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Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.
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Trifosfato de Adenosina/metabolismo , Epilepsia do Lobo Temporal/fisiopatologia , Microglia/patologia , Neurônios/metabolismo , Fagocitose/fisiologia , Adulto , Animais , Apoptose/fisiologia , Receptor 1 de Quimiocina CX3C , Humanos , Ácido Caínico/toxicidade , Antígenos Comuns de Leucócito/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Monócitos/patologia , Neurônios/patologia , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Convulsões/induzido quimicamente , Convulsões/fisiopatologiaRESUMO
[This corrects the article DOI: 10.1371/journal.pbio.1002466.].
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[This corrects the article DOI: 10.1371/journal.pbio.1002466.].
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Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory.
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Hipocampo/crescimento & desenvolvimento , Vigilância Imunológica/fisiologia , Inflamação/fisiopatologia , Microglia/fisiologia , Neurogênese/fisiologia , Fagocitose/fisiologia , Envelhecimento/imunologia , Envelhecimento/fisiologia , Animais , Hipocampo/citologia , Hipocampo/fisiologia , Humanos , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Neurogênese/imunologia , Estresse PsicológicoRESUMO
Recruitment of stem cells is crucial for tissue repair. Although stem cell niches can provide important signals, little is known about mechanisms that coordinate the engagement of disseminated stem cells across an injured tissue. In Drosophila, adult brain lesions trigger local recruitment of scattered dormant neural stem cells suggesting a mechanism for creating a transient stem cell activation zone. Here, we find that injury triggers a coordinated response in neuro-glial clusters that promotes the spread of a neuron-derived stem cell factor via glial secretion of the lipocalin-like transporter Swim. Strikingly, swim is induced in a Hif1-α-dependent manner in response to brain hypoxia. Mammalian Swim (Lcn7) is also upregulated in glia of the mouse hippocampus upon brain injury. Our results identify a central role of neuro-glial clusters in promoting neural stem cell activation at a distance, suggesting a conserved function of the HIF1-α/Swim/Wnt module in connecting injury-sensing and regenerative outcomes.
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Drosophila , Células-Tronco Neurais , Animais , Mamíferos , Camundongos , Neuroglia , Neurônios , Nicho de Células-TroncoRESUMO
Adult tissues undergo continuous cell turnover in response to stress, damage, or physiological demand. New differentiated cells are generated from dedicated or facultative stem cells or from self-renewing differentiated cells. Here we describe a different stem cell strategy for tissue maintenance, distinct from that observed for dedicated or facultative stem cells. We report the presence of nestin-expressing adult stem cells in the perilumenal region of the mature anterior pituitary and, using genetic inducible fate mapping, demonstrate that they serve to generate subsets of all six terminally differentiated endocrine cell types of the pituitary gland. These stem cells, while not playing a significant role in organogenesis, undergo postnatal expansion and start producing differentiated progeny, which colonize the organ that initially entirely consisted of differentiated cells derived from embryonic precursors. This generates a mosaic organ with two phenotypically similar subsets of endocrine cells that have different origins and different life histories. These parallel but distinct lineages of differentiated cells in the gland may help the maturing organism adapt to changes in the metabolic regulatory landscape.
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Células-Tronco Adultas/citologia , Adeno-Hipófise/citologia , Células-Tronco Adultas/metabolismo , Animais , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Proteínas do Tecido Nervoso/metabolismo , Nestina , Neoplasias Hipofisárias/patologiaRESUMO
The mechanisms responsible for determining neural stem cell fate are numerous and complex. To begin to identify the specific components involved in these processes, we generated several mouse neural stem cell (NSC) antibodies against cultured mouse embryonic neurospheres. Our immunohistochemical data showed that the NSC-6 antibody recognized NSCs in the developing and postnatal murine brains as well as in human brain organoids. Mass spectrometry revealed the identity of the NSC-6 epitope as brain abundant, membrane-attached signal protein 1 (BASP1), a signaling protein that plays a key role in neurite outgrowth and plasticity. Western blot analysis using the NSC-6 antibody demonstrated multiple BASP1 isoforms with varying degrees of expression and correlating with distinct developmental stages. Herein, we describe the expression of BASP1 in NSCs in the developing and postnatal mammalian brains and human brain organoids, and demonstrate that the NSC-6 antibody may be a useful marker of these cells.
