ABSTRACT
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.