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Although the molecular composition and architecture of synapses have been widely explored, much less is known about what genetic programs directly activate synaptic gene expression and how they are modulated. Here, using Caenorhabditis elegans dopaminergic neurons, we reveal that EGL-43/MECOM and FOS-1/FOS control an activity-dependent synaptogenesis program. Loss of either factor severely reduces presynaptic protein expression. Both factors bind directly to promoters of synaptic genes and act together with CUT homeobox transcription factors to activate transcription. egl-43 and fos-1 mutually promote each others expression, and increasing the binding affinity of FOS-1 to the egl-43 locus results in increased presynaptic protein expression and synaptic function. EGL-43 regulates the expression of multiple transcription factors, including activity-regulated factors and developmental factors that define multiple aspects of dopaminergic identity. Together, we describe a robust genetic program underlying activity-regulated synapse formation during development.

While extracellular matrix (ECM) stress relaxation is increasingly appreciated to regulate stem cell fate commitment and other behaviors, much remains unknown about how cells process stress-relaxation cues in tissue-like three-dimensional (3D) geometries versus traditional 2D cell culture. Here, we develop an oligonucleotide-crosslinked hyaluronic acid-based ECM platform with tunable stress relaxation properties capable of use in either 2D or 3D. Strikingly, stress relaxation favors neural stem cell (NSC) neurogenesis in 3D but suppresses it in 2D. RNA sequencing and functional studies implicate the membrane-associated protein spectrin as a key 3D-specific transducer of stress-relaxation cues. Confining stress drives spectrins recruitment to the F-actin cytoskeleton, where it mechanically reinforces the cortex and potentiates mechanotransductive signaling. Increased spectrin expression is also accompanied by increased expression of the transcription factor EGR1, which we previously showed mediates NSC stiffness-dependent lineage commitment in 3D. Our work highlights spectrin as an important molecular sensor and transducer of 3D stress-relaxation cues.

Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage results in lasting neurological deficits and an increased risk of autism. The impact of blood-induced pathways on cerebellar development remains largely unknown, so no specific treatments have been developed to counteract the harmful effects of blood after neurovascular damage in preterm infants. Here, we show that fibrinogen, a blood-clotting protein, plays a central role in impairing neonatal cerebellar development. Longitudinal MRI of preterm infants revealed that cerebellar bleeds were the most critical factor associated with poor cerebellar growth. Using inflammatory and hemorrhagic mouse models of neonatal cerebellar injury, we found that fibrinogen increased innate immune activation and impeded neurogenesis in the developing cerebellum. Fibrinogen inhibited sonic hedgehog (SHH) signaling, the main mitogenic pathway in cerebellar granule neuron progenitors (CGNPs), and was sufficient to disrupt cerebellar growth. Genetic fibrinogen depletion attenuated neuroinflammation, promoted CGNP proliferation, and preserved normal cerebellar development after neurovascular damage. Our findings suggest that fibrinogen alters the balance of SHH signaling in the neurovascular niche and may serve as a therapeutic target to mitigate developmental brain injury after CNS hemorrhage.

Nest building is a vital behavior exhibited during breeding in birds, and is possibly induced by environmental and social cues. Although such behavioral plasticity has been hypothesized to be controlled by adult neuronal plasticity, empirical evidence, especially at the neurogenomic level, remains limited. Here, we aim to uncover the gene regulatory networks that govern avian nest construction and examine whether they are associated with circuit rewiring. We designed an experiment to dissect this complex behavior into components in response to pair bonding and nest material acquisition by manipulating the presence of mates and nest materials in 30 pairs of zebra finches. Whole-transcriptome analysis of 300 samples from five brain regions linked to avian nesting behaviors revealed nesting-associated gene expression enriched with neural rewiring functions, including neurogenesis and neuron projection. The enriched expression was observed in the motor/sensorimotor and social behavior networks of female finches, and in the dopaminergic reward system of males. Female birds exhibited predominant neurotranscriptomic changes to initiate the nesting stage, while males showed major changes after entering this stage, underscoring sex-specific roles in nesting behavior. Notably, major neurotranscriptomic changes occurred during pair bonding, with minor changes during nest material acquisition, emphasizing social interactions in nest construction. We also revealed gene expression associated with reproductive behaviors and tactile sensing for nesting behavior. This study presents novel neurogenomic evidence supporting the hypothesis of adult neural plasticity underlying avian nest-construction behavior. By uncovering the genetic toolkits involved, we offer novel insights into the evolution of animals innate ability to construct nests.

Mutations in human nonsense-mediated mRNA decay (NMD) factors are enriched in neurodevelopmental disorders. We show that deletion of key NMD factor Upf2 in mouse embryonic neural progenitor cells causes perinatal microcephaly but deletion in immature neurons does not, indicating NMD's critical roles in progenitors. Upf2 knockout (KO) prolongs the cell cycle of radial glia progenitor cells, promotes their transition into intermediate progenitors, and leads to reduced upper-layer neurons. CRISPRi screening identified Trp53 knockdown rescuing Upf2KO progenitors without globally reversing NMD inhibition, implying marginal contributions of most NMD targets to the cell cycle defect. Integrated functional genomics shows that NMD degrades selective TRP53 downstream targets, including Cdkn1a, which, without NMD suppression, slow the cell cycle. Trp53KO restores the progenitor cell pool and rescues the microcephaly of Upf2KO mice. Therefore, one physiological role of NMD in the developing brain is to degrade selective TRP53 targets to control progenitor cell cycle and brain size.

Acoel flatworms have played a relevant role in classical (and current) discussions on the evolutionary origin of bilaterian animals. This is mostly derived from the apparent simplicity of their body architectures. This tenet has been challenged over the last couple of decades, mostly because detailed studies of their morphology and the introduction of multiple genomic technologies have unveiled a complexity of cell types, tissular arrangements and patterning mechanisms that were hidden below this superficial simplicity. One tissue that has received a particular attention has been the nervous system (NS). The combination of ultrastructural and single cell methodologies has revealed unique cellular diversity and developmental trajectories for most of their neurons and associated sensory systems. Moreover, the great diversity in NS architectures shown by different acoels offers us with a unique group of animals where to study key aspects of neurogenesis and diversification od neural systems over evolutionary time.In this review we revisit some recent developments in the characterization of the acoel nervous system structure and the regulatory mechanisms that contribute to their embryological development. We end up by suggesting some promising avenues to better understand how this tissue is organized in its finest cellular details and how to achieve a deeper knowledge of the functional roles that genes and gene networks play in its construction.

