce a wide range of biological effects throughout the body, including the Central Nervous System (CNS). In the brain, besides acting as neuroprotective agents, estrogens play an important role in many neuronal processes and certain psychiatric disorders such as depression. The precise mechanism by which estrogens induce their positive effects on depressive disorders has not been elucidated; however, it is known that estrogens act on the CNS through the activation of specific receptors. These actions occur in genomic and non-genomics mechanisms through the modulation of synthesis and metabolism of neurotransmitters, neuropeptides, neurosteroids and influencing the morphological features of neurons and synaptic function. In addition, it is known that estrogens can act as modulators of processes related to neuroplasticity and neurogenesis. Adult hippocampal neurogenesis is a neuroplastic process that is affected by antidepressant drugs. These drugs increase the number of new neurons following a temporal course that correlates within the time in which antidepressants cause a behavioral improvement in rodents and in humans. Interestingly, whereas the behavioral antidepressant effects require 2-4 weeks to appear, after treatment initiation, estrogen reduce the depressive-like behavior and induce cell proliferation in terms of days. Thus, antidepressant drugs and the estrogens replacement during the adulthood could influence in a similar manner the new neuron formation. Furthermore, recent works have indicated that the combination of antidepressants plus estrogens could exert beneficial actions at lower doses of estrogens (physiological range). This evidence is important due to the combination of non-effective doses of antidepressants plus estrogens could decrease the side-effects of both compounds, and facilitate the behavioral action of antidepressant drugs shortening the latency to onset their action. The present review discusses recent information about the implication of estrogens in depression, and on their effects as positive regulators of new neuron formation in the adult hippocampus. In addition, we will review the possible implication of last effect of estrogens on their antidepressant effects.

Los estrógenos producen una amplia gama de efectos biológicos en todo el cuerpo, incluyendo el Sistema Nervioso Central (SNC). En el cerebro, además de actuar como agentes neuroprotectores, los estrógenos desempeñan un papel importante en la regulación de procesos neuronales constituyéndose así como posibles factores relacionados con la etiología de algunos trastornos neuropsiquiátricos, tales como la depresión. Durante los últimos años se ha generado evidencia de la relación existente entre los niveles fisiológicos de los estrógenos y el desarrollo de episodios depresivos. Por otra parte, los estrógenos tienen un papel importante en la inducción de cambios a nivel de la plasticidad neuronal y de la neurogénesis en el hipocampo adulto. A este respecto se ha observado que los estrógenos regulan el desarrollo, la maduración y la sobrevivencia de las nuevas neuronas en el cerebro adulto, de la misma manera que lo hacen los tratamientos antidepresivos. Los efectos de los estrógenos sobre la neurogénesis y la plasticidad neuronal podrían estar regulados por los receptores a estrógenos, tanto el receptor alfa (REα), como el receptor beta (REβ). Ambos subtipos de receptores se expresan en el hipocampo del cerebro adulto. Así mismo, el hipocampo es una estructura que participa en procesos cognitivos y de memoria y existe evidencia que muestra su participación en la etiología de la depresión y sobre el efecto de los fármacos antidepresivos. La neurogénesis ha sido considerada como un proceso dinámico por medio del cual se forman neuronas funcionales. De tal modo que este proceso también involucra los eventos de sobrevivencia, maduración dendrítica y axonal, así como el establecimiento de conexiones sinápticas para la integración final de las nuevas neuronas en los circuitos neuronales existentes, eventos que son modulados por los fármacos antidepresivos. En el presente artículo se revisa información reciente acerca de los efectos de los estrógenos sobre la depresión y sobre su relación con la neurogénesis hipocámpica.

Los fármacos antidepresivos como reguladores de la neurogénesis hipocámpica de roedores y humanos adultos / Regulation of rodent and human adult hippocampal neurogenesis by antidepressant drugs