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Antígenos de Diferenciação/metabolismo , Encéfalo/metabolismo , Proteínas de Ligação a Calmodulina/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese , Nicho de Células-Tronco , Animais , CamundongosRESUMO
Dravet syndrome (DS) is an epileptic syndrome caused by mutations in the Scn1a gene encoding the α1 subunit of the sodium channel Nav1.1, which is associated with febrile seizures that progress to severe tonic-clonic seizures and associated comorbidities. Treatment with cannabidiol has been approved to reduce seizures in DS, but it may also be active against these comorbidities. The aim of this study was to validate a new mouse model of DS having lower mortality than previous models, which may serve to further evaluate therapies for the long-term comorbidities. This new model consists of heterozygous conditional knock-in mice carrying a missense mutation (A1783V) in Scn1a gene expressed exclusively in neurons of the CNS (Syn-Cre/Scn1aWT/A1783V). These mice have been used here to determine the extent and persistence of the behavioral deterioration in different postnatal days (PND), as well as to investigate the alterations that the disease produces in the endocannabinoid system and the contribution of inflammatory events and impaired neurogenesis in the pathology. Syn-Cre/Scn1aWT/A1783V mice showed a strong reduction in hindlimb grasp reflex at PND10, whereas at PND25, they presented spontaneous convulsions and a greater susceptibility to pentylenetetrazole-induced seizures, marked hyperactivity, deficient spatial working memory, lower levels of anxiety, and altered social interaction behavior. These differences disappeared at PND40 and PND60, except the changes in social interaction and anxiety. The analysis of CNS structures associated with these behavioral alterations revealed an elevated glial reactivity in the prefrontal cortex and the dentate gyrus. This was associated in the dentate gyrus with a greater cell proliferation detected with Ki67 immunostaining, whereas double-labeling analyses identified that proliferating cells were GFAP-positive suggesting failed neurogenesis but astrocyte proliferation. The analysis of the endocannabinoid system of Syn-Cre/Scn1aWT/A1783V mice confirmed reductions in CB1 receptors and MAGL and FAAH enzymes, mainly in the cerebellum but also in other areas, whereas CB2 receptors became upregulated in the hippocampus. In conclusion, Syn-Cre/Scn1aWT/A1783V mice showed seizuring susceptibility and several comorbidities (hyperactivity, memory impairment, less anxiety, and altered social behavior), which exhibited a pattern of age expression similar to DS patients. Syn-Cre/Scn1aWT/A1783V mice also exhibited greater glial reactivity and a reactive response in the neurogenic niche, and regional changes in the status of the endocannabinoid signaling, events that could contribute in behavioral impairment.
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Neurogenesis in the adult hippocampus is a highly regulated process that originates from multipotent progenitors in the subgranular zone (SGZ). Currently, little is known about molecular mechanisms that regulate proliferation and differentiation in the SGZ. To study the role of transcription factors (TFs), we focused on Tbr2 (T-box brain gene 2), which has been implicated previously in developmental glutamatergic neurogenesis. In adult mouse hippocampus, Tbr2 protein and Tbr2-GFP (green fluorescent protein) transgene expression were specifically localized to intermediate-stage progenitor cells (IPCs), a type of transit amplifying cells. The Tbr2+ IPCs were highly responsive to neurogenic stimuli, more than doubling after voluntary wheel running. Notably, the Tbr2+ IPCs formed cellular clusters, the average size of which (Tbr2+ cells per cluster) likewise more than doubled in runners. Conversely, Tbr2+ IPCs were selectively depleted by antimitotic drugs, known to suppress neurogenesis. After cessation of antimitotic treatment, recovery of neurogenesis was paralleled by recovery of Tbr2+ IPCs, including a transient rebound above baseline numbers. Finally, Tbr2 was examined in the context of additional TFs that, together, define a TF cascade in embryonic neocortical neurogenesis (Pax6 --> Ngn2 --> Tbr2 --> NeuroD --> Tbr1). Remarkably, the same TF cascade was found to be linked to stages of neuronal lineage progression in adult SGZ. These results suggest that Tbr2+ IPCs play a major role in the regulation of adult hippocampal neurogenesis, and that a similar transcriptional program controls neurogenesis in adult SGZ as in embryonic cerebral cortex.
