Search Results (137)

Tuberous Sclerosis Complex (TSC) is a genetic disorder caused by mutations that inactivate TSC1 or TSC2 genes. TSC1 or TSC2 mutations activate the mammalian target of rapamycin complex 1 (mTORC1) protein kinase pathway. Although many patients inherit a single copy of a mutant TSC gene, somatic mutations that cause loss of heterozygosity in inhibitory neuroprogenitor cells are hypothesized to be one cause of abnormal development. This may lead to cortical malformations or benign growths along the ventricular-subventricular zone (V-SVZ), cortex, olfactory tract, and olfactory bulbs (OB). This idea is supported by focal single-cell knockout experiments that induce CRE-mediated recombination following neonatal electroporation of conditional Tsc2 or Tsc1 mice. Loss of Tsc2 causes mTORC1 pathway activation and the formation of striatal hamartomas composed of ectopic clusters of abnormal cells and cytomegalic neurons, including within the OB. Neural phenotypes in this model can be partially rescued with Rapalink-1, a bisteric mTOR inhibitor, demonstrating the importance of mTOR in pathogenesis. We previously demonstrated that global V-SVZ neural stem cell (NSC) Tsc2 mutation induced by nestin-CRE-ER^T2 causes mTORC1 pathway activation, which is accompanied by transcriptional and translational errors. While we previously described cultured NSCs and OB granule cells from these mice, we did not thoroughly describe changes outside this region. Here, we provide evidence that removal of Tsc2 from neonatal V-SVZ NSCs causes subtle and rare brain malformations. This is exemplified by ectopic clusters of cytomegalic neurons and mTORC1 activation. This data supports that loss of Tsc2 in NSCs during neonatal development leads to heterotopic clusters in the adult brain. This model may be useful to study TSC, but the rarity and stochastic nature of lesions make the use challenging for identifying mechanisms and testing therapies. Full article

Paternal deprivation has behavioral, neurochemical, and neuroendocrine consequences in adulthood. Socially monogamous prairie voles (Microtus ochrogaster) raised only by the mother (monoparental care, MP) showed low levels of alloparental behavior and delayed pair bonding formation in adulthood compared to those raised by both parents (biparental care, BP). However, the effects of paternal deprivation on adult neurogenesis and the epigenetic mechanisms involved remain to be elucidated. Here, we focused on the impact of MP rearing on neural stem cells (NSCs) proliferation under basal conditions and in response to cohabitation with the sexual partner during pair bonding formation. At basal conditions, we found a significant decrease in the number of new proliferative NSCs (BrdU⁺/SOX2⁺) in male and female MP voles compared to BP animals in the subventricular (SVZ) and subgranular zone (SGZ). After 24 h of cohabitation, in MP males, there was an increase in the number of newborn cells in the SVZ but not in the SGZ. However, this increased proliferation was lower than in BP males. In females, we did not observe significant differences compared to controls. Finally, we evaluated the enrichment of H3K4me3 (activation) and H3K27me3 (silencing) epigenetic marks in the new cells, finding differences between rearing systems and sexes. Full article