New neuron formation in the adult brain extends our knowledge and incorporates a novel dimension about brain plasticity. Adult neurogenesis is a complex process regulated by different factors within the niche, where adult neural stem cells reside, proliferate and differentiate. Neural stem cell together with astrocytes and endothelial cells form the principle components of this complex niche. Other molecular factors that regulate adult neurogenesis are the neuro-transmitters (GABA, glutamate, serotonin, dopamine); hormones (prolactin, growth hormone, estrogens and melatonin); growth factors (FGF, EGF, VEGF) and neurotrophins (BDNF, NT3). All of them regulate different aspects of the neurogenic process. Behavioral regulators that influence new neuron formation in the adult brain include physical activity, complex stimulatory environment best known as enrichment environment, and social interaction. Voluntary physical activity with free access to the running wheel increases the number of proliferating cells, while the complex stimulatory environment provided by enriched environment preferentially influences survival of newborn cells. In addition, social interaction has a positive influence on the new neuron formation in the dentate gyrus (DG). Although adult hippocampal neurogenesis is positively regulated by the aforementioned factors, there are different conditions with negative influence on this process. Some of these conditions are stress exposure and sleep deprivation. Both conditions are present in neuropsychiatric diseases such as depression, anxiety and schizophrenia. Thus, stress and sleep deprivation impair adult hippocampal neurogenesis. Alteration of the neurogenic process following stress occurs due to the high levels of glucocorticoid receptors within the hippocampus and because exposure to stress causes the increase in glucocorticoid levels. Preclinical studies have shown that exposure to different classes of stressors affect hippocampal neurogenesis. Prolonged exposure to stressors (chronic mild stress), predatory odor, foot shock, acute force swimming and psychosocial stress not only affect mature neuronal plasticity but also hippocampal neurogenesis. Although there is information about the effects of stress on adult neurogenesis, the mechanism by which stress causes inhibition of hippocampal neurogenesis remains unclear. Recent work showed that exposure to stress increases the pro-inflammatory cytokine interleukin-1 β (IL-1 β) in several brain areas. Also, administration of IL-1β exerts stress-like effects including down-regulation of hippocampal brain derived neurotrophic factor (BDNF). Additionally, inhibition of the receptor for IL-1β prevents stress-like effects. Moreover, the suppression of cell proliferation is mediated by direct actions of IL-1 β on IL-1RI receptors localized on precursor cells. These findings support that IL-1 β is a critical mediator of the antineurogenic effect caused by acute and chronic stress. However, IL-1 β is not the unique mediator of stress that could be involved in the alteration of adult hippocampal neurogenesis. Recently it was reported that the decrease in cell proliferation concomitantly occurs with an increase of IL6 and TNFα levels. Preclinical studies have suggested that adult hippocampal neurogenesis is not a sole cause of depression or the sole mechanism of treatment efficacy, but it is likely an important contributor to this complex disorder. In order to revert the effects of stress on adult hippocampal neurogenesis, different therapies have been used, for example: electroconvulsive therapy (ECT), exercise, complex stimulatory environment and antidepressant drugs. Although the most rapid induction of neurogenesis is seen with ECT application, most studies have been done with antidepressant drugs. The effects of antidepressants are time-dependent as highest therapeutic effects are observed within the time course of weeks. Different types of antidepressants (serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors and atypical antidepressants) have been used to study their influence on the neurogenic process. Despite that serotonin reuptake inhibitors are the most prescribed treatments for major depression and that the therapeutic effects of antidepressants require chronic treatment, the mechanisms by which these drugs exert their effects on hippocampal neurogenesis are still unknown. Although serotonin reuptake inhibitors are very fast in increasing serotonin levels, the antidepressant action is delayed possibly because of the induction of structural or functional changes that possibly need longer time (2-4 weeks). In this regard, one of the actions of antidepressants is the regulation of adult hippocampal neurogenesis, a process that is consistent with the delayed onset of therapeutic effects of antidepressants. Fluoxetine is one of the antidepressants more used to study its influence on adult neurogenesis. Fluoxetine targets amplifying neural progenitors by increasing the rate of symmetric divisions without altering the division of stem-like cells in the DG. Considering previous classification based on the temporal protein markers expression, the neural progenitors targeted by fluoxetine correspond to type 2a, 2b and type 3. In addition, the increase in new neurons caused by fluoxetine is due to the expansion of neural progenitors. In addition to cell proliferation, the neurogenic process also involves a maturation step, which is associated with the expression of doublecortin, a protein that binds to microtubules and that is expressed along the cytoplasm of the cell. Further maturation of immature neurons such as dendrite maturation, is controlled independently of the regulation of precursor cell proliferation. Thus, micro-regulatory events influence the course of adult hippocampal neurogenesis. Here, fluoxetine also affects dendrite maturation and functional integration of new neurons. Chronic fluoxetine treatment modifies dendrite morphology increasing dendrite arborisation and favors synaptic plasticity of newborn granule cells. Also, chronic administration of fluoxetine causes behavioral improvement, an effect that was blocked when neurogenesis was ablated by X-ray irradiation. Other important factor that influences the effect of antidepressants on adult neurogenesis is the genetic background. Then antidepressants induced behavioral improvement depending on the genetic background of the mouse strain used. Preclinical studies in mice have revealed different actions of antidepressants on adult hippocampal neurogenesis. However, studies in humans are scarce and deserve greater attention to discover the correlation between preclinical and clinical studies. Recent work in human brains shows contradictory evidences about the regulation of neuronal development by antidepressants. These evidences are in the same line as recent published work in which it was demonstrated that the effects of ADs are age-dependent. Altogether, multiple evidences indicate that antidepressants affect several aspects of the neurogenic process. Therefore, chronic treatment is necessary for the antidepressant-dependent regulation of adult hippocampal neurogenesis. In addition, it has been shown that antidepressants act through different pathways involving both neurogenesis-dependent and neurogenesis-independent actions. Although there is an important increase in the adult hippocampal neurogenesis field, it is necessary to increase the number of studies performed in human beings to correlate the preclinical findings with clinical studies to address the role of adult neurogenesis in neuropsychiatric disorders.

