RESUMEN:

El hallazgo de la formación de neuronas nuevas revolucionó el concepto de que el cerebro era el único órgano incapaz de regenerarse y, por lo tanto, que era estático. Este concepto implica que el cerebro es un órgano plástico que responde a diversos factores, los cuales pueden influir positiva o negativamente en la formación de neuronas nuevas, las cuales a su vez pueden generar un efecto benéfico para el cerebro. Desde 1966 se encontraron evidencias que apoyaban la formación de neuronas nuevas en el cerebro. Veinte años después, los estudios continuaron para confirmar esos primeros hallazgos. Desde entonces se sabe que existen dos regiones en el cerebro adulto donde se lleva a cabo la formación de neuronas nuevas: el bulbo olfatorio y el hipocampo. Estas neuronas nuevas derivan de las células pluripotenciales residentes en la zona subventricular de los ventrículos laterales y en la zona subgranular del giro dentado, respectivamente. Estas dos regiones del cerebro presentan características importantes que permiten que se lleve a cabo el proceso de formación de neuronas nuevas llamado neurogénesis.

La neurogénesis es un proceso complejo que involucra diversas etapas, como la proliferación de las células pluripotenciales, la migración, la diferenciación, la sobrevivencia de las neuronas nuevas, así como la integración de éstas en los circuitos neuronales existentes. Los cambios morfológicos de las células que participan en el proceso de la neurogénesis han permitido identificar diversas características dependiendo de los marcadores proteicos expresados temporalmente. Estos marcadores pueden ser proteínas estructurales como los componentes del citoesqueleto (microtúbulos, microfilamentos y filamentos intermedios), proteínas asociadas a dichos componentes o factores de transcripción.

Las células pluripotenciales presentan características de la glía radial, que expresan el marcador conocido como proteína fibrilar acídica de la glía (GFAP, por sus siglas en inglés), así como el marcador para células no diferenciadas que es la nestina. Los diferentes estadios de desarrollo de las células durante el proceso de formación de neuronas nuevas han sido caracterizados en ambas regiones que presentan neurogénesis constitutiva. En la zona subgranular del giro dentado, las células pluripotenciales expresan nestina, la proteína de unión a lípidos del cerebro (BLBP, en inglés) y GFAP. Esta población celular se caracteriza por tener una baja tasa de división celular. Una vez que estas células se dividen, dan lugar a una población que se amplifica rápidamente, de la cual se generan por división simétrica las células progenitoras de tipo 2 y 3. Las células progenitoras tipo 2a y 2b presentan procesos neuríticos cortos paralelos a la zona granular del giro dentado; en cambio, las de tipo 3 presentan procesos largos integrados en la capa granular. Durante esta etapa se inician los eventos de migración y de diferenciación temprana, y las células expresan la proteína asociada a microtúbulos doblecortina, el factor de transcripción “Prox1” y la proteína nuclear neuronal específica “NeuN”. Una vez que las células salen del ciclo celular, se generan las neuronas inmaduras caracterizadas por procesos dendríticos largos que cruzan la capa granular del giro dentado. Estas neuronas inmaduras van a diferenciarse en su totalidad para integrarse en los circuitos neuronales. En este estadio final, las nuevas neuronas expresan marcadores específicos, como la proteína de unión a calcio llamada calbindina, así como propiedades electrofisiológicas similares a las neuronas viejas.

La formación de neuronas nuevas está modulada finamente para evitar una alteración de los circuitos neuronales. El nicho es uno de los factores que intervienen en la regulación de la neurogénesis. Está constituido por las células pluripotenciales, los astrocitos y las células endoteliales. Los tres componentes del nicho trabajan en sincronía: 1. para mantener la población de células pluripotenciales; 2. los astrocitos modulan la proliferación de las células pluripotenciales y de las células que amplifican rápidamente, así como la migración de estas células a través de la acción de diversos factores secretados por los astrocitos, y 3. para mantener la población de astrocitos y de células endoteliales.

Otros factores involucrados en la formación de neuronas nuevas son los neurotransmisores (GABA, glutamato, serotonina, dopamina), las hormonas (la prolactina y la hormona de crecimiento), los factores de crecimiento (factor de crecimiento de fibroblastos, siglas en inglés: FGF; factor de crecimiento epidermal, siglas en inglés: EGF), las neurotrofinas (factor derivado de cerebro, siglas en inglés: BDNF); neurotrofina 3, siglas en inglés: NT3). Se ha demostrado que hay factores sociales que también pueden modular el proceso de la neurogénesis, como la actividad física, el ambiente enriquecido y la interacción social.