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Células-Tronco Adultas/fisiologia , Hipocampo/citologia , Neurônios/fisiologia , Proteínas com Domínio T/metabolismo , Animais , Comportamento Animal , Bromodesoxiuridina/metabolismo , Proliferação de Células , Análise por Conglomerados , Feminino , Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Corrida/fisiologia , Proteínas com Domínio T/genética , beta-Frutofuranosidase/farmacologiaRESUMO
Psychiatric and neurologic disorders take an enormous toll on society. Alleviating the devastating symptoms and consequences of neuropsychiatric disorders such as addiction, depression, epilepsy, and schizophrenia is a main force driving clinical and basic researchers alike. By elucidating these disease neuromechanisms, researchers hope to better define treatments and preventive therapies. Research suggests that regulation of adult hippocampal neurogenesis represents a promising approach to treating and perhaps preventing mental illness. Here we appraise the role of adult hippocampal neurogenesis in major psychiatric and neurologic disorders within the essential framework of recent progress made in understanding "normal" adult neurogenesis. Topics addressed include the following: the life cycle of an adult hippocampal stem cell and the implications for aging; links between learning and hippocampal neurogenesis; the reciprocal relationship between cocaine self-administration and adult hippocampal neurogenesis; the role of adult neurogenesis in an animal model of depression and response to antidepressant exposure; the impact of neonatal seizures on dentate gyrus neurogenesis; and the contribution of a schizophrenia-susceptibility gene to adult hippocampal neurogenesis. These topics are discussed in light of the regulation of adult neurogenesis, the relationship to normal neurogenesis in adulthood and aging, and, importantly, the manipulation of neurogenesis to promote mental health and treat mental illness.
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Envelhecimento/fisiologia , Hipocampo/fisiologia , Transtornos Neurocognitivos/fisiopatologia , Neurogênese/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Ciclo Celular/fisiologia , Modelos Animais de Doenças , Hipocampo/citologia , Humanos , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/terapia , Neurônios/fisiologia , Células-Tronco/fisiologiaRESUMO
These are exciting times for research on adult hippocampal neurogenesis (AHN). Debate and controversy regarding the existence of generation of new neurons in the adult, and even diseased human brain flourishes as articles against and in favor accumulate. Adult neurogenesis in the human brain is a phenomenon that does not share the qualities of quantum mechanics. The scientific community should agree that human AHN exists or does not, but not both at the same time. In this commentary, we discuss the latest research articles about hAHN and what their findings imply for the neurogenesis field.
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Convulsive seizures promote adult hippocampal neurogenesis (AHN) through a transient activation of neural stem/progenitor cells (NSPCs) in the subgranular zone (SGZ) of the dentate gyrus (DG). However, in a significant population of epilepsy patients, non-convulsive seizures (ncSZ) are observed. The response of NSPCs to non-convulsive seizure induction has not been characterized before. We here studied first the short-term effects of controlled seizure induction on NSPCs fate and identity. We induced seizures of controlled intensity by intrahippocampally injecting increasing doses of the chemoconvulsant kainic acid (KA) and analyzed their effect on subdural EEG recordings, hippocampal structure, NSPC proliferation and the number and location of immature neurons shortly after seizure onset. After establishing a KA dose that elicits ncSZ, we then analyzed the effects of ncSZ on NSPC proliferation and NSC identity in the hippocampus. ncSZ specifically triggered neuroblast proliferation, but did not induce proliferation of NSPCs in the SGZ, 3 days post seizure onset. However, ncSZ induced significant changes in NSPC composition in the hippocampus, including the generation of reactive NSCs. Interestingly, intrahippocampal injection of a combination of two anti microRNA oligonucleotides targeting microRNA-124 and -137 normalized neuroblast proliferation and prevented NSC loss in the DG upon ncSZ. Our results show for the first time that ncSZ induce significant changes in neuroblast proliferation and NSC composition. Simultaneous antagonism of both microRNA-124 and -137 rescued seizure-induced alterations in NSPC, supporting their coordinated action in the regulation of NSC fate and proliferation and their potential for future seizure therapies.
