RESUMEN
Proneural transcription factors establish molecular cascades to orchestrate neuronal diversity. One such transcription factor, Atonal homolog 1 (Atoh1), gives rise to cerebellar excitatory neurons and over 30 distinct nuclei in the brainstem critical for hearing, breathing, and balance. Although Atoh1 lineage neurons have been qualitatively described, the transcriptional programs that drive their fate decisions and the full extent of their diversity remain unknown. Here, we analyzed single-cell RNA sequencing and ATOH1 DNA binding in Atoh1 lineage neurons of the developing mouse hindbrain. This high-resolution dataset identified markers for specific brainstem nuclei and demonstrated that transcriptionally heterogeneous progenitors require ATOH1 for proper migration. Moreover, we identified a sizable population of proliferating unipolar brush cell progenitors in the mouse Atoh1 lineage, previously described in humans as the origin of one medulloblastoma subtype. Collectively, our data provide insights into the developing mouse hindbrain and markers for functional assessment of understudied neuronal populations.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Linaje de la Célula , Neuronas , Rombencéfalo , Análisis de la Célula Individual , Transcriptoma , Animales , Rombencéfalo/metabolismo , Rombencéfalo/citología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Ratones , Neuronas/metabolismo , Neuronas/citología , Linaje de la Célula/genética , Análisis de la Célula Individual/métodos , Transcriptoma/genética , Diferenciación Celular , Regulación del Desarrollo de la Expresión Génica , Neurogénesis/genética , Movimiento CelularRESUMEN
The aim of this study was to investigate the impact and underlying molecular mechanisms of electroacupuncture on mice with poststroke depression (PSD). Mice were randomly allocated into sham, PSD, and electroacupuncture groups. Mice in the PSD and electroacupuncture groups underwent middle cerebral artery occlusion (MCAO) surgery following with sedentary behavior. Electroacupuncture targeting Zusanli (ST36) acupoint was performed 24â h after MCAO for 4â weeks in electroacupuncture group. The sucrose preference test, forced swimming test, open field test, tail suspension test, elevated plus maze, Catwalk analysis, RNA sequencing, Nissl staining, Golgi staining, TUNEL staining, Edu labeling, and doublecortin staining were performed. Lymphocyte subsets in peripheral blood and the levels of IL-1ß, IL-6, TNF-α, and expression of Iba1/CD86, Iba1/NLRP3, TLR4/p38/NF-κB/NLRP3 pathways in the hippocampus were detected. Electroacupuncture effectively protected against the development of depression-like symptoms. The number of granulosa cells and doublecortin-positive cells in the dentate gyrus (DG) were significantly decreased in PSD group, which were significantly upregulated ( P â <â 0.01) by electroacupuncture. Electroacupuncture also significantly reduced ( P â <â 0.05) TUNEL-positive cells in the DG and CA1. RNA-seq revealed that electroacupuncture may exert antidepressant effect by regulating the inflammation mediated by TLR4/NF-κB/NLRP3 pathway in hippocampus. Electroacupuncture remarkably elevated ( P â <â 0.01) the ratio of CD4+ to CD8+ T cells and percentage of CD3-CD49b+ cells in CD45+CD49b+ cells in the peripheral blood. Electroacupuncture significantly reduced ( P â <â 0.05) the high levels of IL-1ß, IL-6, TNF-α, iba1, TLR4, p-p38, p-NF-κB, and NLRP3 and sedentary behavior. Electroacupuncture was observed to mitigate depression symptoms and increase hippocampal neurogenesis in mice with PSD, possibly by inhibiting TLR4/p38/NF-κB/NLRP3 pathways and improving the microglia-mediated inflammatory microenvironment in the hippocampus.