Background/Objectives: Maternal immune activation (MIA) increases the risk of Autism Spectrum Disorders (ASD). Experimental models demonstrate that maternal exposure to bacterial endotoxin or the viral mimic polyinosinic:polycytidylic acid [poly (I:C)] reliably recapitulates ASD-like behavioral abnormalities in offspring, yet the underlying neurobiological mechanisms linking MIA to altered neurodevelopment remain incompletely understood. Increasing evidence highlights the placenta as a critical mediator in shaping fetal brain development through immunological and hormonal regulation. Likewise, disruption of placental regulatory functions upon MIA may therefore represent a mechanistic pathway. Here, we investigated how alterations in placental cytokine profiles, innate immune cell composition, and endocrine outputs relate to neuroinflammation and neurogenesis in the offspring. Methods: Pregnant mice at gestational day 12.5 received a single intraperitoneal injection of poly (I:C). Placental macrophages, neutrophils, inflammatory cytokines, and nerve growth factor (NGF) expression were examined 72 h later. Neurodevelopmental outcomes, including microglial activity and neurogenic markers, were evaluated in mouse offspring at postnatal day (P) 1 and 6. Results: MIA induced a significant accumulation of monocytes and neutrophils in the placenta, which was associated with elevated levels of a broad spectrum of inflammatory mediators, including Th17-biased proinflammatory cytokines, chemokines, and adhesion proteins, in the placenta and amniotic fluid. In contrast, the placenta-derived NGF levels were significantly reduced. MIA induced strong and sustained microglial activation in the fetal and neonatal brain. This inflammatory milieu was accompanied by disrupted cortical neurogenesis, characterized by a marked increase in Ki67+ neuronal progenitor cells (NPCs) in the subventricular zone (SVZ), overproduction of early-born Tbr1+ neurons at P1, later-born Satb2+ neurons at P6. Conclusions: Collectively, these findings suggest that heightened Th17 inflammatory signaling, coupled with impaired placental endocrine function, contributes to dysregulated cortical neurogenesis in the offspring. Full article

Background/Objectives: Neuroinflammation is a leading factor in secondary brain damage following a traumatic brain injury (TBI). Existing therapeutic approaches have limited efficacy against neuroinflammation. The bone marrow, the primary hematopoietic organ, is also a source of inflammatory cells. We propose that targeting the sympathetic regulation of inflammatory cell mobilization could reduce neuroinflammation after TBI. Methods: In ICR mice, we investigated the immune cell response in the blood, bone marrow, motor cortex, and the subventricular zone after TBI modeling and treatment with the sympatholytic agent reserpine. Results: TBI induced neutrophilia and lymphocytosis in the peripheral blood, activated hematopoiesis in the bone marrow, and triggered neuroinflammation and degenerative changes in the cerebral cortex (CC) and the subventricular zone (SVZ) of mice. Reserpine reduced leukocytosis in the blood and hematopoietic activity in the bone marrow of mice with TBI compared to untreated TBI mice. Furthermore, reserpine decreased neutrophilic and lymphocytic infiltration, as well as the number of Iba1⁺ microglial cells, including M1-polarized microglia, Caspase-3⁺ cells, and cells expressing myeloperoxidase (MPO) in the CC and SVZ of treated mice. The activity of degenerative processes was also reduced. Additionally, reserpine reduced the number of M2-polarized microglial cells in the SVZ. Conclusions: The sympatholytic drug reserpine may hold promise for the development of a novel approach to treating neuroinflammation and degeneration following a TBI. This is based on its ability to reduce hematopoiesis and mobilize inflammatory cells from the bone marrow into the bloodstream. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β (Aβ) pathology, synaptic degeneration, impaired neurogenesis, and chronic neuroinflammation. KBN2202, a small-molecule salicylic acid derivative [2-[(2-naphthalen-1-yloxy)ethyl]amino]-4-hydroxybenzoic acid], was investigated for its potential as a multi-target therapeutic agent in advanced-stage AD. To this end, 9-month-old 5xFAD mice with established AD-like pathology received daily oral KBN2202 (5 or 20 mg/kg) or vehicle for 12 weeks. KBN2202 demonstrated broad histopathological benefits. It preserved hippocampal CA1 cytoarchitecture and increased dendritic length in cortical neurons. Neurogenic activity was also enhanced, with elevated doublecortin (DCX) expression in the subventricular zone (SVZ). At the molecular level, KBN2202 reduced amyloid precursor protein C-terminal fragments (APP-CTFs), key intermediates in amyloidogenic processing, and histological staining confirmed a significant reduction in fibrillar and diffuse Aβ plaque burden in the cortex and hippocampus. Furthermore, KBN2202 attenuated astrocytic and microglial activation, indicating suppression of chronic neuroinflammation. In behavioral assessments, KBN2202 significantly improved recognition memory in the novel object recognition (NOR) test, while Y-maze performance remained unchanged. Overall, the compound exhibited robust neuroprotective, pro-neurogenic, anti-amyloid, and anti-inflammatory effects. These findings support the therapeutic potential of KBN2202 as a multi-functional candidate for symptomatic-stage AD. Full article