Nucleotide changes in gene regulatory elements are important determinants of neuronal development and diseases. Using massively parallel reporter assays in primary human cells from mid-gestation cortex and cerebral organoids, we interrogated the cis-regulatory activity of 102,767 open chromatin regions, including thousands of sequences with cell type-specific accessibility and variants associated with brain gene regulation. In primary cells, we identified 46,802 active enhancer sequences and 164 variants that alter enhancer activity. Activity was comparable in organoids and primary cells, suggesting that organoids provide an adequate model for the developing cortex. Using deep learning we decoded the sequence basis and upstream regulators of enhancer activity. This work establishes a comprehensive catalog of functional gene regulatory elements and variants in human neuronal development.

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1, Egfr, and Olig2. The increased Ascl1 expression and appearance of Egfr+ and Olig2+ cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

Neural progenitor cells within the cerebral cortex undergo a characteristic switch between symmetric self-renewing cell divisions early in development and asymmetric neurogenic divisions later. Yet, the mechanisms controlling this transition remain unclear. Previous work has shown that early but not late neural progenitor cells (NPCs) endogenously express the autism-linked transcription factor Foxp1, and both loss and gain of Foxp1 function can alter NPC activity and fate choices. Here, we show that premature loss of Foxp1 upregulates transcriptional programs regulating angiogenesis, glycolysis, and cellular responses to hypoxia. These changes coincide with a premature destabilization of HIF-1α, an elevation in HIF-1α target genes, including Vegfa in NPCs, and precocious vascular network development. In vitro experiments demonstrate that stabilization of HIF-1α in Foxp1-deficient NPCs rescues the premature differentiation phenotype and restores NPC maintenance. Our data indicate that the endogenous decline in Foxp1 expression activates the HIF-1α transcriptional program leading to changes in the tissue environment adjacent to NPCs, which, in turn, might alter their self-renewal and neurogenic capacities.

Lifelong hippocampal neurogenesis is maintained by a pool of multipotent adult neural stem cells (aNSCs) residing in the subgranular zone of the dentate gyrus (DG). The mechanisms guiding transition of NSCs from the developmental to the adult state remain unclear. We show here, by using nestin-based reporter mice deficient for cyclin D2, that the aNSC pool is established through cyclin D2-dependent proliferation during the first two weeks of life. The absence of cyclin D2 does not affect normal development of the dentate gyrus until birth but prevents postnatal formation of radial glia-like aNSCs. Furthermore, retroviral fate mapping reveals that aNSCs are born on-site from precursors located in the dentate gyrus shortly after birth. Taken together, our data identify the critical time window and the spatial location of the precursor divisions that generate the persistent population of aNSCs and demonstrate the central role of cyclin D2 in this process.

The Hedgehog (Hh) pathway plays a crucial role in embryonic development, acting both as a morphogenic signal that organizes tissue formation and a potent mitogenic signal driving cell proliferation. Dysregulated Hh signaling leads to various developmental defects in the brain. This article aims to review the roles of Hh signaling in the development of the neocortex in the mammalian brain, focusing on its regulation of neural progenitor proliferation and neuronal production. The review will summarize studies on genetic mouse models that have targeted different components of the Hh pathway, such as the ligand Shh, the receptor Ptch1, the GPCR-like transducer Smo, the intracellular transducer Sufu, and the three Gli transcription factors. As key insights into the Hh signaling transduction mechanism were obtained from mouse models displaying neural tube defects, this review will also cover some studies on Hh signaling in neural tube development. The results from these genetic mouse models suggest an intriguing hypothesis that elevated Hh signaling may play a role in the gyrification of the brain in certain species. Additionally, the distinctive production of GABAergic interneurons in the dorsal cortex in the human brain may also be linked to the extension of Hh signaling from the ventral to the dorsal brain region. Overall, these results suggest key roles of Hh signaling as both a morphogenic and mitogenic signal during the forebrain development and imply the potential involvement of Hh signaling in the evolutionary expansion of the neocortex.

Neuregulin1 (Nrg1) signaling is critical for neuronal development and function from fate specification to synaptic plasticity. Type III Nrg1 is a synaptic protein which engages in bidirectional signaling with its receptor ErbB4. Forward signaling engages ErbB4 phosphorylation, whereas back signaling engages two known mechanisms: (1) local axonal PI3K-AKT signaling and (2) cleavage by γ-secretase resulting in cytosolic release of the intracellular domain (ICD), which can traffic to the nucleus (Bao et al., 2003; Hancock et al., 2008). To dissect the contribution of these alternate signaling strategies to neuronal development, we generated a transgenic mouse with a missense mutation (V321L) in the Nrg1 transmembrane domain that disrupts nuclear back signaling with minimal effects on forward signaling or local back signaling and was previously found to be associated with psychosis (Walss-Bass et al., 2006). We combined RNA sequencing, retroviral fate mapping of neural stem cells, behavioral analyses, and various network analyses of transcriptomic data to investigate the effect of disrupting Nrg1 nuclear back signaling in the dentate gyrus (DG) of male and female mice. The V321L mutation impairs nuclear translocation of the Nrg1 ICD and alters gene expression in the DG. V321L mice show reduced stem cell proliferation, altered cell cycle dynamics, fate specification defects, and dendritic dysmorphogenesis. Orthologs of known schizophrenia (SCZ)-susceptibility genes were dysregulated in the V321L DG. These genes coordinated a larger network with other dysregulated genes. Weighted gene correlation network analysis and protein interaction network analyses revealed striking similarity between DG transcriptomes of V321L mouse and humans with SCZ. [ABSTRACT FROM AUTHOR]

Songbird vocal behavior, physiology, and brains—including neurogenesis—change between seasons. We examined seasonal differences in neurogenesis in three brain regions associated with vocal production and learning, HVC (letter‐based proper name), robust nucleus of the arcopallium (RA), and Area X, and two brain regions associated with auditory perception, caudomedial nidopallium (NCM) and caudomedial mesopallium (CMM). To do this, we captured wild male and female European starlings (Sturnus vulgaris) in spring and fall, collected a blood sample, and minimized time from capture to tissue collection to limit suppressive effects of captivity on neurogenesis. We quantified neurogenesis using doublecortin (DCX) immunohistochemistry, counting new neurons of three DCX cell morphologies (multipolar, fusiform, and round). We found regional differences in types of morphologies expressed, and amount of neurogenesis across regions: NCM had more fusiform cells than all other regions, and RA had more round cells than other regions. Males had more neurogenesis in HVC in fall than in spring, but there was no seasonal difference in neurogenesis in HVC of females, perhaps reflecting sexually dimorphic vocal learning demands related to repertoire size and complexity. Plasma corticosterone was higher in spring than fall and was correlated with testis volume in males, but it was not correlated with another purported measure of stress, heterophil:lymphocyte ratio (HLR), nor with neurogenesis. Our results suggest that the addition of new neurons to specific regions and circuits may serve different functions for males and females, particularly in the context of vocal production, learning, and perceptual demands across seasons. [ABSTRACT FROM AUTHOR]