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Depresión , Electroacupuntura , Hipocampo , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Neurogénesis , Transducción de Señal , Receptor Toll-Like 4 , Animales , Electroacupuntura/métodos , Neurogénesis/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratones , Depresión/etiología , Depresión/terapia , Depresión/metabolismo , Hipocampo/metabolismo , Receptor Toll-Like 4/metabolismo , FN-kappa B/metabolismo , Transducción de Señal/fisiología , Masculino , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/psicología , Ratones Endogámicos C57BLRESUMEN
DNA methylation is extensively reconfigured during development, but the functional significance and cell type-specific dependencies of DNA demethylation in lineage specification remain poorly understood. Here, we demonstrate that developmental DNA demethylation, driven by ten-eleven translocation 1/2/3 (TET1/2/3) enzymes, is essential for establishment of neural stem cell (NSC) identity and gliogenic potential. We find that loss of all three TETs during NSC specification is dispensable for neural induction and neuronal differentiation but critical for astrocyte and oligodendrocyte formation, demonstrating a selective loss of glial competence. Mechanistically, TET-mediated demethylation was essential for commissioning neural-specific enhancers in proximity to master neurodevelopmental and glial transcription factor genes and for induction of these genes. Consistently, loss of all three TETs in embryonic NSCs in mice compromised glial gene expression and corticogenesis. Thus, TET-dependent developmental demethylation is an essential regulatory mechanism for neural enhancer commissioning during NSC specification and is a cell-intrinsic determinant of NSC identity and gliogenic potential.
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Diferenciación Celular , Desmetilación del ADN , Células-Madre Neurales , Animales , Células-Madre Neurales/metabolismo , Células-Madre Neurales/citología , Ratones , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Neuroglía/metabolismo , Neuroglía/citología , Neurogénesis , Regulación del Desarrollo de la Expresión Génica , Metilación de ADN , Elementos de Facilitación Genéticos , Dioxigenasas/metabolismo , Neuronas/metabolismo , Neuronas/citologíaRESUMEN
Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially because of subventricular zone contact. Despite this, cross-talk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. In addition, GBM brain tumor-initiating cells (BTICs) increase expression of cathepsin B (CTSB) upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal that both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Last, we show LV-proximal CTSB up-regulation in patients, showing the relevance of this cross-talk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.
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Neoplasias Encefálicas , Catepsina B , Glioblastoma , Ventrículos Laterales , Células-Madre Neurales , Proteómica , Transducción de Señal , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , Catepsina B/metabolismo , Catepsina B/genética , Humanos , Proteómica/métodos , Ventrículos Laterales/metabolismo , Ventrículos Laterales/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Animales , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Línea Celular Tumoral , Neurogénesis , Ratones , Microambiente TumoralRESUMEN
Background: Dandouchi polypeptide (DDCP) is derived from Semen Sojae Praeparatum (Dandouchi in Chinese), a fermented product of Glycine max (L.) Merr. Semen Sojae Praeparatum is widely used in the food industry for its unique flavor and nutritional value, and DDCP, as its derivative, also shows potential health benefits in food applications. However, the specific active substances responsible for Semen Sojae Praeparatum and the underlying mechanisms involved have not been fully elucidated. Methods: DDCP was extracted from Semen Sojae Praeparatum using enzymes, and its antidepressant effects were tested in chronic unpredictable mild stress (CUMS)-induced mice. Immunohistochemistry, immunofluorescence, and western blotting were used to analyze neurogenesis and the nuclear factor κB (NF-κB) pathway. Moreover, an adeno-associated virus (AAV) shRNA was used to induce tripartite motif-containing 67 (TRIM67) deficiency to examine the function of TRIM67 in the neuroprotective effects of DDCP in depressive disorders. Results: DDCP reduced depressive behaviors in CUMS mice and the expression of proinflammatory markers in the hippocampus. DDCP promoted neurogenesis and modulated the TRIM67/NF-κB pathway, with TRIM67 deficiency impairing its antidepressant effect. Conclusions: This research revealed that DDCP has a protective effect on countering depression triggered by CUMS. Notably, TRIM67 plays a crucial role in mitigating depression through DDCP, positioning DDCP as a potential therapeutic option for treating depressive disorders.
