Publication: Neurogénesis hipocampal adulta: papel en el deterioro cognitivo post-ictus y estrategias farmacológicas para su modulación
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2019-01-31
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Universidad Complutense de Madrid
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Abstract
En los países occidentales, el ictus sigue considerándose como una de las patologías más devastadoras en términos tanto económicos como sociosanitarios. Mientras que la mayoría de los tratamientos se han enfocado en estudiar y promover la recuperación de la función motora, apenas se conocen los mecanismos por los cuales el ictus da lugar a pérdidas de la función cognitiva a largo plazo. Para entender la fisiopatología de estos déficits, decidimos explorar las alteraciones cognitivas que se producen en un modelo experimental de isquemia cerebral mediante la oclusión permanente de la arteria cerebral media(pMCAO).Con este modelo experimental, pusimos de manifiesto que la isquemia cerebral produce un deterioro cognitivo a largo plazo en las memorias dependientes de hipocampo, tanto de tipo contextual como espacial, y que estos déficits se debían a una alteración en el patrón específico de activación neuronal en la formación hipocampal. Como se ha comentado, los déficits cognitivos que hemos encontrado son dependientes del hipocampo, una de las principales estructuras cerebrales implicadas en procesos de memoria y aprendizaje. En nuestro modelo experimental, a pesar que el daño tisular que se produce es exclusivamente a nivel cortical, la isquemia cerebral, produce un engrosamiento de la capa granular del giro dentado hipocampal que se correlaciona con un mayor deterioro cognitivo.Puesto que dicha región es conocida por ser una de las regiones neurogénicas principales en el cerebro de mamíferos adultos, estudiamos si la neurogénesis estaba participando en este proceso. Mediante un estudio temporal demostramos que, en efecto, el ictus potencia una respuesta neurogénica hipocampal bilateral sostenida durante al menos un mes, que da lugar a nuevas neuronas integradas en los circuitos hipocampales. Sorprendentemente, la respuesta neurogénica paralela al mayor volumen de la capa granular, se correlacionó con un mayor déficit de memoria...
Ischemic stroke is considered one of the most devastating pathologies in both economic and sanitary terms in western countries. Most of the therapies and studies have been focused on the recovery of locomotor impairments. However the mechanisms underlying cognitive deficits after ischemic stroke are still unknown so far. To understand the physiophathology of those mechanisms, we decided to explore the cognitive deficits produced by the permanent oclussion of the middle cerebral artery (pMCAO) in mice. First, in our experimental model we have demonstrated that ischemic stroke produces an hippocampal-dependent long term cognitive decline, specifically regarding contextual and spatial memories. Those deficits were not due to a hippocampal activation inhibition, but to a specific neuronal activation pattern alteration throughout the hippocampus. As previously mentioned, memories affected were dependent on hippocampus, one of the main brain structures involved in learning and memory. Even thought the damage caused is limited to the somatosensory cortex, our model also produces an increased granular cell layer volume in the hippocampal dentategyrus, which correlates with the cognitive decline. Given that this structure is one of the main neurogenic regions in the adult mammal brain, we reasoned that neurogenesis could be involved in this process. By performing a longitudinal study, we demonstrate that stroke produces a bilateral hippocampal neurogenesis burst lasting at least one month that promotes the generation of new fully mature and integrated neurons in the hippocampal circuits. This neurogenesis burst that is parallel to the increased granular cell volume observed, strikingly correlated with the memory loss. Since neurogenesis enhancement by physical activity or memantine treatment worsened the cognitive deficits, our data suggest that stroke-inducedn eurogenesis is a major contributor to post-stroke cognitive decline...
Ischemic stroke is considered one of the most devastating pathologies in both economic and sanitary terms in western countries. Most of the therapies and studies have been focused on the recovery of locomotor impairments. However the mechanisms underlying cognitive deficits after ischemic stroke are still unknown so far. To understand the physiophathology of those mechanisms, we decided to explore the cognitive deficits produced by the permanent oclussion of the middle cerebral artery (pMCAO) in mice. First, in our experimental model we have demonstrated that ischemic stroke produces an hippocampal-dependent long term cognitive decline, specifically regarding contextual and spatial memories. Those deficits were not due to a hippocampal activation inhibition, but to a specific neuronal activation pattern alteration throughout the hippocampus. As previously mentioned, memories affected were dependent on hippocampus, one of the main brain structures involved in learning and memory. Even thought the damage caused is limited to the somatosensory cortex, our model also produces an increased granular cell layer volume in the hippocampal dentategyrus, which correlates with the cognitive decline. Given that this structure is one of the main neurogenic regions in the adult mammal brain, we reasoned that neurogenesis could be involved in this process. By performing a longitudinal study, we demonstrate that stroke produces a bilateral hippocampal neurogenesis burst lasting at least one month that promotes the generation of new fully mature and integrated neurons in the hippocampal circuits. This neurogenesis burst that is parallel to the increased granular cell volume observed, strikingly correlated with the memory loss. Since neurogenesis enhancement by physical activity or memantine treatment worsened the cognitive deficits, our data suggest that stroke-inducedn eurogenesis is a major contributor to post-stroke cognitive decline...
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Tesis de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Farmacología y Toxicología, leída el 28-07-2018