RESUMEN
The cell-intrinsic mechanisms underlying the decision of a stem/progenitor cell to either proliferate or differentiate remain incompletely understood. Here, we identify the transmembrane protein Lrig1 as a physiological homeostatic regulator of FGF2-driven proliferation and self-renewal of neural progenitors at early-to-mid embryonic stages of cortical development. We show that Lrig1 is expressed in cortical progenitors (CPs), and its ablation caused expansion and increased proliferation of radial/apical progenitors and of neurogenic transit-amplifying Tbr2+ intermediate progenitors. Notably, our findings identify a previously unreported EGF-independent mechanism through which Lrig1 negatively regulates neural progenitor proliferation by modulating the FGF2-induced IL6/Jak2/Stat3 pathway, a molecular cascade that plays a pivotal role in the generation and maintenance of CPs. Consistently, Lrig1 knockout mice showed a significant increase in the density of pyramidal glutamatergic neurons placed in superficial layers 2 and 3 of the postnatal neocortex. Together, these results support a model in which Lrig1 regulates cortical neurogenesis by influencing the cycling activity of a set of progenitors that are temporally specified to produce upper layer glutamatergic neurons.
Asunto(s)
Janus Quinasa 2 , Glicoproteínas de Membrana , Ratones Noqueados , Células-Madre Neurales , Neurogénesis , Neuronas , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Janus Quinasa 2/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Ratones , Neurogénesis/genética , Neuronas/metabolismo , Neuronas/citología , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Proliferación Celular , Corteza Cerebral/metabolismo , Corteza Cerebral/citología , Corteza Cerebral/embriología , Diferenciación Celular , Factores de Crecimiento de Fibroblastos/metabolismo , Proteínas del Tejido NerviosoRESUMEN
TRPM4 is a non-selective cation channel activated by intracellular Ca2+ but only permeable to monovalent cations, its activation regulates membrane potential and intracellular calcium. This channel participates in the migration and adhesion of non-excitable cells and forms an integral part of the focal adhesion complex. In neurons, TRPM4 expression starts before birth and its function at this stage is not clear, but it may function in processes such as neurite development. Here we investigate the role of TRPM4 in neuritogenesis. We found that neurons at DIV 0 express TRPM4, the inhibition of TRPM4 using 9-Ph reduces neurite number and slows the progression of neurite development, keeping neurons in stage 1. The genetic suppression of TRPM4 using an shRNA at later stages (DIV2) reduces neurite length. Conversely, at DIV 0, TRPM4 inhibition augments the Cch-induced Ca2 + i increase, altering the calcium homeostasis. Together, these results show that TRPM4 participates in progression of neurite development and suggest a critical role of the calcium modulation during this stage of neuronal development.
Asunto(s)
Calcio , Corteza Cerebral , Neuritas , Neurogénesis , Canales Catiónicos TRPM , Canales Catiónicos TRPM/metabolismo , Canales Catiónicos TRPM/antagonistas & inhibidores , Animales , Neuritas/metabolismo , Neuritas/efectos de los fármacos , Calcio/metabolismo , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Neuronas/metabolismoRESUMEN
The adult hippocampus generates new granule cells (aGCs) with functional capabilities that convey unique forms of plasticity to the preexisting circuits. While early differentiation of adult radial glia-like cells (RGLs) has been studied extensively, the molecular mechanisms guiding the maturation of postmitotic neurons remain unknown. Here, we used a precise birthdating strategy to study aGC differentiation using single-nuclei RNA sequencing. Transcriptional profiling revealed a continuous trajectory from RGLs to mature aGCs, with multiple immature stages bearing increasing levels of effector genes supporting growth, excitability, and synaptogenesis. Analysis of differential gene expression, pseudo-time trajectory, and transcription factors (TFs) revealed critical transitions defining four cellular states: quiescent RGLs, proliferative progenitors, immature aGCs, and mature aGCs. Becoming mature aGCs involved a transcriptional switch that shuts down pathways promoting cell growth, such SoxC TFs, to activate programs that likely control neuronal homeostasis. aGCs overexpressing Sox4 or Sox11 remained immature. Our results unveil precise molecular mechanisms driving adult RGLs through the pathway of neuronal differentiation.