El hallazgo de la formación de nuevas neuronas en el giro dentado (GD) del hipocampo amplió el conocimiento acerca de la plasticidad del encéfalo. En este sentido, la neurogénesis es un proceso que involucra diferentes eventos celulares tales como: la división de las células madre, la proliferación de los neuroblastos, la migración y la sobrevivencia celular, así como la maduración dendrítica, la elongación axonal y la integración de las neuronas nuevas a los circuitos neuronales existentes. En conjunto, todas estas etapas causan cambios estructurales y funcionales en el cerebro. Por lo tanto, la formación de neuronas es un proceso regulado de manera fina por diferentes factores entre los que se incluyen: el nicho; algunos neurotransmisores como la serotonina, la dopamina, el glutamato y el GABA; factores de crecimiento como el factor de crecimiento de fibroblastos, el factor de crecimiento epidermal y el factor de crecimiento vascular endotelial (FGF, EGF y VEGF, por sus siglas en inglés); neurotrofinas como el factor neurotrópico derivado del cerebro y por la neurotrofina 3 (BDNF y NT3, por sus siglas en inglés). Aunado a la existencia de factores que favorecen la neurogénesis hipocámpica, también hay factores que influyen de manera negativa en la formación de neuronas. Entre éstos se encuentra el estrés, el cual se relaciona con algunas enfermedades neuropsiquiátricas como la depresión y la ansiedad. A este respecto, estudios preclínicos han revelado que la aplicación de diferentes tipos de estresores puede afectar la plasticidad neuronal al inducir alteraciones morfológicas y funcionales en el hipocampo, así como afectar el proceso neurogénico. Las alteraciones causadas por el estrés se han relacionado con un aumento considerable y sostenido de los niveles de glucocorticoides. Esto último afecta el proceso neurogénico debido a que el hipocampo es una estructura cerebral que expresa niveles altos de receptores para estas hormonas. Al ser activados de forma persistente, los receptores a glucocorticoides causan una alteración en la neuroplasticidad hipocámpica. De tal modo y considerando lo anterior, teorías recientes han asociado un fallo en la formación de neuronas en el hipocampo con algunos trastornos psiquiátricos como la demencia, la esquizofrenia y la depresión. No esta del todo elucidado el mecanismo a través del cual el estrés altera el proceso neurogénico. Sin embargo, trabajos recientes han revelado que la exposición a estrés causa un aumento en los niveles de ciertas citocinas proinflamatorias, tales como la interleucina-1 β (IL-1 β). El aumento en los niveles de esta citocina provoca un efecto tipo depresivo y una disminución en los niveles del BDNF, así como una alteración en la formación de nuevas neuronas. Estos hallazgos apoyan la idea de que la IL-1 β es un mediador crítico del efecto antineurogénico causado por el estrés crónico y agudo. Sin embargo, la IL-1 β no es la única citocina asociada con las alteraciones en el proceso neurogénico, ya que recientemente se reportó que la disminución en la proliferación celular causada por el estrés ocurre de manera paralela con el aumento en la expresión de los mensajeros de la IL-6 y del TNF-α. Una manera de contrarrestar los efectos del estrés sobre la plasticidad neuronal es a través de la administración de fármacos antidepresivos. Diversos trabajos han mostrado que el tratamiento crónico con este tipo de fármacos revierte las alteraciones en la neurogénesis hipocámpica y en la plasticidad neuronal causadas por el estrés. Finalmente, aun cuando existen evidencias del papel que desempeña la neurogénesis en modelos animales de algunas enfermedades neuropsiquiátricas y de la forma en que los fármacos antidepresivos favorecen la formación de neuronas, es importante contar con más estudios en humanos que permitan corroborar los hallazgos que se han obtenido en los estudios preclínicos. De algún modo todos los reportes apuntan a que los fármacos antidepresivos pueden actuar por mecanismos independientes o dependientes de la neurogénesis hipocámpica.