Adipose-derived mesenchymal stem cells (ADMSCs) possess the ability to transform into various cell types, including neurons. It has been proposed that the optimization of this transformation can be achieved by using photobiomodulation (PBM). The objective of this laboratory-based investigation was to induce the transformation of immortalized ADMSCs (iADMSCs) into neurons with chemical triggers and then evaluate the supportive effects of PBM at two different wavelengths, 525 nm and 825 nm, each administered at a dose of 5 J/cm2, as well as the combined application of these wavelengths. The results revealed that the treated cells retained their stem cell characteristics, although the cells exposed to the green laser exhibited a reduction in the CD44 marker. Furthermore, early, and late neuronal markers were identified using flow cytometry analysis. The biochemical analysis included the assessment of cell morphology, viability, cell proliferation, potential cytotoxicity, and the generation of reactive oxygen species (ROS). The findings of this study indicate that PBM does not harm the differentiation process and may even enhance it, but it necessitates a longer incubation period in the induction medium. These research findings contribute to the validation of stem cell technology for potential applications in in vivo, pre-clinical, and clinical research environments. [ABSTRACT FROM AUTHOR]

Understanding how neural circuits are regenerated following injury is a fundamental question in neuroscience. Hydra is a powerful model for studying this process because it has a simple neural circuit structure, significant and reproducible regenerative abilities, and established methods for creating transgenics with cell-type-specific expression. While Hydra is a long-standing model for regeneration and development, little is known about how neural activity and behavior is restored following significant injury. In this study, we ask if regenerating neurons terminally differentiate prior to reforming functional neural circuits, or if neural circuits regenerate first and then guide the constituent naive cells toward their terminal fate. To address this question, we developed a dual-expression transgenic Hydra line that expresses a cell-type-specific red fluorescent protein (tdTomato) in ec5 peduncle neurons, and a calcium indicator (GCaMP7s) in all neurons. With this transgenic line, we can simultaneously record neural activity and track the reappearance of the terminally-differentiated ec5 neurons. Using SCAPE (Swept Confocally Aligned Planar Excitation) microscopy, we monitored both calcium activity and expression of tdTomato-positive neurons in 3D with single-cell resolution during regeneration of Hydra's aboral end. The synchronized neural activity associated with a regenerated neural circuit was observed approximately 4 to 8 hours after expression of tdTomato in ec5 neurons. These data suggest that regenerating ec5 neurons undergo terminal differentiation prior to re-establishing their functional role in the nervous system. The combination of dynamic imaging of neural activity and gene expression during regeneration make Hydra a powerful model system for understanding the key molecular and functional processes involved in neural regeneration following injury. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mitochondria are unique organelles that have their own genome (mtDNA) and perform various pivotal functions within a cell. Recently, evidence has highlighted the role of mitochondria in the process of stem cell differentiation, including differentiation of neural stem cells (NSCs). Here we studied the importance of mtDNA function in the early differentiation process of NSCs in two cell culture models: the CGR8‐NS cell line that was derived from embryonic stem cells by a lineage selection technique, and primary NSCs that were isolated from embryonic day 14 mouse fetal forebrain. We detected a dramatic increase in mtDNA content upon NSC differentiation to adapt their mtDNA levels to their differentiated state, which was not accompanied by changes in mitochondrial transcription factor A expression. As chemical mtDNA depletion by ethidium bromide failed to generate living ρ° cell lines from both NSC types, we used inhibition of mtDNA polymerase‐γ by 2′‐3′‐dideoxycytidine to reduce mtDNA replication and subsequently cellular mtDNA content. Inhibition of mtDNA replication upon NSC differentiation reduced neurogenesis but not gliogenesis. The mtDNA depletion did not change energy production/consumption or cellular reactive oxygen species (ROS) content in the NSC model used. In conclusion, mtDNA replication is essential for neurogenesis but not gliogenesis in fetal NSCs through as yet unknown mechanisms, which, however, are largely independent of energy/ROS metabolism. [ABSTRACT FROM AUTHOR]

Depressive disorder contributes to the initiation and prognosis of patients with cancer, but the interaction between cancer and depressive disorder remains unclear. We generated a gastric adenocarcinoma patient-derived xenograft mice model, treated with chronic unpredictable mild stimulation. Based on the RNA-sequence from the mouse model, patient data from TCGA, and MDD-related (major depressive disorder) genes from the GEO database, 56 hub genes were identified by the intersection of differential expression genes from the three datasets. Molecular subtypes and a prognostic signature were generated based on the 56 genes. A depressive mouse model was constructed to test the key changes in the signatures. The signature was constructed based on the NDUFA4L2, ANKRD45, and AQP3 genes. Patients with high risk-score had a worse overall survival than the patients with low scores, consistent with the results from the two GEO cohorts. The comprehensive results showed that a higher risk-score was correlated with higher levels of tumor immune exclusion, higher infiltration of M0 macrophages, M2 macrophages, and neutrophils, higher angiogenetic activities, and more enriched epithelial–mesenchymal transition signaling pathways. A higher risk score was correlated to a higher MDD score, elevated MDD-related cytokines, and the dysfunction of neurogenesis-related genes, and parts of these changes showed similar trends in the animal model. With the Genomics of Drug Sensitivity in Cancer database, we found that the gastric adenocarcinoma patients with high risk-score may be sensitive to Pazopanib, XMD8.85, Midostaurin, HG.6.64.1, Elesclomol, Linifanib, AP.24534, Roscovitine, Cytarabine, and Axitinib. The gene signature consisting of the NDUFA4L2, ANKRD45, and AQP3 genes is a promising biomarker to distinguish the prognosis, the molecular and immune characteristics, the depressive risk, and the therapy candidates for gastric adenocarcinoma patients. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) affects movement; however, most patients with PD also develop nonmotor symptoms, such as hyposmia, sleep disorder, and depression. Dopamine levels in the brain have a critical influence on movement control, but other neurotransmitters are also involved in the progression of PD. This study analyzed the fluctuation of neurotransmitters in PC12 cells during neurogenesis and neurodegeneration by performing mass spectrometry. We found that the dopaminergic metabolism pathway of PC12 cells developed vigorously during the neuron differentiation process and that the neurotransmitters were metabolized into 3-methoxytyramine, which was released from the cells. The regulation of the intracellular and extracellular concentrations of adenosine indicated that adenine nucleotides were actively utilized in neural differentiation. Moreover, we exposed the differentiated PC12 cells to rotenone, which is a suitable material for modeling PD. The cells exposed to rotenone in the early stage of differentiation exhibited stimulated serotoninergic metabolism, and the contents of the serotoninergic neurotransmitters returned to their normal levels in the late stage of differentiation. Interestingly, the nondifferentiated cells can resist the toxicant rotenone and produce normal dopaminergic metabolites. However, when differentiated neuron cells were exposed to rotenone, they were seriously damaged, leading to a failure to produce dopaminergic neurotransmitters. In the low-dosage damage process, the amino acids that functioned as dopaminergic pathway precursors could not be absorbed by the cells, and dopamine and L-dopa were secreted and unable to be reuptaken to trigger the cell damage. [ABSTRACT FROM AUTHOR]