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Depresión , Hipocampo , FN-kappa B , Neurogénesis , Animales , Humanos , Masculino , Ratones , Antidepresivos/química , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Conducta Animal/efectos de los fármacos , Depresión/metabolismo , Depresión/tratamiento farmacológico , Depresión/genética , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Endogámicos C57BL , Neurogénesis/efectos de los fármacos , FN-kappa B/metabolismo , FN-kappa B/genética , Péptidos/administración & dosificación , Péptidos/química , Péptidos/farmacología , Péptidos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Estrés Psicológico/tratamiento farmacológico , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Hippocampal seizures mimicking mesial temporal lobe epilepsy cause a profound disruption of the adult neurogenic niche in mice. Seizures provoke neural stem cells to switch to a reactive phenotype (reactive neural stem cells, React-NSCs) characterized by multibranched hypertrophic morphology, massive activation to enter mitosis, symmetric division, and final differentiation into reactive astrocytes. As a result, neurogenesis is chronically impaired. Here, using a mouse model of mesial temporal lobe epilepsy, we show that the epidermal growth factor receptor (EGFR) signaling pathway is key for the induction of React-NSCs and that its inhibition exerts a beneficial effect on the neurogenic niche. We show that during the initial days after the induction of seizures by a single intrahippocampal injection of kainic acid, a strong release of zinc and heparin-binding epidermal growth factor, both activators of the EGFR signaling pathway in neural stem cells, is produced. Administration of the EGFR inhibitor gefitinib, a chemotherapeutic in clinical phase IV, prevents the induction of React-NSCs and preserves neurogenesis.
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Receptores ErbB , Factor de Crecimiento Similar a EGF de Unión a Heparina , Hipocampo , Células-Madre Neurales , Neurogénesis , Convulsiones , Transducción de Señal , Animales , Receptores ErbB/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Factor de Crecimiento Similar a EGF de Unión a Heparina/metabolismo , Convulsiones/metabolismo , Neurogénesis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Masculino , Modelos Animales de Enfermedad , Gefitinib/farmacología , Epilepsia del Lóbulo Temporal/metabolismo , Diferenciación Celular/efectos de los fármacos , Ácido Kaínico/farmacología , Ratones Endogámicos C57BLRESUMEN
The trigeminal ganglion, the largest of the vertebrate cranial ganglia, is comprised of sensory neurons that relay sensations of pain, touch, and temperature to the brain. These neurons are derived from two embryonic cell types, the neural crest and ectodermal placodes, whose interactions are critical for proper ganglion formation. While the T-cell leukemia homeobox 3 (Tlx3) gene is known to be expressed in placodally-derived sensory neurons and necessary for their differentiation, little was known about Tlx3 expression and/or function in the neural crest-derived component of the developing trigeminal ganglion. By combining lineage labeling with in situ hybridization in the chick embryo, we show that neural crest-derived cells that contribute to the cranial trigeminal ganglion express Tlx3 at a time point that coincides with the onset of ganglion condensation. Importantly, loss of Tlx3 function in vivo diminishes the overall size and abundance of neurons within the trigeminal ganglion. Conversely, ectopic expression of Tlx3 in migrating cranial neural crest results in their premature neuronal differentiation. Taken together, our results demonstrate a critical role for Tlx3 in neural crest-derived cells during chick trigeminal gangliogenesis.
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Diferenciación Celular , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio , Cresta Neural , Ganglio del Trigémino , Animales , Ganglio del Trigémino/metabolismo , Ganglio del Trigémino/embriología , Ganglio del Trigémino/citología , Embrión de Pollo , Cresta Neural/metabolismo , Cresta Neural/embriología , Cresta Neural/citología , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Neuronas/metabolismo , Neurogénesis/genética , Movimiento Celular , Linaje de la CélulaRESUMEN
Congenital hydrocephalus (CH), occurring in approximately 1/1,000 live births, represents an important clinical challenge due to the limited knowledge of underlying molecular mechanisms. The discovery of novel CH genes is thus essential to shed light on the intricate processes responsible for ventricular dilatation in CH. Here, we identify FLVCR1 (feline leukemia virus subgroup C receptor 1) as a gene responsible for a severe form of CH in humans and mice. Mechanistically, our data reveal that the full-length isoform encoded by the FLVCR1 gene, FLVCR1a, interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1a in mouse neural progenitor cells (NPCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NPCs calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.