Asunto(s)
Diferenciación Celular , Hipocampo , Neurogénesis , Neuronas , Factores de Transcripción SOXC , Animales , Hipocampo/metabolismo , Hipocampo/citología , Neuronas/metabolismo , Neuronas/citología , Factores de Transcripción SOXC/metabolismo , Factores de Transcripción SOXC/genética , Diferenciación Celular/genética , Neurogénesis/genética , Ratones , Transcripción Genética , Perfilación de la Expresión Génica , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Células Ependimogliales/metabolismo , Células Ependimogliales/citologíaRESUMEN
The arginine vasopressin (AVP)-magnocellular neurosecretory system (AVPMNS) in the hypothalamus plays a critical role in homeostatic regulation as well as in allostatic motivational behaviors. However, it remains unclear whether adult neurogenesis exists in the AVPMNS. By using immunoreaction against AVP, neurophysin II, glial fibrillar acidic protein (GFAP), cell division marker (Ki67), migrating neuroblast markers (doublecortin, DCX), microglial marker (Ionized calcium binding adaptor molecule 1, Iba1), and 5'-bromo-2'-deoxyuridine (BrdU), we report morphological evidence that low-rate neurogenesis and migration occur in adult AVPMNS in the rat hypothalamus. Tangential AVP/GFAP migration routes and AVP/DCX neuronal chains as well as ascending AVP axonal scaffolds were observed. Chronic water deprivation significantly increased the BrdU+ nuclei within both the supraaoptic (SON) and paraventricular (PVN) nuclei. These findings raise new questions about AVPMNS's potential hormonal role for brain physiological adaptation across the lifespan, with possible involvement in coping with homeostatic adversities.
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Movimiento Celular , Proteína Doblecortina , Neurogénesis , Neuronas , Animales , Ratas , Neuronas/metabolismo , Neuronas/citología , Masculino , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/citología , Hipotálamo/metabolismo , Hipotálamo/citología , Arginina Vasopresina/metabolismoRESUMEN
Taurine (2-aminoethanesulfonic acid) is a non-protein ß-amino acid essential for cellular homeostasis, with antioxidant, anti-inflammatory, and cytoprotective properties that are crucial for life maintenance. This study aimed to evaluate the effects of taurine administration on hippocampal neurogenesis, neuronal preservation, or reverse damage in rats exposed to forced ethanol consumption in an animal model. Wistar rats were treated with ethanol (EtOH) for a 28-day period (5% in the 1st week, 10% in the 2nd week, and 20% in the 3rd and 4th weeks). Two taurine treatment protocols (300 mg/kg i.p.) were implemented: one during ethanol consumption to analyze neuroprotection, and another after ethanol consumption to assess the reversal of ethanol-induced damage. Overall, the results demonstrated that taurine treatment was effective in protecting against deficits induced by ethanol consumption in the dentate gyrus. The EtOH+TAU group showed a significant increase in cell proliferation (145.8%) and cell survival (54.0%) compared to the EtOH+Sal group. The results also indicated similar effects regarding the reversal of ethanol-induced damage 28 days after the cessation of ethanol consumption. The EtOH+TAU group exhibited a significant increase (41.3%) in the number of DCX-immunoreactive cells compared to the EtOH+Sal group. However, this amino acid did not induce neurogenesis in the tissues of healthy rats, implying that its activity may be contingent upon post-injury stimuli.