Adult neurogenesis is well established in canonical niches—the dentate gyrus and the subventricular zone, where aerobic exercise reliably enhances progenitor proliferation, survival, and synaptic integration via increased cerebral blood flow, neurotrophins (e.g., BDNF, IGF-1), neurotransmitter regulation, and reduced neuroinflammation. Nutraceuticals (e.g., polyphenols, omega-3, creatine, vitamins) further support neuroplasticity and neuronal survival through convergent trophic, anti-inflammatory, and metabolic pathways. By contrast, the hypothalamus, a metabolically pivotal, non-canonical niche, remains comparatively understudied. Here, we synthesize anatomical and functional features of hypothalamic neural stem cells, primarily tanycytes (α1, α2, β1, β2), which line the third ventricle and differentially contribute to neuronal activity regulation, metabolic signaling, and cerebrospinal fluid–portal vasculature coupling, thereby linking neurogenesis to endocrine control. Notably, tanycytes can form neurospheres in vitro, enabling mechanistic interrogation. Although evidence for adult hypothalamic neurogenesis in humans is debated due to methodological constraints, animal data suggest potential relevance to disorders characterized by neuronal loss, metabolic dysregulation, and impaired neuroendocrine function. We propose that an integrative framework is timely: exercise and diet likely interact in the hypothalamic niche through shared mediators (BDNF, IGF-1, CNTF, GPR40) and exercise-derived signals (e.g., lactate, IL-6) that may be complemented by defined nutraceuticals. Yet critical uncertainties persist, including the extent of bona fide hypothalamic neurogenesis, nucleus-specific responses (arcuate nucleus, paraventricular nucleus, ventromedial hypothalamic nucleus), and the mechanistic integration of lifestyle signals in this region. To address these gaps, we outline actionable priorities: (i) single-cell and lineage-tracing studies of tanycyte subtypes under distinct training modalities (aerobic, high-intensity interval training, resistance); (ii) combinatorial interventions pairing structured exercise with nutraceuticals to test synergy on progenitor dynamics and inflammation; and (iii) multi-omics and translational studies to identify biomarkers and establish clinical relevance. Clarifying these interactions will determine whether lifestyle and supplementation strategies can synergistically modulate hypothalamic neurogenesis and inform therapies for neurological, neuropsychiatric, and metabolic disorders. Full article

The glial tube is a longitudinal structure predominantly composed of densely bundled, aligned astrocytes that projects from the subventricular zone (SVZ) to the olfactory bulb. Neural precursor cells (NPCs) generated in the SVZ migrate through this glial tube—referred to as the rostral migratory stream (RMS)—to replace olfactory bulb interneurons in the mammalian brain. RMS astrocytes have distinct morphological and functional characteristics. These characteristics facilitate the unique purpose of the RMS as an endogenous living scaffold directing NPC migration and maturation. However, the transcriptomic factors underlying these unique structure–function attributes versus standard stellate astrocytes have not been examined. We previously developed biofabrication techniques to create the first tissue-engineered rostral migratory stream (TE-RMS) that replicates key features of the glial tube in vivo. We have shown that TE-RMS astrocytes exhibit elongated nuclei, longitudinally aligned intermediate filaments, and enrichment of key functional proteins—cytoarchitectural and surface features characteristic of native RMS astrocytes. In the current study, we performed RNA-seq on TE-RMS astrocytes in comparison to planar astrocyte cultures to identify gene expression patterns that may underlie their profound morphological and functional differences. Remarkably, we found 4,008 differentially expressed genes in TE-RMS astrocytes, with 2076 downregulated (e.g., LOC690251 and ccn5) and 1932 upregulated (e.g., lrrc45 and cntn1) compared to planar astrocytes. Moreover, there were 256 downregulated and 91 upregulated genes with >3-fold change. We also conducted analyses of gene sets related to cytoskeleton and nuclear structure, revealing the greatest enrichment of actin-related components. Overall, the TE-RMS offers a platform to study the interplay between transcriptomic and cytoarchitectural dynamics in a unique astrocyte population. Full article