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Calcio , Hidrocefalia , Proteínas de Transporte de Membrana , Mitocondrias , Células-Madre Neurales , Receptores Virales , Animales , Humanos , Ratones , Calcio/metabolismo , Hidrocefalia/metabolismo , Hidrocefalia/genética , Hidrocefalia/patología , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Membrana/genética , Mitocondrias/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neurogénesis/genética , Receptores Virales/metabolismo , Receptores Virales/genéticaRESUMEN
Congenital human cytomegalovirus (HCMV) infection is a major cause of abnormalities and disorders in the central nervous system (CNS) and/or the peripheral nervous system (PNS). However, the complete pathogenesis of neural differentiation disorders caused by HCMV infection remains to be fully elucidated. Stem cells from human exfoliated deciduous teeth (SHEDs) are mesenchymal stem cells (MSCs) with a high proliferation and neurogenic differentiation capacity. Since SHEDs originate from the neural crest of the early embryonic ectoderm, SHEDs were hypothesized to serve as a promising cell line for investigating the pathogenesis of neural differentiation disorders in the PNS caused by congenital HCMV infection. In this work, SHEDs were demonstrated to be fully permissive to HCMV infection and the virus was able to complete its life cycle in SHEDs. Under neurogenic inductive conditions, HCMV infection of SHEDs caused an abnormal neural morphology. The expression of stem/neural cell markers was also disturbed by HCMV infection. The impairment of neural differentiation was mainly due to a reduction of intracellular cholesterol levels caused by HCMV infection. Sterol regulatory element binding protein-2 (SREBP2) is a critical transcription regulator that guides cholesterol synthesis. HCMV infection was shown to hinder the migration of SREBP2 into nucleus and resulted in perinuclear aggregations of SREBP2 during neural differentiation. Our findings provide new insights into the prevention and treatment of nervous system diseases caused by congenital HCMV infection.
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Diferenciación Celular , Colesterol , Infecciones por Citomegalovirus , Citomegalovirus , Células Madre Mesenquimatosas , Proteína 2 de Unión a Elementos Reguladores de Esteroles , Humanos , Colesterol/metabolismo , Colesterol/biosíntesis , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Citomegalovirus/fisiología , Citomegalovirus/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/virología , Células Madre Mesenquimatosas/citología , Células Cultivadas , Diente Primario/virología , Diente Primario/citología , Diente Primario/metabolismo , Neuronas/metabolismo , Neuronas/virología , NeurogénesisRESUMEN
Cocoa is widely known for its health benefits, but its neurocognitive impact remains underexplored. This preclinical study aimed to investigate the effects of cocoa and cocoa polyphenols on hippocampal neuroplasticity, cognitive function and emotional behavior. Seventy young-adult C57BL/6JRj male and female mice were fed either a standard diet (CTR) or a diet enriched with 10% high-phenolic content cocoa (HPC) or low-phenolic content cocoa (LPC) for at least four weeks. In a first experiment, behavioral tests assessing exploratory behavior, emotional responses and hippocampal-dependent memory were conducted four weeks into the diet, followed by animal sacrifice a week later. Adult hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) expression in the hippocampus and prefrontal cortex were evaluated using immunohistochemistry and western blot. In a different experiment, hippocampal synaptic response, long-term potentiation and presynaptic-dependent short-term plasticity were studied by electrophysiology. Cocoa-enriched diets had minimal effects on exploratory activity and anxiety-like behavior, except for reduced locomotion in the LPC group. Only the HPC diet enhanced object recognition memory, while place recognition memory and spatial navigation remained unaffected. The HPC diet also increased adult hippocampal neurogenesis, boosting the proliferation, survival and number of young adult-born neurons. However, both cocoa-enriched diets increased immobility in the forced swimming test and hippocampal BDNF expression. Hippocampal electrophysiology revealed no alterations in neuroplasticity among diets. The results were mostly unaffected by sex. Overall, the HPC diet demonstrated greater potential regarding cognitive and neuroplastic benefits, suggesting a key role of cocoa flavanols in dietary interventions aimed at enhancing brain health.