Asunto(s)
Proteína Doblecortina , Etanol , Hipocampo , Neurogénesis , Fármacos Neuroprotectores , Ratas Wistar , Taurina , Animales , Taurina/farmacología , Neurogénesis/efectos de los fármacos , Masculino , Fármacos Neuroprotectores/farmacología , Ratas , Hipocampo/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Neuronas/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Toll-like receptors (TLRs) are among the main components of the innate immune system. They can detect conserved structures in microorganisms and molecules associated with stress and cellular damage. TLRs are expressed in resident immune cells and both neurons and glial cells of the nervous system. Increasing evidence is emerging on the participation of TLRs not only in the immune response but also in processes of the nervous system, such as neurogenesis and cognition. Below, we present a review of the literature that evaluates the expression and role of TLRs in processes such as neurodevelopment, behavior, cognition, infection, neuroinflammation, and neurodegeneration.
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Sistema Nervioso , Neurogénesis , Receptores Toll-Like , Humanos , Receptores Toll-Like/metabolismo , Animales , Sistema Nervioso/metabolismo , Sistema Nervioso/inmunología , Inmunidad Innata , Neuronas/metabolismo , Neuronas/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Transducción de SeñalRESUMEN
Here, we explored the impact of prolonged environmental enrichment (EE) on behavioral, neurochemical, and epigenetic changes in the serotonin transporter gene in mice subjected to a two-hit schizophrenia model. The methodology involved administering the viral mimetic PolyI:C to neonatal Swiss mice as a first hit during postnatal days (PND) 5-7, or a sterile saline solution as a control. At PND21, mice were randomly assigned either to standard environment (SE) or EE housing conditions. Between PND35-44, the PolyI:C-treated group was submitted to various unpredictable stressors, constituting the second hit. Behavioral assessments were conducted on PND70, immediately after the final EE exposure. Following the completion of behavioral assessments, we evaluated the expression of proteins in the hippocampus that are indicative of microglial activation, such as Iba-1, as well as related to neurogenesis, including doublecortin (Dcx). We also performed methylation analysis on the serotonin transporter gene (Slc6a4) to investigate alterations in serotonin signaling. The findings revealed that EE for 50 days mitigated sensorimotor gating deficits and working memory impairments in two-hit mice and enhanced their locomotor and exploratory behaviors. EE also normalized the overexpression of hippocampal Iba-1 and increased the expression of hippocampal Dcx. Additionally, we observed hippocampal demethylation of the Slc6a4 gene in the EE-exposed two-hit group, indicating epigenetic reprogramming. These results contribute to the growing body of evidence supporting the protective effects of long-term EE in counteracting behavioral disruptions caused by the two-hit schizophrenia model, pointing to enhanced neurogenesis, diminished microglial activation, and epigenetic modifications of serotonergic pathways as underlying mechanisms.
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Modelos Animales de Enfermedad , Ambiente , Hipocampo , Esquizofrenia , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Animales , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Hipocampo/metabolismo , Esquizofrenia/metabolismo , Esquizofrenia/genética , Ratones , Masculino , Proteína Doblecortina , Regiones Promotoras Genéticas , Metilación de ADN , Poli I-C , Neurogénesis/fisiología , Filtrado Sensorial/fisiologíaRESUMEN
OBJECTIVE: To investigate the effects of cannabidiol (CBD) on emotional and cognitive symptoms in rats with intra-nigral 6-hydroxydopamine (6-OHDA) lesions. METHODS: Adult male Wistar rats received bilateral intranigral 6-OHDA infusions and were tested in a battery of behavioural paradigms to evaluate non-motor symptoms. The brains were obtained to evaluate the effects of CBD on hippocampal neurogenesis. RESULTS: 6-OHDA-lesioned rats exhibited memory impairments and despair-like behaviour in the novelty-suppressed feeding test and forced swim test, respectively. The animals also exhibited dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), striatum, and ventral tegmental area and a reduction of hippocampal neurogenesis. CBD decreased dopaminergic neuronal loss in the SNpc, reduced the mortality rate and decreased neuroinflammation in 6-OHDA-lesioned rats. In parallel, CBD prevented memory impairments and attenuated despair-like behaviour that were induced by bilateral intranigral 6-OHDA lesions. Repeated treatment with CBD favoured the neuronal maturation of newborn neurons in the hippocampus in Parkinsonian rats. CONCLUSION: The present findings suggest a potential beneficial effect of CBD on non-motor symptoms induced by intra-nigral 6-OHDA infusion in rats.