Neuroinflammation is a key response to disturbed CNS homeostasis, largely mediated by activated microglia, and excessive microglia-driven inflammation can negatively impact neurogenesis. ZEB1 plays a crucial role in neurogenesis and brain development by influencing neural stem cell (NSC) maintenance, proliferation, and differentiation. This study aimed to evaluate how the knockdown of ZEB1 influences the behavior of NSCs in inflammatory environments. NSCs were isolated from the subventricular zone of rats, and ZEB1 knockdown was achieved using ZEB1 siRNA. A conditioned medium derived from lipopolysaccharide-activated microglia was utilized to induce inflammatory responses in NSCs. The silencing of ZEB1 in NSCs significantly reduced the expression of ZEB1. Furthermore, ZEB1 knockdown in NSCs resulted in a significant decrease in neurosphere formation, cell migration ability, reactive oxygen species generation, and various cytokine levels under both non-inflammatory and inflammatory conditions. These findings reveal the regulatory role of ZEB1 in the modulation of NSC behavior, suggesting that targeting ZEB1 may provide a potential therapeutic strategy for neuroinflammatory CNS disorders. Full article

While significant progress has been made in understanding the heterogeneity of Neural Stem Cells (NSCs), our understanding of similar heterogeneity among the more abundant transit amplifying progenitors is lagging. Our work on the neural progenitors (NPs) of the neonatal subventricular zone (SVZ) began over a decade ago, when we used antibodies to the four antigens, CD133, LeX, CD140a, and NG2 to perform Fluorescence-activated cell sorting to classify subsets of the neonatal mouse SVZ as either multi-potential (MP1, MP2, MP3, MP4 and PFMPs), glial-restricted (GRP1, GRP2, and GRP3), or neuron-astrocyte restricted (BNAP). Using RNA sequencing, we have characterized the distinctive molecular fingerprints of four SVZ neural progenitor subtypes and compared their gene expression profiles to those of the NSCs. We performed bioinformatic analyses to provide insights into each NP type’s unique interactome and the transcription factors regulating their development. Overall, we identified 1581 genes upregulated in at least one NP subset compared to the NSCs. Of these genes, 796 genes were upregulated in BNAP/GRP1 compared to NSCs; 653 in GRP2/MP3; 440 in GRP3; and 527 in PFMPs. One gene that emerged from our analysis that can be used to distinguish the NPs from the NSCs is Etv1, also known as Er81. Also notable is that the NSCs downregulated cilia formation genes as they differentiated to become multipotential progenitors. Among the NPs, both PFMP and GRP3 subtypes differentially expressed genes related to neuron and oligodendrocyte development, including Matn4, Lhfpl3 and Olig2. GRP3s uniquely expressed Etv5, a transcription factor known to promote glial cell fate specification, while PFMPs uniquely expressed Lhx6, a transcription factor that regulates interneuron specification. PFMPs also expressed transcripts for olfactory receptors. Unlike the other NPs, the GRP1 and GRP2 NPs upregulated expression of genes for proteins involved in immune function. The present work will serve as an important resource for investigators interested in further defining the transit amplifying progenitors of the mammalian SVZ. Full article