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Lack of scientific reproducibility is a growing concern and weak experimental practices may contribute to irreproducibility. Here, we describe an optimized and versatile protocol for stereotaxic intrahippocampal administration of Kainic Acid (KA) in mice with a C57Bl6 background. In this protocol, KA administration is combined with in vivo recording of neuronal activity with wired and wireless setups. Following our protocol, KA administration results in a robust dose-dependent induction of low-level epileptiform activity or Status Epilepticus (SE) and induces previously characterized hallmarks of seizure-associated pathology. The procedure consists of three main steps: Craniotomy, stereotaxic administration of KA, and placement of recording electrodes in intrahippocampal, and subdural locations. This protocol offers extended possibilities compared to the systemic administration of KA, as it allows the researcher to accurately regulate the local dose of KA and resulting seizure activity, and permits the use and study of convulsive and non-convulsive KA doses, resulting in higher reproducibility and lower inter-individual variability and mortality rates. Caution should be taken when translating this procedure to different strains of mice as inter-strain sensitivity to KA has been described before. The procedure can be performed in ~1 h by a trained researcher, while intrahippocampal administration of KA without placing recording electrodes can be done in 25 min, and can be easily adapted to the titrated intrahippocampal administration of other drugs.
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Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge" initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities.
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Cooperação Internacional , Neurociências/história , Europa (Continente) , História do Século XV , História do Século XXI , História Antiga , História Medieval , Humanos , Oriente MédioRESUMO
Adult hippocampal neurogenesis is a highly plastic process that responds swiftly to neuronal activity. Adult hippocampal neurogenesis can be regulated at the level of neural stem cell recruitment and activation, progenitor proliferation, as well as newborn cell survival and differentiation. An "excitation-neurogenesis" rule was proposed after the demonstration of the capability of cultured neural stem and progenitor cells to intrinsically sense neuronal excitatory activity. In vivo, this property has remained elusive although recently the direct response of neural stem cells to GABA in the hippocampus via GABAA receptors has evidenced a mechanism for a direct talk between neurons and neural stem cells. As it is pro-neurogenic, the effect of excitatory neuronal activity has been generally considered beneficial. But what happens in situations of neuronal hyperactivity in which neurogenesis can be dramatically boosted? In animal models, electroconvulsive shock markedly increases neurogenesis. On the contrary, in epilepsy rodent models, seizures induce the generation of misplaced neurons with abnormal morphological and electrophysiological properties, namely aberrant neurogenesis. We will herein discuss what is known about the mechanisms of influence of neurons on neural stem cells, as well as the severe effects of neuronal hyperexcitation on hippocampal neurogenesis.
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Adult hippocampal neurogenesis is believed to maintain a range of cognitive functions, many of which decline with age. We recently reported that radial neural stem cells (rNSCs) in the hippocampus undergo activation-dependent conversion into astrocytes, a mechanism that over time contributes to a reduction in the rNSC population. Here, we injected low and high levels of kainic acid (KA) in the dentate gyrus to assess whether neuronal hyperexcitation, a hallmark of epileptic disorders, could accelerate this conversion. At low levels of KA, generating epileptiform activity without seizures, we indeed found increased rNSC activation and conversion into astrocytes. At high levels, generating sustained epileptic seizures, however, we find that rNSCs divide symmetrically and that both mother and daughter cells convert into reactive astrocytes. Our results demonstrate that a threshold response for neuronal hyperexcitation provokes a dramatic shift in rNSC function, which impairs adult hippocampal neurogenesis in the long term.