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Factor Neurotrófico Derivado del Encéfalo , Cacao , Hipocampo , Memoria , Ratones Endogámicos C57BL , Neurogénesis , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Neurogénesis/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones , Masculino , Femenino , Memoria/efectos de los fármacos , Cacao/química , Plasticidad Neuronal/efectos de los fármacos , DietaRESUMEN
OBJECTIVE: To investigate the effects of luteolin on chronic unpredictable mild stress (CUMS)-induced depressive rats and corticosterone (CORT)-induced depressive primary hippocampal neurons, and to elucidate the mechanism behind the action. METHODS: The antidepressant mechanism of luteolin was studied by using CUMS rat model and primary hippocampal neurons in fetal rats. In vivo, novelty suppressed feeding, open-field and sucrose preference tests as well as Morris water maze were evaluated. The content of brain derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) in serum were detected by enzyme-linked immunosorbent assay. The mechanisms of luteolin were explored based on neurotrophin and hippocampal neurogenesis, and proliferation. Survival of the septo-temporal axis in hippocampus was assayed using the 5-bromo-2-deoxyuridine (BrdU), the expression of BDNF, neurotrophin-3 (NT-3), and nerve growth factor (NGF) in hippocampus dentate gyrus region were measured by Western-blotting. In vitro, BDNF, NT-3, tropomyosin receptor kinase B (TrkB), and phosphorylated cyclic adenosine monophosphate responsive element binding protein (p-CREB) were detected through the high content analysis (HCA) to investigate neurotrophin and apoptosis. RESULTS: Induction of CUMS in rats induced depressive symptoms, while luteolin significantly enhanced sucrose consumption, decreased feeding latency, increased locomotor activity, escape latency, distance of target quadrant and regulated the content of depressive-like biomarkers. Histology analysis revealed that luteolin increased the abundance of new born neurons that had been labeled with BrdU, BrdU + neuronal nuclear antigen, and BrdU + doublecortin in septo-temporal axis of S2 (mid-septal) and T3 (mid-temporal). Moreover, expression of BDNF, NT-3, and NGF increased significantly in the septo-temporal axis of S2 and T3. HCA showed increased expression of BDNF, NT-3, TrkB and p-CREB in primary hippocampal neurons. CONCLUSION: The results provided direct evidence that luteolin has an antidepressant effect and could effectively promote the regeneration of the septotemporal axis nerve and hippocampal neuronutrition, which suggested that the antidepressant effect of luteolin may be related to hippocampal neurogenesis.
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Factor Neurotrófico Derivado del Encéfalo , Hipocampo , Luteolina , Neurogénesis , Neuronas , Ratas Sprague-Dawley , Animales , Luteolina/farmacología , Ratas , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Neurogénesis/efectos de los fármacos , Masculino , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Humanos , Estrés Psicológico/fisiopatología , Estrés Psicológico/tratamiento farmacológico , Femenino , Depresión/tratamiento farmacológico , Depresión/metabolismo , Depresión/fisiopatología , Antidepresivos/farmacología , Neurotrofina 3/metabolismo , Neurotrofina 3/genéticaRESUMEN
Schizophrenia impacts about 1 % of the global population, with clozapine (CLZ) being a critical treatment for refractory cases despite its limitations in effectiveness and adverse effects. Therefore, the search for more effective treatments remains urgent. Light treatment (LT) recognized for enhancing cognition and mood, presents a promising complementary approach. This study investigated the effects of CLZ and LT on cognitive impairments in a sub-chronic MK-801 induced schizophrenia mouse model. Results showed that both CLZ and CLZ + LT treatment elevate cognitive performance of sub-chronic MK-801 treated mice in serial behavioral tests over two months. Histological analysis revealed increased dendritic spine density and branching, and synaptic repair in the hippocampus with CLZ and CLZ + LT interventions. Furthermore, both treatments increased brain-derived neurotrophic factor (BDNF) expression in the hippocampus, likely contributing to cognitive amelioration in MK-801 treated mice. Additionally, BrdU labeling revealed that CLZ + LT further enhances neurogenesis in the dentate gyrus (DG) and lateral ventricle (LV) of sub-chronic MK-801 treated mice. These findings may have implications for the development of noninvasive and adjunctive treatment strategies aimed at alleviating cognitive impairments and improving functional outcomes in individuals with schizophrenia.