The African turquoise killifish (Nothobranchius furzeri) combines a short lifespan with spontaneous age‐associated loss of neuro‐regenerative capacity, an intriguing trait atypical for a teleost. The impact of aging on the cellular composition of the adult stem cell niches, leading to this dramatic decline in the postnatal neuro‐ and gliogenesis, remains elusive. Single‐cell RNA sequencing of the telencephalon of young adult female killifish of the short‐lived GRZ‐AD strain unveiled progenitors of glial and non‐glial nature, different excitatory and inhibitory neuron subtypes, as well as non‐neural cell types. Sub‐clustering of the progenitors identified four radial glia (RG) cell types, two non‐glial progenitor (NGP) and four intermediate (intercell) cell states. Two astroglia‐like, one ependymal, and one neuroepithelial‐like (NE) RG subtype were found at different locations in the forebrain in line with their role, while proliferative, active NGPs were spread throughout. Lineage inference pointed to NE‐RG and NGPs as start and intercessor populations for glio‐ and neurogenesis. Upon aging, single‐cell RNA sequencing revealed major perturbations in the proportions of the astroglia and intercell states, and in the molecular signatures of specific subtypes, including altered MAPK, mTOR, Notch, and Wnt pathways. This cell catalog of the young regeneration‐competent killifish telencephalon, combined with the evidence for aging‐related transcriptomic changes, presents a useful resource to understand the molecular basis of age‐dependent neuroplasticity. This data is also available through an online database (killifishbrain_scseq). [ABSTRACT FROM AUTHOR]

Hydrocephalus, characterized by progressive expansion of the CSF-filled ventricles (ventriculomegaly), is the most common reason for brain surgery. 'Communicating' (i.e. non-obstructive) hydrocephalus is classically attributed to a primary derangement in CSF homeostasis, such as choroid plexus-dependent CSF hypersecretion, impaired cilia-mediated CSF flow currents, or decreased CSF reabsorption via the arachnoid granulations or other pathways. Emerging data suggest that abnormal biomechanical properties of the brain parenchyma are an under-appreciated driver of ventriculomegaly in multiple forms of communicating hydrocephalus across the lifespan. We discuss recent evidence from human and animal studies that suggests impaired neurodevelopment in congenital hydrocephalus, neurodegeneration in elderly normal pressure hydrocephalus and, in all age groups, inflammation-related neural injury in post-infectious and post-haemorrhagic hydrocephalus, can result in loss of stiffness and viscoelasticity of the brain parenchyma. Abnormal brain biomechanics create barrier alterations at the brain–CSF interface that pathologically facilitates secondary enlargement of the ventricles, even at normal or low intracranial pressures. This 'brain-centric' paradigm has implications for the diagnosis, treatment and study of hydrocephalus from womb to tomb. [ABSTRACT FROM AUTHOR]

Animals rely on their nervous systems to process sensory inputs, integrate these with internal signals, and produce behavioral outputs. This is enabled by the highly specialized morphologies and functions of neurons. Neuronal cells share multiple structural and physiological features, but they also come in a large diversity of types or classes that give the nervous system its broad range of functions and plasticity. This diversity, first recognized over a century ago, spurred classification efforts based on morphology, function, and molecular criteria. Caenorhabditis elegans , with its precisely mapped nervous system at the anatomical level, an extensive molecular description of most of its neurons, and its genetic amenability, has been a prime model for understanding how neurons develop and diversify at a mechanistic level. Here, we review the gene regulatory mechanisms driving neurogenesis and the diversification of neuron classes and subclasses in C. elegans. We discuss our current understanding of the specification of neuronal progenitors and their differentiation in terms of the transcription factors involved and ensuing changes in gene expression and chromatin landscape. The central theme that has emerged is that the identity of a neuron is defined by modules of gene batteries that are under control of parallel yet interconnected regulatory mechanisms. We focus on how, to achieve these terminal identities, cells integrate information along their developmental lineages. Moreover, we discuss how neurons are diversified postembryonically in a time-, genetic sex-, and activity-dependent manner. Finally, we discuss how the understanding of neuronal development can provide insights into the evolution of neuronal diversity. [ABSTRACT FROM AUTHOR]

Background: The global aging population underscores the critical importance of understanding factors that influence cognitive health and quality of life in the elderly. Physical activity and nutrition are pivotal in maintaining cognitive function and enhancing overall wellbeing among older adults. This review aims to synthesize the current literature on the impact of physical activity and nutrition on cognitive health and quality of life in the elderly. Methods: A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar to identify peer-reviewed articles published from January 2000 to December 2023. The search terms included "physical activity," "exercise," "nutrition," "diet," "cognitive health," "cognitive function," "quality of life," "elderly," "older adults," and "aging." Studies were selected based on inclusion criteria focusing on participants aged 60 years and older, examining the effects of physical activity or nutritional interventions on cognitive health or quality of life, and being published in English. Data from selected studies were extracted and synthesized using a descriptive analysis approach. Results: The review found that physical activity improves cognitive health through increased cerebral blood flow, neurogenesis, and reduced inflammation. Aerobic exercises, resistance training, and balance exercises were all beneficial for cognitive function. Nutrition, including adequate intake of vitamins, minerals, antioxidants, and omega-3 fatty acids, supports cognitive health and reduces the risk of cognitive decline. Specific dietary patterns, such as the Mediterranean and DASH diets, were associated with better cognitive outcomes and quality of life. Combined physical activity and nutritional interventions provided synergistic benefits, enhancing cognitive function and overall well-being. Conclusion: Physical activity and nutrition are essential for maintaining cognitive health and quality of life among the elderly. Regular exercise and a balanced diet rich in essential nutrients contribute significantly to brain health and overall well-being. Policymakers, healthcare providers, and community organizations should promote these interventions to support healthy aging. Future research should focus on longitudinal and intervention studies to further explore the synergistic effects of physical activity and nutrition. [ABSTRACT FROM AUTHOR]