Asunto(s)
Cannabidiol , Modelos Animales de Enfermedad , Hipocampo , Neurogénesis , Oxidopamina , Trastornos Parkinsonianos , Ratas Wistar , Animales , Cannabidiol/farmacología , Masculino , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ratas , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/inducido químicamente , Oxidopamina/farmacología , Neurogénesis/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Neuronas/efectos de los fármacos , Neuronas/patología , Conducta Animal/efectos de los fármacosRESUMEN
New hippocampal neurons are continuously generated in the adult human brain. Several studies have demonstrated that the proliferation of hippocampal cells is strongly influenced by a variety of stimuli, including pesticides exposure. These effects are particularly important because neurogenesis dysregulation could be associated with the decline of neuronal and cognitive functions and the possible development of neuropsychiatric disorders.
Novos neurônios hipocampais são gerados continuamente no cérebro humano adulto. Vários estudos têm demonstrado que a proliferação de células do hipocampo é influenciada por uma variedade de estímulos, incluindo a exposição a pesticidas. Estes efeitos são particularmente importantes porque a desregulação da neurogênese pode estar associada ao declínio das funções neuronais e cognitivas e ao possível desenvolvimento de doenças neuropsiquiátricas.
Asunto(s)
Hipocampo , Neurogénesis , Neuronas , Plaguicidas , Plaguicidas/toxicidad , Humanos , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Neurogénesis/efectos de los fármacos , Neurogénesis/fisiología , Neuronas/efectos de los fármacos , Neuronas/fisiología , AnimalesRESUMEN
C-Jun-N-terminal-kinases (JNKs), members of the mitogen-activated-protein-kinase family, are significantly linked with neurological and neurodegenerative pathologies and cancer progression. However, JNKs serve key roles under physiological conditions, particularly within the central-nervous-system (CNS), where they are critical in governing neural proliferation and differentiation during both embryogenesis and adult stages. These processes control the development of CNS, avoiding neurodevelopment disorders. JNK are key to maintain the proper activity of neural-stem-cells (NSC) and neural-progenitors (NPC) that exist in adults, which keep the convenient brain plasticity and homeostasis. This review underscores how the interaction of JNK with upstream and downstream molecules acts as a regulatory mechanism to manage the self-renewal capacity and differentiation of NSC/NPC during CNS development and in adult neurogenic niches. Evidence suggests that JNK is reliant on non-canonical Wnt components, Fbw7-ubiquitin-ligase, and WDR62-scaffold-protein, regulating substrates such as transcription factors and cytoskeletal proteins. Therefore, understanding which pathways and molecules interact with JNK will bring knowledge on how JNK activation orchestrates neuronal processes that occur in CNS development and brain disorders.
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Diferenciación Celular , Células-Madre Neurales , Neurogénesis , Humanos , Animales , Diferenciación Celular/fisiología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Neurogénesis/fisiología , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Neuronas/metabolismo , Neuronas/citologíaRESUMEN
The plains vizcacha, Lagostomus maximus, is a precocial hystricomorph rodent with a gyrencephalic brain. This work aimed to perform a time-lapse analysis of the embryonic brain cortical development in the plains vizcacha to establish a species-specific temporal window for corticogenesis and the gyrencephaly onset. Additionally, a comparative examination with evolutionarily related rodents was conducted. Embryos from 40 embryonic days (ED) until the end of pregnancy ( â¼ $\sim $ 154 ED) were evaluated. The neuroanatomical examination determined transverse sulci at 80 ED and rostral lateral and caudal intraparietal sulci around 95 ED. Histological examination of corticogenesis showed emergence of the subplate at 43 ED and expansion of the subventricular zone (SVZ) and its division into inner and outer SVZs around 54 ED. The neocortical layers formation followed an inside-to-outside spatiotemporal gradient beginning with the emergence of layers VI and V at 68 ED and establishing the final six neocortical layers around 100 ED. A progressive increment of gyrencephalization index (GI) from 1.005 ± 0.003 around 70 ED, which reflects a smooth cortex, up to 1.07 ± 0.009 at the end of gestation, reflecting a gyrencephalic neuroanatomy, was determined. Contrarily, the minimum cortical thickness (MCT) progressively decreased from 61 ED up to the end of gestation. These results show that the decrease in the cortical thickness, which enables the onset of neocortical invaginations, occurs together with the expansion and subdivision of the SVZ. The temporal comparison of corticogenesis in plains vizcacha with that in relative species reflects a prenatal long process compared with other rodents that may give an evolutionary advantage to L. maximus as a precocial species.