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Antipsicóticos , Clozapina , Disfunción Cognitiva , Maleato de Dizocilpina , Hipocampo , Neurogénesis , Plasticidad Neuronal , Esquizofrenia , Animales , Clozapina/farmacología , Maleato de Dizocilpina/farmacología , Ratones , Neurogénesis/efectos de los fármacos , Masculino , Disfunción Cognitiva/tratamiento farmacológico , Esquizofrenia/tratamiento farmacológico , Plasticidad Neuronal/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Antipsicóticos/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Luz , Terapia CombinadaRESUMEN
Puberty is a critical period of emotional development and neuroplasticity. However, most studies have focused on early development, with limited research on puberty, particularly the parental presence. In this study, four groups were established, and pubertal maternal presence (PMP) was assessed until postnatal days 21 (PD21), 28 (PD28), 35 (PD35), and 42 (PD42), respectively. The social interaction and anxiety behaviors, as well as the expression of oxytocin (OT) in the paraventricular nucleus (PVN) and supraoptic nucleus (SON), and the number of new generated neurons and the expression of estrogen receptor alpha (ERα) in the dentate gyrus (DG) were assessed. The results suggest that there is a lot of physical contact between the mother and offspring from 21 to 42 days of age, which reduces anxiety in both female and male offspring in adulthood; for example, the PMP increased the amount of time mice spent in the center area in the open field experiment and in the bright area in the light-dark box experiment. PMP increased OT expression in the PVN and SON and the number of newly generated neurons in the DG. However, there was a sexual difference in ERα, with ERα increasing in females but decreasing in males. In conclusion, PMP reduces the anxiety of offspring in adulthood, increases OT in the PVN and SON, and adult neurogenesis; ERα in the DG may be involved in this process.
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Ansiedad , Giro Dentado , Receptor alfa de Estrógeno , Neurogénesis , Oxitocina , Núcleo Hipotalámico Paraventricular , Animales , Ansiedad/metabolismo , Ratones , Masculino , Femenino , Receptor alfa de Estrógeno/metabolismo , Oxitocina/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Giro Dentado/metabolismo , Maduración Sexual , Núcleo Supraóptico/metabolismo , Conducta Materna/fisiología , Conducta Animal , Interacción SocialRESUMEN
Microglia (µG), the resident immune cells in the central nervous system, surveil the parenchyma to maintain the structural and functional homeostasis of neurons. Besides, they influence neurogenesis and synaptogenesis through complement-mediated phagocytosis. Emerging evidence suggests that µG may also influence development through proinflammatory cytokines. Here, we examined the premise that tumor necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß), the two most prominent components of the µG secretome, influence retinal development, specifically the morphological and functional differentiation of human retinal ganglion cells (hRGCs). Using controlled generation of hRGCs and human µG (hµG) from pluripotent stem cells, we demonstrate that TNF-α and IL-1ß secreted by unchallenged hµG did not influence hRGC generation. However, their presence significantly facilitated neuritogenesis along with the basal function of hRGCs, which involved the recruitment of the AKT/mTOR pathway. We present ex vivo evidence that proinflammatory cytokines may play an important role in the morphological and physiological maturation of hRGCs, which may be recapitulated for regeneration.
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Diferenciación Celular , Citocinas , Microglía , Células Ganglionares de la Retina , Humanos , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/citología , Microglía/metabolismo , Microglía/citología , Citocinas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacología , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Neurogénesis , Regeneración , Mediadores de Inflamación/metabolismo , Regeneración NerviosaRESUMEN
Critical-size bone defect repair presents multiple challenges, such as osteogenesis, vascularization, and neurogenesis. Current biomaterials for bone repair need more consideration for the above functions. Organic-inorganic composites combined with bioactive ions offer significant advantages in bone regeneration. In our work, we prepared an organic-inorganic composite material by blending polylactic acid (PLA) with 3-aminopropyltriethoxysilane (APTES)-modified magnesium silicate (A-M2S) and fabricated it by 3D printing. With the increase of A-M2S proportion, the hydrophilicity and mineralization ability showed an enhanced trend, and the compressive strength and elastic modulus were increased from 15.29 MPa and 94.61 MPa to 44.30 MPa and 435.77 MPa, respectively. Furthermore, A-M2S/PLA scaffolds not only exhibited good cytocompatibility of bone marrow mesenchymal stem cells (BMSCs), human umbilical vein endothelial cells (HUVECs), and Schwann cells (SCs), but also effectively promoted osteogenesis, angiogenesis, and neurogenesis in vitro. After implanting 10% A-M2S/PLA scaffolds in vivo, the scaffolds showed the most effective repair of cranium defects compared to the blank and control group (PLA). Additionally, they promoted the secretion of proteins related to bone regeneration and neurovascular formation. These results provided the basis for expanding the application of A-M2S and PLA in bone tissue engineering and presented a novel concept for neurovascularized bone repair.