Activation of endogenous neural stem cells (NSC) is one of the most potential measures for neural repair after spinal cord injury. However, methods for regulating neural stem cell behavior are still limited. Here, we investigated the effects of nicotinamide riboside promoting the proliferation of endogenous neural stem cells to repair spinal cord injury. Nicotinamide riboside promotes the proliferation of endogenous neural stem cells and regulates their differentiation into neurons. In addition, nicotinamide riboside significantly restored lower limb motor dysfunction caused by spinal cord injury. Nicotinamide riboside plays its role in promoting the proliferation of neural stem cells by activating the Wnt signaling pathway through the LGR5 gene. Knockdown of the LGR5 gene by lentivirus eliminates the effect of nicotinamide riboside on the proliferation of endogenous neural stem cells. In addition, administration of Wnt pathway inhibitors also eliminated the proliferative effect of nicotinamide riboside. Collectively, these findings demonstrate that nicotinamide promotes the proliferation of neural stem cells by targeting the LGR5 gene to activate the Wnt pathway, which provides a new way to repair spinal cord injury. [ABSTRACT FROM AUTHOR]

The nuclei are the main output structures of the cerebellum. Each and every cerebellar cortical computation reaches several areas of the brain by means of cerebellar nuclei processing and integration. Nevertheless, our knowledge of these structures is still limited compared to the cerebellar cortex. Here, we present a mouse genetic inducible fate‐mapping study characterizing rhombic lip‐derived glutamatergic neurons of the nuclei, the most conspicuous family of long‐range cerebellar efferent neurons. Glutamatergic neurons mainly occupy dorsal and lateral territories of the lateral and interposed nuclei, as well as the entire medial nucleus. In mice, they are born starting from about embryonic day 9.5, with a peak between 10.5 and 12.5, and invade the nuclei with a lateral‐to‐medial progression. While some markers label a heterogeneous population of neurons sharing a common location (BRN2), others appear to be lineage specific (TBR1, LMX1a, and MEIS2). A comparative analysis of TBR1 and LMX1a distributions reveals an incomplete overlap in their expression domains, in keeping with the existence of separate efferent subpopulations. Finally, some tagged glutamatergic progenitors are not labeled by any of the markers used in this study, disclosing further complexity. Taken together, our results obtained in late embryonic nuclei shed light on the heterogeneity of the excitatory neuron pool, underlying the diversity in connectivity and functions of this largely unexplored cerebellar territory. Our findings contribute to laying the groundwork for a comprehensive functional analysis of nuclear neuron subpopulations. [ABSTRACT FROM AUTHOR]

Nonprocessed foodstuffs of plant origin, especially whole-grain cereals, are considered to be health-promoting components of the human diet. While most of their well-studied effects derive from their high fiber content and low glycemic index, the presence of underrated phenolic phytonutrients has recently been brought to the attention of nutritionists. In this review, we report and discuss findings on the sources and bioactivities of 3,5-dihydroxybenzoic acid (3,5-DHBA), which is both a direct dietary component (found, e.g., in apples) and, more importantly, a crucial metabolite of whole-grain cereal-derived alkylresorcinols (ARs). 3,5-DHBA is a recently described exogenous agonist of the HCAR1/GPR81 receptor. We concentrate on the HCAR1-mediated effects of 3,5-DHBA in the nervous system, on the maintenance of cell stemness, regulation of carcinogenesis, and response to anticancer therapy. Unexpectedly, malignant tumors take advantage of HCAR1 expression to sense 3,5-DHBA to support their growth. Thus, there is an urgent need to fully identify the role of whole-grain-derived 3,5-DHBA during anticancer therapy and its contribution in the regulation of vital organs of the body via its specific HCAR1 receptor. We discuss here in detail the possible consequences of the modulatory capabilities of 3,5-DHBA in physiological and pathological conditions in humans. [ABSTRACT FROM AUTHOR]

Background: Spinal cord injury (SCI) presents a major global health challenge, with rising incidence rates and substantial disability. Although progress has been made in understanding SCI's pathophysiology and early management, there is still a lack of effective treatments to mitigate long-term consequences. This study investigates the potential of sovateltide, a selective endothelin B receptor agonist, in improving clinical outcomes in an acute SCI rat model. Methods: Thirty male Sprague–Dawley rats underwent sham surgery (group A) or SCI and treated with vehicle (group B) or sovateltide (group C). Clinical tests, including Basso, Beattie, and Bresnahan scoring, inclined plane, and allodynia testing with von Frey hair, were performed at various time points. Statistical analyses assessed treatment effects. Results: Sovateltide administration significantly improved motor function, reducing neurological deficits and enhancing locomotor recovery compared with vehicle-treated rats, starting from day 7 post injury. Additionally, the allodynic threshold improved, suggesting antinociceptive properties. Notably, the sovateltide group demonstrated sustained recovery, and even reached preinjury performance levels, whereas the vehicle group plateaued. Conclusions: This study suggests that sovateltide may offer neuroprotective effects, enhancing neurogenesis and angiogenesis. Furthermore, it may possess anti-inflammatory and antinociceptive properties. Future clinical trials are needed to validate these findings, but sovateltide shows promise as a potential therapeutic strategy to improve functional outcomes in SCI. Sovateltide, an endothelin B receptor agonist, exhibits neuroprotective properties, enhancing motor recovery and ameliorating hyperalgesia in a rat SCI model. These findings could pave the way for innovative pharmacological interventions for SCI in clinical settings. [ABSTRACT FROM AUTHOR]