Cellular transplantation therapies have been extensively used in experimental spinal cord injury research. However, there is no consensus as to what the most effective cellular controls for the therapeutic cell of interest are. For this reason, we examined whether dead cells obtained through prolonged heat treatment can act as an appropriate cellular control for intravenously injected Sca-1+ mesenchymal precursor cells (MPCs) in C5 unilateral contusion cervical spinal cord injury. This was tested in single intravenous MPC injection alone or intravenous MPC plus intraspinal neural stem cell (NSC) combinatory transplantation studies. MPCs were isolated from the compact bone of FVB mice, while NSCs were isolated from the subventricular zone of luciferase–GFP transgenic FVB mice. Dead MPCs were obtained by heating at 72 °C for at least 12 h. In the MPC only transplant study, injured mice received an injection of 1 × 10⁶ dead or live MPCs D1 post-injury. Mice were then sacrificed at 8 weeks post-injury. In this study, intravenous injections of dead MPCs showed no statistical difference in injured paw usage compared to live MPCs, but behavior was improved compared to the media-vehicle-only control at D7 and D21. In the combinatory MPC plus NSC transplant study, injured mice received an intravenous injection of 1 × 10⁶ dead or live MPCs D1 post-injury followed by intraspinal injection of 100,000 NSCs at D3 or D7 post-injury. Another two cohorts of mice received only NSCs at D3 or D7 post-injury. Mice were then sacrificed at 6 weeks post-injury. In this study, there was no functional difference in any of the groups in the dual injection study. Morphologically, mice receiving IV injection of dead MPCs had a smaller lesion size compared to the vehicular control, but the lesion size was larger than that of the lesion size in mice receiving live MPC injection. Dead cells elicited functional and anatomical benefits for the spinal-cord-injured mice. In summary, dead cells obtained through prolonged heat treatment proved to be inconsistent and not optimal for use as cellular controls for cell transplantation studies in spinal cord injury but provide positive evidence for non-transplantation-based cell therapies. Full article

Background: Spinal metastasis is a rare complication of supratentorial glioblastoma. We report the clinical features and prognosis of this phenomenon and review the relevant literature. Methods: This is a territory-wide, multicentre, retrospective review using data from the Hong Kong High-grade Glioma Registry from 2006 to 2023. Data of consecutive adult patients diagnosed with supratentorial glioblastoma and spinal metastasis were extracted and analyzed. Results: Among the 1342 patients with supratentorial glioblastoma, 15 were diagnosed to have spinal metastasis (1.1%). The median time to spinal metastasis from the initial diagnosis of glioblastoma was 38.7 weeks (IQR: 15.1–57.6). Multi-level spinal involvement was present in 60% (9/15) of patients. Neither the topographical location of the tumor in relation to the subventricular zone, extent of resection, occurrence of intraoperative ventricular entry, nor methylguanine methyltransferase (MGMT) promoter methylation status predicted the time to spinal metastasis. The median overall survival was 44.1 weeks (IQR: 29.9–80.2), and the median post-spinal metastasis survival was 12.6 weeks (IQR: 5.0–15.0). Two-thirds of patients received spinal radiotherapy, 26.7% had systemic therapy (chemotherapy, targeted therapy, and/or immunotherapy), and 13.3% underwent surgical spinal decompression. No significant survival improvement was observed among patients who received spinal radiotherapy (HR: 0.61; 95% CI: 0.17–2.23) or systemic therapy (HR: 0.94; 95% CI: 0.20–4.39). Conclusions: This case series illustrates the management practices and clinical course of glioblastoma patients with spinal metastasis. No treatment modality was proven to be superior. Treatment remains largely palliative and should be tailored on an individual basis. Full article