Asunto(s)
Corteza Cerebral , Roedores , Animales , Corteza Cerebral/crecimiento & desarrollo , Roedores/anatomía & histología , Femenino , Embarazo , Neurogénesis/fisiología , Neocórtex/crecimiento & desarrolloRESUMEN
Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by haploinsufficiency of transcription factor 4 (TCF4). In this work, we focused on the cerebral cortex and investigated in detail the progenitor cell dynamics and the outcome of neurogenesis in a PTHS mouse model. Labeling and quantification of progenitors and newly generated neurons at various time points during embryonic development revealed alterations affecting the dynamic of cortical progenitors since the earliest stages of cortex formation in PTHS mice. Consequently, establishment of neuronal populations and layering of the cortex were found to be altered in heterozygotes subjects at birth. Interestingly, defective layering process of pyramidal neurons was partially rescued by reintroducing TCF4 expression using focal in utero electroporation in the cerebral cortex. Coincidentally with a defective dorsal neurogenesis, we found that ventral generation of interneurons was also defective in this model, which may lead to an excitation/inhibition imbalance in PTHS. Overall, sex-dependent differences were detected with more marked effects evidenced in males compared with females. All of this contributes to expand our understanding of PTHS, paralleling the advances of research in autism spectrum disorder and further validating the PTHS mouse model as an important tool to advance preclinical studies.
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Corteza Cerebral , Modelos Animales de Enfermedad , Hiperventilación , Discapacidad Intelectual , Neurogénesis , Factor de Transcripción 4 , Animales , Factor de Transcripción 4/metabolismo , Factor de Transcripción 4/genética , Femenino , Masculino , Ratones , Hiperventilación/metabolismo , Hiperventilación/genética , Hiperventilación/patología , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Discapacidad Intelectual/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Facies , Caracteres Sexuales , Interneuronas/metabolismo , Interneuronas/patología , Células Piramidales/metabolismo , Células Piramidales/patología , HaploinsuficienciaRESUMEN
Obesity is a chronic disease caused by excessive fat accumulation that impacts the body and brain health. Insufficient leptin or leptin receptor (LepR) is involved in the disease pathogenesis. Leptin is involved with several neurological processes, and it has crucial developmental roles. We have previously demonstrated that leptin deficiency in early life leads to permanent developmental problems in young adult mice, including an imbalance in energy homeostasis, alterations in melanocortin and the reproductive system and a reduction in brain mass. Given that in humans, obesity has been associated with brain atrophy and cognitive impairment, it is important to determine the long-term consequences of early-life leptin deficiency on brain structure and memory function. Here, we demonstrate that leptin-deficient (LepOb) mice exhibit altered brain volume, decreased neurogenesis and memory impairment. Similar effects were observed in animals that do not express the LepR (LepRNull). Interestingly, restoring the expression of LepR in 10-week-old mice reverses brain atrophy, in addition to neurogenesis and memory impairments in older animals. Our findings indicate that leptin deficiency impairs brain development and memory, which are reversible by restoring leptin signalling in adulthood.