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Astrócitos/fisiologia , Epilepsia/fisiopatologia , Hipocampo/citologia , Células-Tronco Neurais/fisiologia , Agitação Psicomotora/fisiopatologia , Adulto , Animais , Células Cultivadas , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Humanos , Ácido Caínico/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , NeurogêneseRESUMO
The generation of new neurons from neural stem cells (NSCs) throughout adult life in the mammalian brain is a biological process that fascinates scientists for its uniqueness and restorative potential. In the dentate gyrus (DG) of the hippocampus NSCs are able to self-renew and generate new granule cells and astrocytes through a complex and plastic mechanism that can be regulated by endogenous and exogenous cues at different levels. Unexpected recent findings suggest that the population of NSCs is heterogeneous in morphology and behavior. We herein explore the hypothesis that NSC heterogeneity and the neurogenic potential of the DG depends on their developmental origin. We provide an up-to-date picture of the process of neurogenesis in the adult hippocampus with an especial focus on NSCs and outline key unsolved aspects. Further, we discuss the origin of NSCs in the adult DG from a developmental perspective and explore the possibility of NSC heterogeneity being determined from early postnatal periods and being responsible for the neurogenic output of the DG in the long term.
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Células-Tronco Adultas/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Neurogênese/fisiologia , Animais , HumanosRESUMO
Newborn neurons derived from radial glia-like stem cells located in the dentate gyrus integrate into the adult hippocampal circuitry and participate in memory formation, spatial learning, pattern separation, fear conditioning, and anxiety. This process takes place throughout the life span of mammals, including humans; however, it follows a sharp declining curve. New neurons are generated abundantly during youth but very scarcely in the aged brain. The absolute number of newly generated neurons, or neurogenic output, is determined at different levels along the neurogenic cascade: the activation of quiescent stem cells; the mitotic potential of proliferating precursors; and the survival of neuronal fate-committed precursors. A continuous depletion of the hippocampal neural stem cell pool has been recently proposed as the main force underlying the age-related decline of neurogenesis, in contrast to the previous view of population of neural stem cells whose number remains constant but loses its ability to bear fruit. Nevertheless, the diminished neurogenic output may be reflecting other phenomena such as decreased mitotic capability of proliferating progenitors, decreased survival or changes in differentiation. We describe herein the most important events in determining the amount of neurogenesis in the dentate gyrus and examine the literature to understand the effects of age throughout the cascade.
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Envelhecimento/fisiologia , Hipocampo/fisiologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Animais , Astrócitos/citologia , Astrócitos/fisiologia , Hipocampo/citologia , Humanos , Células-Tronco Neurais/citologia , Neurônios/citologiaRESUMO
Neural stem cells reside in well-defined areas of the adult human brain and are capable of generating new neurons throughout the life span. In rodents, it is well established that the new born neurons are involved in olfaction as well as in certain forms of memory and learning. In humans, the functional relevance of adult human neurogenesis is being investigated, in particular its implication in the etiopathology of a variety of brain disorders. Adult neurogenesis in the human brain was discovered by utilizing methodologies directly imported from the rodent research, such as immunohistological detection of proliferation and cell-type specific biomarkers in postmortem or biopsy tissue. However, in the vast majority of cases, these methods do not support longitudinal studies; thus, the capacity of the putative stem cells to form new neurons under different disease conditions cannot be tested. More recently, new technologies have been specifically developed for the detection and quantification of neural stem cells in the living human brain. These technologies rely on the use of magnetic resonance imaging, available in hospitals worldwide. Although they require further validation in rodents and primates, these new methods hold the potential to test the contribution of adult human neurogenesis to brain function in both health and disease. This review reports on the current knowledge on adult human neurogenesis. We first review the different methods available to assess human neurogenesis, both ex vivo and in vivo and then appraise the changes of adult neurogenesis in human diseases.