Microglia, the resident immune cells of the central nervous system, play a crucial role in regulating adult neurogenesis and contribute significantly to the pathogenesis of Alzheimer's disease (AD). Under physiological conditions, microglia support and modulate neurogenesis through the secretion of neurotrophic factors, phagocytosis of apoptotic cells, and synaptic pruning, thereby promoting the proliferation, differentiation, and survival of neural progenitor cells (NPCs). However, in AD, microglial function becomes dysregulated, leading to chronic neuroinflammation and impaired neurogenesis. This review explores the intricate interplay between microglia and adult neurogenesis in health and AD, synthesizing recent findings to provide a comprehensive overview of the current understanding of microglia-mediated regulation of adult neurogenesis. Furthermore, it highlights the potential of microglia-targeted therapies to modulate neurogenesis and offers insights into potential avenues for developing novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Epidemiological studies report an elevated risk of Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed dipeptidyl peptidase 4 (DPP-4) inhibitors. With an objective to characterize clinically translatable doses of DPP-4 inhibitors (gliptins) in a well-characterized PD rodent model, sitagliptin, PF-00734,200 or vehicle were orally administered to rats initiated either 7-days before or 7-days after unilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) lesioning. Measures of dopaminergic cell viability, dopamine content, neuroinflammation and neurogenesis were evaluated thereafter in ipsi- and contralateral brain. Plasma and brain incretin and DPP-4 activity levels were quantified. Furthermore, brain incretin receptor levels were age-dependently evaluated in rodents, in 6-OHDA challenged animals and human subjects with/without PD. Cellular studies evaluated neurotrophic/neuroprotective actions of combined incretin administration. Pre-treatment with oral sitagliptin or PF-00734,200 reduced methamphetamine (meth)-induced rotation post-lesioning and dopaminergic degeneration in lesioned substantia nigra pars compacta (SNc) and striatum. Direct intracerebroventricular gliptin administration lacked neuroprotective actions, indicating that systemic incretin-mediated mechanisms underpin gliptin-induced favorable brain effects. Post-treatment with a threefold higher oral gliptin dose, likewise, mitigated meth-induced rotation, dopaminergic neurodegeneration and neuroinflammation, and augmented neurogenesis. These gliptin-induced actions associated with 70–80% plasma and 20–30% brain DPP-4 inhibition, and elevated plasma and brain incretin levels. Brain incretin receptor protein levels were age-dependently maintained in rodents, preserved in rats challenged with 6-OHDA, and in humans with PD. Combined GLP-1 and GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone. In conclusion, these studies support further evaluation of the repurposing of clinically approved gliptins as a treatment strategy for PD. [ABSTRACT FROM AUTHOR]

Neuroblasts were first derived from the adult mammalian brains in the 1990s by Reynolds et al. Since then, persistent neurogenesis in the subgranular zone (SGZ) of the hippocampus and subventricular zone (SVZ) has gradually been recognized. To date, reviews on neuroblast migration have largely investigated glial cells and molecular signaling mechanisms, while the relationship between vasculature and cell migration remains a mystery. Thus, this paper underlines the partial biological features of neuroblast migration and unravels the significance and mechanisms of the vasculature in the process to further clarify theoretically the neural repair mechanism after brain injury. Neuroblast migration presents three modes according to the characteristics of cells that act as scaffolds during the migration process: gliophilic migration, neurophilic migration, and vasophilic migration. Many signaling molecules, including brain-derived neurotrophic factor (BDNF), stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), and angiopoietin-1 (Ang-1), affect vasophilic migration, synergistically regulating the migration of neuroblasts to target areas along blood vessels. However, the precise role of blood vessels in the migration of neuroblasts needs to be further explored. The in-depth study of neuroblast migration will most probably provide theoretical basis and breakthrough for the clinical treatment of brain injury diseases. [ABSTRACT FROM AUTHOR]

Patients with spinal cord injury (SCI) have permanent devastating motor and sensory disabilities. Secondary SCI is known for its complex progression and presents with sophisticated aberrant inflammation, vascular changes, and secondary cellular dysfunction, which aggravate the primary damage. Since their initial discovery, the potent neuroprotective effects and powerful delivery abilities of exosomes (Exos) have been reported in different research fields, including SCI. In this study, we summarize therapeutic advances related to the application of Exos in preclinical animal studies. Subsequently, we discuss the mechanisms of action of Exos derived from diverse cell types, including neurogenesis, angiogenesis, blood–spinal cord barrier preservation, anti-apoptosis, and anti-inflammatory potential. We also evaluate the relationship between the Exo delivery cargo and signaling pathways. Finally, we discuss the challenges and advantages of using Exos to offer innovative insights regarding the development of efficient clinical strategies for SCI. [ABSTRACT FROM AUTHOR]

Regulatory cell death is an important way to eliminate the DNA damage that accompanies the rapid proliferation of neural stem cells during cortical development, including pyroptosis, apoptosis, and so on. Here, the study reports that the absence of GSDMD‐mediated pyroptosis results in defective DNA damage sensor pathways accompanied by aberrant neurogenesis and autism‐like behaviors in adult mice. Furthermore, GSDMD is involved in organizing the mitochondrial electron transport chain by regulating the AMPK/PGC‐1α pathway to target Aifm3. This process promotes a switch from oxidative phosphorylation to glycolysis. The perturbation of metabolic homeostasis in neural progenitor cells increases lactate production which acts as a signaling molecule to regulate the p38MAPK pathway. And activates NF‐휿B transcription to disrupt cortex development. This abnormal proliferation of neural progenitor cells can be rescued by inhibiting glycolysis and lactate production. Taken together, the study proposes a metabolic axis regulated by GSDMD that links pyroptosis with metabolic reprogramming. It provides a flexible perspective for the treatment of neurological disorders caused by genotoxic stress and neurodevelopmental disorders such as autism. [ABSTRACT FROM AUTHOR]

Background: MK-801 is a drug widely used in preclinical studies to model schizophrenia in animals. Its distinctive feature is the ability to mimic pathological changes in social interactions. Unlike humans, rodents rely heavily on their sense of smell for social interaction. Since, as previously demonstrated, it also impairs neurogenesis, we set out to determine whether olfactory impairment is associated with chronic administration of the drug. Methods: The mice were divided into two groups, of which one was administered the drug for 3 weeks, and the other only once. Olfaction and social transfer of food preferences were tested after the drug administration period. At the end of the experiment, an immunofluorescence study was performed to determine differences in neurogenesis in the olfactory bulbs. Results: An olfactory deficit was observed in animals that received the drug for 3 weeks. These changes were also accompanied by an abnormal lack of food preference in the social transmission test. As a result of a morphological study, a pronounced decrease in the number of new neurons was found in the olfactory bulbs of the animals that had received the drug. Conclusion: Our results indicate that at least some of the impairments in social behavior of the animals exposed to NMDA receptor antagonists are likely caused by changes in the sense of smell. These changes are associated with disruptions of neurogenesis. [ABSTRACT FROM AUTHOR]

Once we are born, the number and location of nerve cells in most parts of the brain remain unchanged. These types of structural changes are therefore a significant form of flexibility for the neural circuits where they occur. In humans, the postnatal birth of neurons is limited; however, neurons do continue to migrate into some brain regions throughout infancy and even into adolescence. In human infants, multiple migratory pathways deliver interneurons to destinations across the frontal and temporal lobe cortex. Shorter-range migration of excitatory neurons also appears to continue during adolescence, particularly near the amygdala paralaminar nucleus, a region that follows a delayed trajectory of growth from infancy to adulthood. The significance of the timing for when different brain regions recruit new neurons through these methods is unknown; however, both processes of protracted migration and maturation are prominent in humans. Mechanisms like these that reconfigure neuronal circuits are a substrate for critical periods of plasticity and could contribute to distinctive circuit functionality in human brains. [ABSTRACT FROM AUTHOR]