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Encéfalo , Leptina , Neurogénesis , Receptores de Leptina , Animales , Receptores de Leptina/deficiencia , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Ratones , Encéfalo/metabolismo , Leptina/deficiencia , Leptina/metabolismo , Neurogénesis/fisiología , Ratones Noqueados , Ratones Endogámicos C57BL , Masculino , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/genética , Atrofia/patologíaRESUMEN
Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by motor and non-motor symptoms. Motor symptoms include bradykinesia, resting tremors, muscular rigidity, and postural instability, while non-motor symptoms include cognitive impairments, mood disturbances, sleep disturbances, autonomic dysfunction, and sensory abnormalities. Some of these symptoms may be influenced by the proper hippocampus functioning, including adult neurogenesis. Doublecortin (DCX) is a microtubule-associated protein that plays a pivotal role in the development and differentiation of migrating neurons. This study utilized postmortem human brain tissue of PD and age-matched control individuals to investigate DCX expression in the context of adult hippocampal neurogenesis. Our findings demonstrate a significant reduction in the number of DCX-expressing cells within the subgranular zone (SGZ), as well as a decrease in the nuclear area of these DCX-positive cells in postmortem brain tissue obtained from PD cases, suggesting an impairment in the adult hippocampal neurogenesis. Additionally, we found that the nuclear area of DCX-positive cells correlates with pH levels. In summary, we provide evidence supporting that the process of hippocampal adult neurogenesis is likely to be compromised in PD patients before cognitive dysfunction, shedding light on potential mechanisms contributing to the neuropsychiatric symptoms observed in affected individuals. Understanding these mechanisms may offer novel insights into the pathophysiology of PD and possible therapeutic avenues.
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Proteínas de Dominio Doblecortina , Proteína Doblecortina , Hipocampo , Proteínas Asociadas a Microtúbulos , Neurogénesis , Neuropéptidos , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Hipocampo/metabolismo , Masculino , Neuropéptidos/metabolismo , Neuropéptidos/biosíntesis , Anciano , Proteínas Asociadas a Microtúbulos/metabolismo , Femenino , Neurogénesis/fisiología , Anciano de 80 o más Años , Persona de Mediana EdadRESUMEN
The Zika virus received significant attention in 2016, following a declaration by the World Health Organization of an epidemic in the Americas, in which infections were associated with microcephaly. Indeed, prenatal Zika virus infection is detrimental to fetal neural stem cells and can cause premature cell loss and neurodevelopmental abnormalities in newborn infants, collectively described as congenital Zika syndrome. Contrastingly, much less is known about how neonatal infection affects the development of the newborn nervous system. Here, we investigated the development of the dentate gyrus of wild-type mice following intracranial injection of the virus at birth (postnatal day 0). Through this approach, we found that Zika virus infection affected the development of neurogenic regions within the dentate gyrus and caused reactive gliosis, cell death and a decrease in cell proliferation. Such infection also altered volumetric features of the postnatal dentate gyrus. Thus, we found that Zika virus exposure to newborn mice is detrimental to the subgranular zone of the dentate gyrus. These observations offer insight into the cellular mechanisms that underlie the neurological features of congenital Zika syndrome in children.
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Infección por el Virus Zika , Virus Zika , Humanos , Niño , Lactante , Femenino , Embarazo , Animales , Ratones , Infección por el Virus Zika/complicaciones , Neurogénesis , Muerte Celular , Proliferación CelularRESUMEN
Zika virus (ZIKV) infection was first associated with Central Nervous System (CNS) infections in Brazil in 2015, correlated with an increased number of newborns with microcephaly, which ended up characterizing the Congenital Zika Syndrome (CZS). Here, we investigated the impact of ZIKV infection on the functionality of iPSC-derived astrocytes. Besides, we extrapolated our findings to a Brazilian cohort of 136 CZS children and validated our results using a mouse model. Interestingly, ZIKV infection in neuroprogenitor cells compromises cell migration and causes apoptosis but does not interfere in astrocyte generation. Moreover, infected astrocytes lost their ability to uptake glutamate while expressing more glutamate transporters and secreted higher levels of IL-6. Besides, infected astrocytes secreted factors that impaired neuronal synaptogenesis. Since these biological endophenotypes were already related to Autism Spectrum Disorder (ASD), we extrapolated these results to a cohort of children, now 6-7 years old, and found seven children with ASD diagnosis (5.14 %). Additionally, mice infected by ZIKV revealed autistic-like behaviors, with a significant increase of IL-6 mRNA levels in the brain. Considering these evidence, we inferred that ZIKV infection during pregnancy might lead to synaptogenesis impairment and neuroinflammation, which could increase the risk for ASD.