Control of neuronal migration through rostral migration stream in mice / 대한해부학회지

During the nervous system development, immature neuroblasts have a strong potential to migrate toward their destination. In the adult brain, new neurons are continuously generated in the neurogenic niche located near the ventricle, and the newly generated cells actively migrate toward their destination, olfactory bulb, via highly specialized migratory route called rostral migratory stream (RMS). Neuroblasts in the RMS form chains by their homophilic interactions, and the neuroblasts in chains continually migrate through the tunnels formed by meshwork of astrocytes, glial tube. This review focuses on the development and structure of RMS and the regulation of neuroblast migration in the RMS. Better understanding of RMS migration may be crucial for improving functional replacement therapy by supplying endogenous neuronal cells to the injury sites more efficiently.

Effects of 6-hydroxydopamine on the Adult Neurogenesis of Dopaminergic Neurons in the Mouse Midbrain

Recently, restricted progenitor cells have been identified in the substantia nigra (SN) of the rat and mouse, raising a hope that resident stem/progenitor cells may be useful for the therapy of Parkinson's disease. However, it is controversial whether dopamine (DA) neurons can be spontaneously or injury-dependently generated from the endogenous stem cells in the adult brain. Here, we explored the neurogenesis in C57Bl/6 adult mice under the normal and neurotoxin-injured conditions. To monitor adult neurogenesis, we injected 5-bromodeoxyuridine (BrdU) 2 weeks after striatal injection of neurotoxin 6-hydroxydopamine (6-OHDA), and sacrificed the animals 6 weeks after 6-OHDA injection. Whereas the number of BrdU-labeled cells was slightly increased in ipsilateral side than contralateral side of the midbrain, none of BrdU- labeled cells, however, exhibited neuronal markers, NeuN or DCX. Instead, BrdU- labeled cells expressed glial markers such as GFAP (astrocyte), Olig2 (oligodendrocyte) and Iba-1 (microglia). Especially, larger portion of BrdU-labeled cells in the ipsilateral side exhibited microglial marker, indicating that increased cell production in response to the 6-OHDA injection is not related to the adult neurogenesis.

Neurogênese no cérebro adulto e na condição epiléptica: [revisão] / Neurogenesis in the adult brain and in epileptic condition: [review]

INTRODUÇÃO: Relatos sobre a possibilidade de neurogênese no cérebro de mamíferos adultos existem desde o início do século XX. A dificuldade na verificação de tal evento, somada à firme convicção da maioria dos pesquisadores da época sobre a impossibilidade do nascimento de neurônios no sistema nervoso adulto, resultou em expressiva demora no avanço do conhecimento nesta área. O desenvolvimento de técnicas refinadas de estudo celular e a observação comprovada de neurogênese no cérebro de vertebrados adultos como o de pássaros canoros e roedores, serviu como importante alavanca para a desmistificação da impossibilidade de nascimento de neurônios no cérebro adulto. RESULTADOS: A descoberta da neurogênese em áreas específicas do cérebro adulto tem fomentado avanços em diversas áreas da pesquisa médica. No contexto de alterações neurológicas temos a constatação de neurogênese reativa no hipocampo de modelos animais de epilepsia do lobo temporal, logo após um episódio de estado de mal epiléptico. Diferenças filogenéticas entre roedores e humanos provavelmente existem, visto que há evidências de diminuição da neurogênese em crianças com epilepsia grave. A neurogênese pode estar também alterada frente ao uso de drogas, como parece ocorrer no tratamento com antidepressivos. CONCLUSÃO: O entendimento cada vez maior da neurogênese no cérebro adulto pode significar uma revolução no conceito da plasticidade do cérebro de um mamífero adulto, além de ter grande importância para o desenvolvimento de estratégias terapêuticas no tratamento de doenças neurodegenerativas e na possibilidade de promover a recuperação funcional de áreas lesadas do sistema nervoso central.

INTRODUCTION: Since the early XX century, there have been numerous reports considering the possibility of neurogenesis in the adult mammalian brain. However, it took 30 years before the widespread skepticism and the technical limitations were overcome. Refined cell technique developments and clear-cut evidences of neurogenesis in avian and rodent brains boosted additional research and counteracted the "no-new-neuron-in-the-adult-brain" myth. Now, the debate has focused on its importance to existing neural circuits, which promises interesting perspectives in medical research. RESULTS: Reactive neurogenesis in the hippocampus occurs in different experimental models of temporal lobe epilepsy, among them those that present spontaneous limbic seizures after an episode of status epilepticus. Phylogenetic differences between rodents and humans probably exist, since it has been described a reduction of neurogenesis in children with severe epilepsy. Neurogenesis may also be altered in many other conditions including chronic antidepressant drug treatment. CONCLUSION: Therefore, understanding the mechanisms and functional implications of adult neurogenesis in different brain regions can shed light into how such neuronal plasticity can help in the treatment of neurological disorders. In particular, cell therapy is a promising approach in the biomedical field that will possibly have great impact in the treatment of neurodegenerative diseases, as well as in the functional recovery of brain injuries.