RESUMEN
Adult hippocampal neural stem cells can be activated by hippocampal neural activities. When focal cerebral ischemia, known as middle cerebral artery occlusion (MCAO), occurs, neural stem cells are activated to promote their proliferation. However, the mechanism by which these cells are activated is still unclear. Here, we indicate the involvement of metabotropic glutamate receptor 5 (mGluR5) signaling in neural stem cells in their activity-related proliferation after MCAO. We found mGluR5 molecules on neural stem cells by using calcium imaging. We detected the activation of neural stem cells by adding the mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine. On a hippocampal slice, the activation of neural stem cells to promote their proliferation was initiated by theta-burst electrical stimulation at the perforant pathway, and this activation was significantly blocked by an mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP). In addition to this, the injection of the blood-brain barrier-permeable mGluR5 agonist 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide into live mice promoted the proliferation of neural stem cells. Moreover, in vivo theta-burst electrical stimulation induced proliferation of neural stem cells. A chronic field recording study showed that the activity of the hippocampal formation was elevated after MCAO. Finally, we observed that the mGluR5 antagonist MPEP significantly blocked the stimulated proliferation of neural stem cells induced by MCAO, by blocking mGluR5 signaling. Our results suggest that glutamates released by the elevated neural activities after MCAO may trigger mGluR5 signaling in neural stem cells to promote their proliferation.
Asunto(s)
Proliferación Celular , Hipocampo/crecimiento & desarrollo , Células-Madre Neurales/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Transducción de Señal , Ritmo Teta , Células Madre Adultas/citología , Células Madre Adultas/metabolismo , Animales , Benzamidas/farmacología , Señalización del Calcio , Estimulación Eléctrica , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Hipocampo/irrigación sanguínea , Hipocampo/patología , Infarto de la Arteria Cerebral Media/patología , Ratones , Ratones Endogámicos ICR , Células-Madre Neurales/citología , Fenilacetatos/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inhibidoresRESUMEN
In this study, diffusion tensor MRI was used to examine the restoration of the cerebral white matter of macaque monkeys after unilateral cerebral multiple microinfarctions. Post-stroke, the monkeys showed deficits in several neurological functions, including motor functions, but most of the deficits resolved within 6 weeks. Very interestingly, the fractional anisotropy (a value determined by diffusion tensor MRI), of the monkeys' affected motor pathways dropped transiently, indicating a damage in the neural tracts. However, it returned to normal levels within 6 weeks after the stroke, concomitant with the gradual recovery of motor functions at subacute phase.
Asunto(s)
Corteza Cerebral/fisiopatología , Ataque Isquémico Transitorio/fisiopatología , Accidente Cerebrovascular/fisiopatología , Animales , Infarto Encefálico/etiología , Infarto Encefálico/patología , Infarto Encefálico/fisiopatología , Imagen de Difusión por Resonancia Magnética , Vías Eferentes , Ataque Isquémico Transitorio/complicaciones , Ataque Isquémico Transitorio/patología , Macaca fascicularis , Masculino , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/patologíaRESUMEN
Lacunar-type stroke accounts for approximately a quarter of all ischemic strokes, and is the most common cause of vascular dementia. Despite its importance, there are few specific treatments for lacunar stroke, probably due largely to a lack of animal models. In this study, we developed a stroke model in a higher primate, the Macaque monkey. This was achieved by occluding the deep subcortical penetrating arteries with agarose spheres of mean diameters around 50 microm, and the appropriateness of this model as a lacunar-type stroke was verified by MRI. We observed widespread gliosis in the ipsilateral white matter (WM) of the stroke monkey. We also analyzed the expression of neurotrophins in the activated glial cells, and found that their expression of BDNF was stimulated in the affected WM following ischemic injury. Our results support the idea that WM glial cells play an active role in protecting and promoting the regeneration of nerve fibers in the affected WM of the ischemic brain, by producing BDNF. These findings may be useful for the development of new therapeutic strategies aimed at preventing or treating stroke.