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Regeneración Ósea , Células Endoteliales de la Vena Umbilical Humana , Silicatos de Magnesio , Células Madre Mesenquimatosas , Osteogénesis , Poliésteres , Impresión Tridimensional , Andamios del Tejido , Regeneración Ósea/efectos de los fármacos , Andamios del Tejido/química , Poliésteres/química , Humanos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Osteogénesis/efectos de los fármacos , Animales , Silicatos de Magnesio/química , Ingeniería de Tejidos/métodos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Células de Schwann/efectos de los fármacos , Células de Schwann/citología , Silanos/química , Silanos/farmacología , Neurogénesis/efectos de los fármacos , Propilaminas/química , Propilaminas/farmacología , Neovascularización Fisiológica/efectos de los fármacosRESUMEN
INTS11 and CPSF73 are metal-dependent endonucleases for Integrator and pre-mRNA 3'-end processing, respectively. Here, we show that the INTS11 binding partner BRAT1/CG7044, a factor important for neuronal fitness, stabilizes INTS11 in the cytoplasm and is required for Integrator function in the nucleus. Loss of BRAT1 in neural organoids leads to transcriptomic disruption and precocious expression of neurogenesis-driving transcription factors. The structures of the human INTS9-INTS11-BRAT1 and Drosophila dIntS11-CG7044 complexes reveal that the conserved C terminus of BRAT1/CG7044 is captured in the active site of INTS11, with a cysteine residue directly coordinating the metal ions. Inspired by these observations, we find that UBE3D is a binding partner for CPSF73, and UBE3D likely also uses a conserved cysteine residue to directly coordinate the active site metal ions. Our studies have revealed binding partners for INTS11 and CPSF73 that behave like cytoplasmic chaperones with a conserved impact on the nuclear functions of these enzymes.
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Núcleo Celular , Citoplasma , Proteínas de Drosophila , Unión Proteica , Humanos , Animales , Núcleo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Citoplasma/metabolismo , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Endonucleasas/metabolismo , Endonucleasas/genética , Células HEK293 , Neurogénesis/genética , Factor de Especificidad de Desdoblamiento y Poliadenilación/metabolismo , Factor de Especificidad de Desdoblamiento y Poliadenilación/genética , Dominio CatalíticoRESUMEN
Neuronal differentiation requires building a complex intracellular architecture, and therefore the coordinated regulation of defined sets of genes. RNA-binding proteins (RBPs) play a key role in this regulation. However, while their action on individual mRNAs has been explored in depth, the mechanisms used to coordinate gene expression programs shaping neuronal morphology are poorly understood. To address this, we studied how the paradigmatic RBP IMP1 (IGF2BP1), an essential developmental factor, selects and regulates its RNA targets during the human neuronal differentiation. We perform a combination of system-wide and molecular analyses, revealing that IMP1 developmentally transitions to and directly regulates the expression of mRNAs encoding essential regulators of the microtubule network, a key component of neuronal morphology. Furthermore, we show that m6A methylation drives the selection of specific IMP1 mRNA targets and their protein expression during the developmental transition from neural precursors to neurons, providing a molecular principle for the onset of target selectivity.
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Diferenciación Celular , Microtúbulos , Neuronas , ARN Mensajero , Proteínas de Unión al ARN , Humanos , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Microtúbulos/metabolismo , Neuronas/metabolismo , Neuronas/citología , Diferenciación Celular/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética , Metilación , Neurogénesis/genética , Adenosina/metabolismo , Adenosina/análogos & derivados , Regulación del Desarrollo de la Expresión GénicaRESUMEN
Increasing evidence shows that the administration of mesenchymal stem cells (MSCs) is a promising option for various brain diseases, including ischemic stroke. Studies have demonstrated that MSC transplantation after ischemic stroke provides beneficial effects, such as neural regeneration, partially by activating endogenous neural stem/progenitor cells (NSPCs) in conventional neurogenic zones, such as the subventricular and subgranular zones. However, whether MSC transplantation regulates the fate of injury-induced NSPCs (iNSPCs) regionally activated at injured regions after ischemic stroke remains unclear. Therefore, mice were subjected to ischemic stroke, and mCherry-labeled human MSCs (h-MSCs) were transplanted around the injured sites of nestin-GFP transgenic mice. Immunohistochemistry of brain sections revealed that many GFP+ cells were observed around the grafted sites rather than in the regions in the subventricular zone, suggesting that transplanted mCherry+ h-MSCs stimulated GFP+ locally activated endogenous iNSPCs. In support of these findings, coculture studies have shown that h-MSCs promoted the proliferation and neural differentiation of iNSPCs extracted from ischemic areas. Furthermore, pathway analysis and gene ontology analysis using microarray data showed that the expression patterns of various genes related to self-renewal, neural differentiation, and synapse formation were changed in iNSPCs cocultured with h-MSCs. We also transplanted h-MSCs (5.0 × 104 cells/µL) transcranially into post-stroke mouse brains 6 weeks after middle cerebral artery occlusion. Compared with phosphate-buffered saline-injected controls, h-MSC transplantation displayed significantly improved neurological functions. These results suggest that h-MSC transplantation improves neurological function after ischemic stroke in part by regulating the fate of iNSPCs.