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Astrocitos , Trastorno del Espectro Autista , Enfermedades Neuroinflamatorias , Sinapsis , Infección por el Virus Zika , Virus Zika , Infección por el Virus Zika/patología , Infección por el Virus Zika/metabolismo , Infección por el Virus Zika/virología , Infección por el Virus Zika/complicaciones , Trastorno del Espectro Autista/virología , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/etiología , Trastorno del Espectro Autista/patología , Humanos , Animales , Ratones , Virus Zika/fisiología , Femenino , Niño , Sinapsis/metabolismo , Sinapsis/patología , Enfermedades Neuroinflamatorias/virología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/etiología , Astrocitos/virología , Astrocitos/metabolismo , Astrocitos/patología , Masculino , Interleucina-6/metabolismo , Interleucina-6/genética , Embarazo , Factores de Riesgo , Células Madre Pluripotentes Inducidas/virología , Células Madre Pluripotentes Inducidas/metabolismo , Brasil/epidemiología , Modelos Animales de Enfermedad , NeurogénesisRESUMEN
Stem cells possess extraordinary capacities for self-renewal and differentiation, making them highly valuable in regenerative medicine. Among these, neural stem cells (NSCs) play a fundamental role in neural development and repair processes. NSC characteristics and fate are intricately regulated by the microenvironment and intracellular signaling. Interestingly, metabolism plays a pivotal role in orchestrating the epigenome dynamics during neural differentiation, facilitating the transition from undifferentiated NSC to specialized neuronal and glial cell types. This intricate interplay between metabolism and the epigenome is essential for precisely regulating gene expression patterns and ensuring proper neural development. This review highlights the mechanisms behind metabolic regulation of NSC fate and their connections with epigenetic regulation to shape transcriptional programs of stemness and neural differentiation. A comprehensive understanding of these molecular gears appears fundamental for translational applications in regenerative medicine and personalized therapies for neurological conditions.
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Diferenciación Celular , Epigénesis Genética , Células-Madre Neurales , Humanos , Animales , Diferenciación Celular/genética , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Neurogénesis/genéticaRESUMEN
SUMO (small ubiquitin-like modifier) conjugation or SUMOylation, a post-translational modification, is a crucial regulator of protein function and cellular processes. In the context of neural stem cells (NSCs), SUMOylation has emerged as a key player, affecting their proliferation, differentiation, and survival. By modifying transcription factors, such as SOX1, SOX2, SOX3, SOX6, Bmi1, and Nanog, SUMOylation can either enhance or impair their transcriptional activity, thus impacting on NSCs self-renewal. Moreover, SUMOylation regulates neurogenesis and neuronal differentiation by modulating key proteins, such as Foxp1, Mecp2, MEF2A, and SOX10. SUMOylation is also crucial for the survival and proliferation of NSCs in both developing and adult brains. By regulating the activity of transcription factors, coactivators, and corepressors, SUMOylation acts as a molecular switch, inducing cofactor recruitment and function during development. Importantly, dysregulation of NSCs SUMOylation has been implicated in various disorders, including embryonic defects, ischemic cerebrovascular disease, glioma, and the harmful effects of benzophenone-3 exposure. Here we review the main findings on SUMOylation-mediated regulation of NSCs self-renewal, differentiation and survival. Better understanding NSCs SUMOylation mechanisms and its functional consequences might provide new strategies to promote neuronal differentiation that could contribute for the development of novel therapies targeting neurodegenerative diseases.