In the present study, the PC12 cells as a bioassay system were used to screen the small molecules with nerve growth factor (NGF)- mimic effect from Lavandula angustifolia Mill. The β-Cyclocitral (β-cyc) as an active compound was discovered, and its chemical structure was also determined. Furthermore, we focused on the bioactive and action mechanism of this compound to do an intensive study with specific protein inhibitors and Western blotting analysis. The β-cyc had novel NGF-mimic and NGF-enhancer effects on PC12 cells, while the insulin-like growth factor-1 receptor (IGF-1R)/phosphatidylinositol 3 kinase, (PI3K)/serine/threonine-protein kinase (AKT), and glucocorticoid receptor (GR)/phospholipase C (PLC)/protein kinase C (PKC) signaling pathways were involved in the bioactivity of β-cyc. In addition, the important role of the rat sarcoma (Ras)/protooncogene serine-threonine protein kinase (Raf) signaling pathway was observed, although it was independent of tyrosine kinase (Trk) receptors. Moreover, the non-label target protein discovery techniques, such as the cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS), were utilized to make predictions of its target protein. The stability of IGF-R and GR, proteins for temperature and protease, was dose-dependently increased after treatment of β-cyc compared with control groups, respectively. These findings indicated that β-cyc promoted the neuron differentiation of PC12 cells via targeting IGF-1R and GR and modification of downstream signaling pathways. [ABSTRACT FROM AUTHOR]

Domestic strains of canaries (Serinus canaria) variably respond to photoperiod changes and apparently stay in breeding state for extended periods. Fife Fancy canaries are supposed to be similar to the native species living at 27–39° north where photoperiod significantly changes across the year. Our birds showed reproductive cycles when exposed to light regimes mimicking the annual cycle of photoperiod. However after 6 months in short days (SD: 8L:16D), males developed large testes, as observed by X‐ray tomography, and intense singing. Switching to long days (LD: 16L:8D) did not further increase song rate nor testes size but increased song duration, number of syllables per song, and trill occurrence frequency. No sign of regression was observed after 12 weeks in LD but return to SD produced a rapid decrease in testes size and singing activity below values in birds maintained throughout in SD. Fife Fancy thus does not seem to develop absolute but only relative refractoriness. The relatively high singing activity expressed by SD‐photosensitive males does not seem to depend on high testosterone (T) concentrations. Singing did not correlate with plasma testosterone (T). Treatment with ATD + Flutamide only marginally decreased song rate and did not affect song quality nor song control nuclei volume. These birds are either supersensitive to low T levels or their reproductive physiology is activated by other mechanisms. Neurogenesis is increased by T and by LD but the function of new neurons incorporated in HVC is poorly understood. We developed a procedure based on X‐ray focal irradiation to deplete neural progenitors adjacent to HVC and study the functional consequences. The decrease in neurogenesis increased the variability of T‐induced songs in females and decreased their bandwidth. Neurogenesis in HVC thus plays a role in song production and X‐ray focal irradiation represents an excellent tool to analyze adult neurogenesis. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) results from various causes, including sports‐related incidents, degenerative cervical myelopathy, traffic accidents, and falls. SCI typically leads to sensory and motor dysfunction and even paralysis. Current treatments for SCI include systemic administration of high‐dose steroids and surgical decompression and stabilization. However, excessive use of glucocorticoids may increase susceptibility to infections and systemic bleeding. The long‐term effect of surgery intervention remains unclear, with ongoing debates regarding its timing, efficacy, and safety. Therefore, innovative approaches are urgently needed to alleviate secondary injuries and promote spinal recovery. One emerging therapeutic approach for SCI is modulating the microenvironments to achieve neuroprotection and neurogenesis during recovery. Several biomaterials with favorable physicochemical properties have been developed to enhance therapeutic effects by regulating microenvironments. This Review first discusses the pathology of SCI microenvironments and then introduces biomaterials‐based regulatory strategies targeting various microenvironmental components, including anti‐inflammation, anti‐oxidation, reduction of excitotoxicity, revascularization, neurogenesis, and scar density reduction. Additionally, the research and clinical application prospects for microenvironment regulation are presented. [ABSTRACT FROM AUTHOR]

Plasmalogens (Pls) are specialized phospholipids integral to brain health, whose decline due to aging and stress contributes to cognitive impairment and neuroinflammation. This study explores the potential of a novel Pls derivative, KIT-13 (1-O-octadecyl-2-arachidonoyl-sn-glycerol-3-phosphoethanolamine), in mitigating neuroinflammation and enhancing cognition. When administered to mice, KIT-13 exhibited potent memory enhancement attributed to upregulated brain-derived neurotrophic factor (BDNF), a key player in cognitive processes. In vitro experiments with neuronal cells revealed KIT-13’s ability to induce robust cellular signaling, surpassing natural plasmalogens. KIT-13 also promoted neurogenesis and inhibited apoptosis of neuronal-like cells, highlighting its potential in fostering neuronal growth and plasticity. Additionally, KIT-13 treatments reduced pro-inflammatory cytokine expression and attenuated glial activation in the brain. KIT-13’s superior efficacy over natural Pls positions it as a promising therapeutic candidate for neurodegenerative conditions such as Alzheimer’s disease, characterized by cognitive decline and neuroinflammation. This study presents KIT-13 as an innovative approach for addressing cognitive impairment and neuroinflammatory pathologies. [ABSTRACT FROM AUTHOR]