Aun cuando la formación de neuronas nuevas es influida positivamente por los factores antes mencionados, este proceso puede ser modulado de forma negativa por factores como el estrés psicológico. Este disminuye la formación de neuronas nuevas, o bien en las enfermedades psiquiátricas tales como la depresión, suceso que es revertido con el uso de fármacos antidepresivos. Recientemente, se describió que la falta de sueño afecta negativamente la formación de neuronas nuevas. Efecto similar surten las drogas de abuso. Además, existe información sobre lo que sucede en las enfermedades neurodegenerativas en relación con la formación de nuevas neuronas.

En esta revisión se mencionan los diferentes aspectos del proceso de formación de neuronas nuevas, así como los factores que lo modulan de forma positiva o negativa. Asimismo, revisaremos algunas evidencias en que se ha reportado que la neurogénesis disminuye en la depresión y en las enfermedades neurodegenerativas. Finalmente se hace una breve mención de la posible función de estas nuevas neuronas en el hipocampo y su relación con los procesos de aprendizaje y memoria.

Palabras clave: Hipocampo; neurogénesis; células pluripotenciales; depresión; neurodegeneración

SUMMARY

New neuron formation in the adult brain was an interesting finding that extended the knowledge about brain plasticity. In 1966 Joseph Altman reported the incorporation of tritiated thymidine to neural cell DNA. This finding indicated the proliferation event in the adult brain. After twenty years of this finding, new information was generated that confirmed the new neuron formation in the adulthood.

In this review, we will mention different aspects of the new neuron formation process called neurogenesis, as well as some of the factors that modulate such process, citing the information already known about the neuronal development stages that take place for the new neuron formation in the hippocampus. Finally, we will review some evidence about the neurogenic process in depression and in neurodegenerative diseases, as well as the possible role of the new neurons when they are integrated into the neuronal network.

In the adult brain there are two regions where new neuron formation process takes place: the olfactory bulb and the hippocampus. New neurons are derived from neural stem cells, which reside in the subventricular zone of the lateral ventricles and in the subgranular zone of the dentate gyrus. Neural stem cells may proliferate and generate the rapid amplifying progenitor and neuroblast populations. These populations will migrate and differentiate in neurons to finally be integrated into the neuronal network.

In the adult brain, neural stem cells have radial glial features expressing specific markers as the glial fibrilar acidic protein (GFAP), as well as the un-differentiated cell marker nestin. This characteristic makes suitable neural stem cells identification. Thus, the new neurons can be identified by both the specific marker expression and by electrophysiological properties. The different cell development stages during the neurogenic process have been characterized in the subventricular zone as well as in the subgranular zone of the dentate gyrus. In addition to the radial-glia features, neural stem cells show a slowly dividing ratio and once the neural stem cells divide by asymmetric division a rapid amplifying progenitor population is generated. In the hippocampus, phenotype analysis had allowed cell classification in three different types according to the kind of protein marker expression. These progenitors are generated during the expansion phase by symmetric cell division. Type 2a and 2b present short neuritic processes parallel to the granular cell layer and the Type 3 present longer processes integrated into the granular cell layer. During this step, where the migration and cell fate decision take place, the cells express different markers as the microtubule associated protein doublecortin, the homeobox gene related to the Drosophila gene prospero Prox-1 and the neuron-specific nuclear protein Neu-N. Once the cells exit the cell cycle, immature neurons are generated showing longer dendritic processes crossing the granular cell layer. These immature neurons will fully differentiate to be integrated into the neuronal network. At this final stage the cells are fully differentiated and the new neurons express specific markers as the calcium binding protein calbindin and their electrophysiological properties are similar to the old neurons.

Neurogenesis is a complex process that is modulated and regulated by different factors. One of these is the niche which is formed by the neural stem cells, astrocytes and endothelial cells. Adult neural stem cells proliferate and differentiate depending on the cellular and molecular composition of the niche. The three components work in synchrony in both neurogenic areas with active proliferation. The role of the niche is the maintenance of the stem cells pool. The astrocytes modulate the proliferation of the neural stem cell and of the rapid amplifying cell population, as well as the migration of these cells by the action of the secreting factors. The niche also plays a key role in maintaining the astrocytic and the endothelial cell populations.