Neural stem/progenitor cells (NSPCs) in the subventricular zone (SVZ) of the central nervous system (CNS) are critical for tissue repair following injury or disease. These cells retain the capacity to proliferate, migrate, and differentiate into neurons, astrocytes, and oligodendrocytes, making them a promising therapeutic target for neurodegenerative disorders and traumatic injuries. However, the molecular mechanisms regulating their proliferation remain incompletely understood. This study investigates the role of cAMP responsive element-binding protein 5 (CREB5) in the proliferation of rat SVZ-derived NSPCs and elucidates its regulatory mechanism. Using RNA interference, we demonstrated that CREB5 knockdown significantly reduced cell viability, neurosphere formation capacity, and the number of proliferating cells (BrdU- and Ki-67-positive cells) both in vitro and in vivo. In contrast, CREB5 overexpression played opposing roles in cell proliferation. Additionally, alteration of CREB5 expression did not affect apoptosis, as assessed by TUNEL staining, indicating a specific role in proliferation rather than in cell death. Mechanistically, we identified Nuclear Factor One X (NFIX) as a transcriptional target of CREB5. CREB5 binds to the AP-1 site in the NFIX promoter, enhancing its expression. CREB5 knockdown inhibited NFIX expression, while CREB5 overexpression exerted the opposite function. ChIP and luciferase reporter assays further confirmed that CREB5 directly regulates NFIX promoter activity. More importantly, alteration of NFIX expression could reverse the effect of CREB5 on NSPC proliferation. These findings highlight CREB5 as a key regulator of NSPC proliferation through its interaction with NFIX, providing a potential therapeutic target for stem cell-based treatments of CNS disorders. Full article

Hydrocephalus is a neurological disorder caused by cerebrospinal fluid (CSF) accumulation due to impaired production, circulation, or reabsorption from trauma, neurocysticercosis, neoplasms, subarachnoid hemorrhage, or genetic mutations. This review examines glial remodeling in the ventricular–subventricular zone (V-SVZ) and corpus callosum (CC) in response to hydrocephalus, as ventricular enlargement leads to structural alterations that impact cellular composition in the V-SVZ and CC of patients with hydrocephalus. Animal models of hydrocephalus indicate V-SVZ niche remodeling, ependymal thinning, reduced neuroblast proliferation, increased microglia and astrocytes, increased cell death, and enlarged extracellular matrix structures (fractones). Alterations in the corpus callosum encompass a reduction in width, abnormalities in myelin, astrogliosis, microglial reactivity, a decreased expression of myelin-related proteins (MOG and CNPase), and a reduced number of oligodendrocytes. Additionally, this narrative review highlights important cellular and molecular findings before and after CSF diversion surgery. This primary treatment restores the ventricular size but does not completely reverse glial changes, indicating that ongoing neuroinflammatory processes may interfere with neural recovery. Full article

The rodent olfactory system is unique in harboring two distinct postnatal neurogenic niches, the olfactory epithelium and the subventricular zone. This results in the ongoing generation of both olfactory sensory neurons (OSNs), which provide odor input to the brain, and multiple molecularly distinct populations of GABAergic interneurons that modulate both input to and output from the olfactory bulb, continuing throughout life for some neuronal types. Here, we review the roles played by these postnatally generated neurons in olfactory processing, plasticity and regeneration. We identify specific roles for individual types of postnatally generated neurons, as well as identifying overarching principles that span multiple neuronal types. Full article

Neural stem cells (NSCs) are crucial components of the nervous system, primarily located in the subventricular zone (SVZ) and subgranular zone (SGZ). The SVZ neural stem cell niche (NSCN) is a specialized microenvironment where growth factors and extracellular matrix (ECM) components collaborate to regulate NSC self-renewal and differentiation. Despite its importance, our understanding of the SVZ remains incomplete due to the inherent challenges of animal research, particularly given the tissue’s dynamic nature. To address these limitations, we developed a proof-of-concept, dynamic, and tissue-specific 3D organotypic SVZ model to reduce reliance on animal models. This static 3D organotypic model integrates a region-specific decellularized ECM derived from the SVZ, mimicking the native NSCN and supporting mouse-derived ependymal cells (ECs), radial glial cells (RGCs), astrocytes, and NSCs. To further improve physiological relevance, we incorporated a dynamic microfluidic culture system (SVZonChip), replicating cerebrospinal fluid (CSF) flow as observed in vivo. The resulting SVZonChip platform, combining region-specific ECM proteins with dynamic culture conditions, provides a sustainable and reproducible tool to minimize animal model use. It holds significant promise for studying SVZ-related diseases, such as congenital hydrocephalus, stroke, and post-stroke neurogenesis, while advancing translational research and enabling personalized medicine protocols. Full article