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Accidente Cerebrovascular Isquémico , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Células-Madre Neurales , Animales , Humanos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/trasplante , Células-Madre Neurales/citología , Trasplante de Células Madre Mesenquimatosas/métodos , Ratones , Accidente Cerebrovascular Isquémico/terapia , Accidente Cerebrovascular Isquémico/metabolismo , Diferenciación Celular , Ratones Transgénicos , Masculino , Proliferación Celular , Neurogénesis , Ratones Endogámicos C57BLRESUMEN
Up to 25% of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit postacute cognitive sequelae. Although millions of cases of coronavirus disease 2019 (COVID-19)-mediated memory dysfunction are accumulating worldwide, the underlying mechanisms and how vaccination lowers risk are unknown. Interleukin-1 (IL-1), a key component of innate immune defense against SARS-CoV-2 infection, is elevated in the hippocampi of individuals with COVID-19. Here we show that intranasal infection of C57BL/6J mice with SARS-CoV-2 Beta variant leads to central nervous system infiltration of Ly6Chi monocytes and microglial activation. Accordingly, SARS-CoV-2, but not H1N1 influenza virus, increases levels of brain IL-1ß and induces persistent IL-1R1-mediated loss of hippocampal neurogenesis, which promotes postacute cognitive deficits. Vaccination with a low dose of adenoviral-vectored spike protein prevents hippocampal production of IL-1ß during breakthrough SARS-CoV-2 infection, loss of neurogenesis and subsequent memory deficits. Our study identifies IL-1ß as one potential mechanism driving SARS-CoV-2-induced cognitive impairment in a new mouse model that is prevented by vaccination.
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COVID-19 , Hipocampo , Interleucina-1beta , Trastornos de la Memoria , Ratones Endogámicos C57BL , Neurogénesis , SARS-CoV-2 , Animales , Interleucina-1beta/metabolismo , Interleucina-1beta/inmunología , Ratones , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Hipocampo/inmunología , Hipocampo/metabolismo , Trastornos de la Memoria/inmunología , Neurogénesis/inmunología , Vacunación , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas contra la COVID-19/inmunología , Masculino , Humanos , Microglía/inmunología , Microglía/metabolismo , Modelos Animales de Enfermedad , Receptores Tipo I de Interleucina-1/metabolismo , Receptores Tipo I de Interleucina-1/genética , Monocitos/inmunología , Monocitos/metabolismo , FemeninoRESUMEN
Bioenergetics describe the biochemical processes responsible for energy supply in organisms. When these changes become dysregulated in brain development, multiple neurodevelopmental diseases can occur, implicating bioenergetics as key regulators of neural development. Historically, the discovery of disease processes affecting individual stages of brain development has revealed critical roles that bioenergetics play in generating the nervous system. Bioenergetic-dependent neurodevelopmental disorders include neural tube closure defects, microcephaly, intellectual disability, autism spectrum disorders, epilepsy, mTORopathies, and oncogenic processes. Developmental timing and cell-type specificity of these changes determine the long-term effects of bioenergetic disease mechanisms on brain form and function. Here, we discuss key metabolic regulators of neural progenitor specification, neuronal differentiation (neurogenesis), and gliogenesis. In general, transitions between glycolysis and oxidative phosphorylation are regulated in early brain development and in oncogenesis, and reactive oxygen species (ROS) and mitochondrial maturity play key roles later in differentiation. We also discuss how bioenergetics interface with the developmental regulation of other key neural elements, including the cerebrospinal fluid brain environment. While questions remain about the interplay between bioenergetics and brain development, this review integrates the current state of known key intersections between these processes in health and disease.