Besides the niche, other factors are involved in the neurogenic process, such as the neurotransmitters (GABA, glutamate, serotonin, dopamine), hormones (prolactin, growth hormone), growth factors (FGF, EGF) and neurotrophins (BDNF, NT3). All of them modulate different steps of the process. Some other factors that influence the new neuron formation include the physical activity, enrichment environment and social interaction. It has been shown that physical activity increases the number of surviving newborn cells when rodents have free access to the running wheel. Another positive regulator of the neurogenic process is the enrichment environment. The influence of this factor on the new neuron formation was demonstrated when the animals were maintained in a cage with tunnels and toys. In addition, when the rodents were forced to learn a particular task, more new neurons were found in the dentate gyrus. Additionally, the social interaction has a positive influence on the new neuron formation.

Even when neurogenesis is positively regulated by the afore mentioned factors, different conditions and factors have a negative influence on this process. It is known that psychological stress affects in a negative manner the neurogenic process. The stress decreases the proliferation of progenitor cells in the dentate gyrus. This negative effect involves glucocorticoids whose increased levels inhibit the new neuron formation. Also, an exogenous administered corticosterone suppresses the new neuron formation. Another negative factor on neurogenesis related to glucocorticoids, is the sleep deprivation, which impairs the neurogenic process by increasing corticosterone levels causing a reduction in cell proliferation. Also, the abuse drugs cause a negative effect in the new neuron formation. It is known that chronic alcoholism negatively impact neurogenesis as well as cocaine, drug that impairs the proliferation dynamics in the dentate gyrus.

Psychiatric disorders, such as depression, have been associated with an impaired neurogenesis, which is reverted by antidepressant drugs. In contrast to the effects of stress, an antidepressant pharmacologic treatment increases the new neuron formation. The antidepressant effect is dependent on chronic treatment, consistent with the time course of the therapeutic action of these compounds. Recently, it has been shown that fluoxetine increases symmetric divisions of early progenitor cells and that these cells called or named neuronal progenitors targeted by fluoxetine in the adult brain.

This report describes one mechanism for antidepressant; however, the mechanisms by which antidepressant drugs act is not known at all and can be complex. Nevertheless, it has been reported that antidepressants induce an increase in serotonin or norephinephrine levels which activate the corresponding receptors and their downstream signaling pathways. One of these signaling pathways is the cAMP-CREB cascade. This second messenger is upregulated in the hippocampus together with the activity of the cAMP-dependent protein kinase. On the same pathway, the cAMP response element binding protein (CREB) shows an increase in function and expression.

In patients with neurodegeneration, a defect in the neurogenesis process has been described. In Alzheimer’s disease, cell proliferation and the potential regenerative factors levels are diminished. However, several studies have revealed an increase in the expression of the neurogenic marker doublecortin. Recently, it has been reported the presence of proliferative cells in presenile Alzheimer hippocampus without indications for altered dentate gyrus. In addition to this finding, the influence of the enrichment environment on the new neuron formation has been explored. In these studies, it was shown that rodents housed under enrichment conditions had an increased neurotrophin 3 (NT-3) and brain derived neurotrophic factor, as well as an increased hippocampal neurogenesis accomplished with the improvement in the water maze performance. In another study, described by Lazarov in 2005, the enrichment environment leads a reduction in the levels of cerebral beta-amyloid and an increase in the genes associated with learning-memory, neurogenesis and cell survival pathways. In amyotrophic lateral sclerosis that is characterized by motor neuron degeneration the new neuron formation is impaired. By using mutant mice for the superoxide dismutase-1 enzyme, an enzyme that is altered in amyotrophic lateral sclerosis and with the precursor cells isolated from the subventricular zone of the this mutants there is a reduction in the incorporation of the DNA synthesis marker bromodeoxyuridine(BrdU), and in the response to mitogen stimulation, in presymptomatic and symptomatic mice, respectively.

Evidence obtained so far strongly suggest that neural stem cells manipulation can be a good possibility to induce the neuron replacement in the treatment of neurodegenerative and psychiatric illnesses. However it is necessary to go deeply in the mechanisms and signaling pathways involved in the neurogenesis processes.

Key words: Hippocampus; neurogenesis; stem cells; depression; neurodegeneration