Asunto(s)
Células-Madre Neurales , Sumoilación , Diferenciación Celular , Células-Madre Neurales/metabolismo , Neurogénesis/fisiología , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Impaired pattern separation occurs in the early stage of Alzheimer's disease (AD), and hippocampal dentate gyrus (DG) neurogenesis participates in pattern separation. Here, we investigated whether spatial memory discrimination impairment can be improved by promoting the hippocampal DG granule cell neogenesis-mediated pattern separation in the early stage of AD by electroacupuncture (EA). METHODS: Five familial AD mutations (5 × FAD) mice received EA treatment at Baihui and Shenting points for 4 weeks. During EA, mice were intraperitoneally injected with BrdU (50 mg/kg) twice a day. rAAV containing Wnt5a shRNA was injected into the bilateral DG region, and the viral efficiency was evaluated by detecting Wnt5a mRNA levels. Cognitive behavior tests were conducted to assess the impact of EA treatment on cognitive function. The hippocampal DG area Aß deposition level was detected by immunohistochemistry after the intervention; The number of BrdU+/CaR+ cells and the gene expression level of calretinin (CaR) and prospero homeobox 1(Prox1) in the DG area of the hippocampus was detected to assess neurogenesis by immunofluorescence and western blotting after the intervention; The gene expression levels of FZD2, Wnt5a, DVL2, p-DVL2, CaMKII, and p-CaMKII in the Wnt signaling pathway were detected by Western blotting after the intervention. RESULTS: Cognitive behavioral tests showed that 5 × FAD mice had impaired pattern separation (P < 0.001), which could be improved by EA (P < 0.01). Immunofluorescence and Western blot showed that the expression of Wnt5a in the hippocampus was decreased (P < 0.001), and the neurogenesis in the DG was impaired (P < 0.001) in 5 × FAD mice. EA could increase the expression level of Wnt5a (P < 0.05) and promote the neurogenesis of immature granule cells (P < 0.05) and the development of neuronal dendritic spines (P < 0.05). Interference of Wnt5a expression aggravated the damage of neurogenesis (P < 0.05), weakened the memory discrimination ability (P < 0.05), and inhibited the beneficial effect of EA (P < 0.05) in AD mice. The expression level of Wnt pathway related proteins such as FZD2, DVL2, p-DVL2, CAMKII, p-CAMKII increased after EA, but the effect of EA was inhibited after Wnt5a was knocked down. In addition, EA could reduce the deposition of Aß plaques in the DG without any impact on Wnt5a. CONCLUSION: EA can promote hippocampal DG immature granule cell neogenesis-mediated pattern separation to improve spatial memory discrimination impairment by regulating Wnt5a in 5 × FAD mice.
Asunto(s)
Enfermedad de Alzheimer , Electroacupuntura , Ratones , Animales , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/metabolismo , Bromodesoxiuridina , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Hipocampo/metabolismo , Modelos Animales de Enfermedad , Neurogénesis , Giro Dentado/metabolismoRESUMEN
Congenital Zika syndrome (CZS) is a set of birth defects caused by Zika virus (ZIKV) infection during pregnancy. Microcephaly is its main feature, but other brain abnormalities are found in CZS patients, such as ventriculomegaly, brain calcifications, and dysgenesis of the corpus callosum. Many studies have focused on microcephaly, but it remains unknown how ZIKV infection leads to callosal malformation. To tackle this issue, we infected mouse embryos in utero with a Brazilian ZIKV isolate and found that they were born with a reduction in callosal area and density of callosal neurons. ZIKV infection also causes a density reduction in PH3+ cells, intermediate progenitor cells, and SATB2+ neurons. Moreover, axonal tracing revealed that callosal axons are reduced and misrouted. Also, ZIKV-infected cultures show a reduction in callosal axon length. GFAP labeling showed that an in utero infection compromises glial cells responsible for midline axon guidance. In sum, we showed that ZIKV infection impairs critical steps of corpus callosum formation by disrupting not only neurogenesis, but also axon guidance and growth across the midline.