Background: The established association between Alzheimer's disease (AD) and compromised neural regeneration is well-documented. In addition to the mitigation of apoptosis in neural stem cells (NSCs), the induction of neurogenesis has been proposed as a promising therapeutic strategy for AD. Our previous research has demonstrated the effective inhibition of NSC injury induced by microglial activation through the repression of oxidative stress and mitochondrial dysfunction by Sirtuin 3 (SIRT3). Nonetheless, the precise role of SIRT3 in neurogenesis remains incompletely understood. Methods: In vivo, SIRT3 overexpression adenovirus was firstly injected by brain stereotaxic localization to affect the hippocampal SIRT3 expression in APP/PS1 mice, and then behavioral experiments were performed to investigate the cognitive improvement of SIRT3 in APP/PS1 mice, as well as neurogenic changes in hippocampal region by immunohistochemistry and immunofluorescence. In vitro, under the transwell co-culture condition of microglia and neural stem cells, the mechanism of SIRT3 improving neurogenesis of neural stem cells through DVL/GSK3/ISL1 axis was investigated by immunoblotting, immunofluorescence and other experimental methods. Results: Our findings indicate that the overexpression of SIRT3 in APP/PS1 mice led to enhanced cognitive function and increased neurogenesis. Additionally, SIRT3 was observed to promote the differentiation of NSCs into neurons during retinoic acid (RA)-induced NSC differentiation in vitro, suggesting a potential role in neurogenesis. Furthermore, we observed the activation of the Wnt/ß-catenin signaling pathway during this process, with Glycogen Synthase Kinase-3a (GSK3a) primarily governing NSC proliferation and GSK3ß predominantly regulating NSC differentiation. Moreover, the outcomes of our study demonstrate that SIRT3 exerts a protective effect against microglia-induced apoptosis in neural stem cells through its interaction with DVLs. Conclusions: Our results show that SIRT3 overexpressing APP/PS1 mice have improved cognition and neurogenesis, as well as improved neurogenesis of NSC in microglia and NSC transwell co-culture conditions through the DVL/GSK3/ISL1 axis. [ABSTRACT FROM AUTHOR]

The generation of new neurons at the hippocampal neurogenic niche, known as adult hippocampal neurogenesis (AHN), and its impairment, have been implicated in Alzheimer's disease (AD). MicroRNA-132 (miR-132), the most consistently downregulated microRNA (miRNA) in AD, was recently identified as a potent regulator of AHN, exerting multilayered proneurogenic effects in adult neural stem cells (NSCs) and their progeny. Supplementing miR-132 in AD mouse brain restores AHN and relevant memory deficits, yet the exact mechanisms involved are still unknown. Here, we identify NACC2 as a novel miR-132 target implicated in both AHN and AD. miR-132 deficiency in mouse hippocampus induces Nacc2 expression and inflammatory signaling in adult NSCs. We show that miR-132-dependent regulation of NACC2 is involved in the initial stages of human NSC differentiation towards astrocytes and neurons. Later, NACC2 function in astrocytic maturation becomes uncoupled from miR-132. We demonstrate that NACC2 is present in reactive astrocytes surrounding amyloid plaques in mouse and human AD hippocampus, and that there is an anticorrelation between miR-132 and NACC2 levels in AD and upon induction of inflammation. Unraveling the molecular mechanisms by which miR-132 regulates neurogenesis and cellular reactivity in AD, will provide valuable insights towards its possible application as a therapeutic target. [ABSTRACT FROM AUTHOR]

The function of some genetic variants associated with brain-relevant traits has been explained through colocalization with expression quantitative trait loci (eQTL) conducted in bulk postmortem adult brain tissue. However, many brain-trait associated loci have unknown cellular or molecular function. These genetic variants may exert context-specific function on different molecular phenotypes including post-transcriptional changes. Here, we identified genetic regulation of RNA editing and alternative polyadenylation (APA) within a cell-type-specific population of human neural progenitors and neurons. More RNA editing and isoforms utilizing longer polyadenylation sequences were observed in neurons, likely due to higher expression of genes encoding the proteins mediating these post-transcriptional events. We also detected hundreds of cell-type-specific editing quantitative trait loci (edQTLs) and alternative polyadenylation QTLs (apaQTLs). We found colocalizations of a neuron edQTL in CCDC88A with educational attainment and a progenitor apaQTL in EP300 with schizophrenia, suggesting that genetically mediated post-transcriptional regulation during brain development leads to differences in brain function. Aygün et al. identify genetic regulation of RNA editing and alternative polyadenylation within a cell-type-specific population of human neural progenitors and neurons. They find more RNA editing and longer polyadenylation sequences in neurons, as well as cell-type-specific editing quantitative trait loci and alternative polyadenylation QTLs, including colocalizations with brain-related traits. [ABSTRACT FROM AUTHOR]

Background: Reduction of adult hippocampal neurogenesis is an early critical event in Alzheimer's disease (AD), contributing to progressive memory loss and cognitive decline. Reduced levels of the nucleoporin 153 (Nup153), a key epigenetic regulator of NSC stemness, characterize the neural stem cells isolated from a mouse model of AD (3×Tg) (AD-NSCs) and determine their altered plasticity and gene expression. Methods: Nup153-regulated mechanisms contributing to NSC function were investigated: (1) in cultured NSCs isolated from AD and wild type (WT) mice by proteomics; (2) in vivo by lentiviral-mediated delivery of Nup153 or GFP in the hippocampus of AD and control mice analyzing neurogenesis and cognitive function; (3) in human iPSC-derived brain organoids obtained from AD patients and control subjects as a model of neurodevelopment. Results: Proteomic approach identified Nup153 interactors in WT- and AD-NSCs potentially implicated in neurogenesis regulation. Gene ontology (GO) analysis showed that Nup153-bound proteins in WT-NSCs were involved in RNA metabolism, nuclear import and epigenetic mechanisms. Nup153-bound proteins in AD-NSCs were involved in pathways of neurodegeneration, mitochondrial dysfunction, proteasomal processing and RNA degradation. Furthermore, recovery of Nup153 levels in AD-NSCs reduced the levels of oxidative stress markers and recovered proteasomal activity. Lentiviral-mediated delivery of Nup153 in the hippocampal niche of AD mice increased the proliferation of early progenitors, marked by BrdU/DCX and BrdU/PSANCAM positivity and, later, the integration of differentiating neurons in the cell granule layer (BrdU/NeuN+ cells) compared with GFP-injected AD mice. Consistently, Nup153-injected AD mice showed an improvement of cognitive performance in comparison to AD-GFP mice at 1 month after virus delivery assessed by Morris Water Maze. To validate the role of Nup153 in neurogenesis we took advantage of brain organoids derived from AD-iPSCs characterized by fewer neuroepithelial progenitor loops and reduced differentiation areas. The upregulation of Nup153 in AD organoids recovered the formation of neural-like tubes and differentiation. Conclusions: Our data suggest that the positive effect of Nup153 on neurogenesis is based on a complex regulatory network orchestrated by Nup153 and that this protein is a valuable disease target. [ABSTRACT FROM AUTHOR]

Aerobic exercise has many effects on brain function, particularly at the hippocampus. Exercise has been shown to increase the rate of adult neurogenesis within the dentate gyrus and decrease the density of perineuronal nets in area CA1. The relationship between the rate of neurogenesis and the density of perineuronal nets in CA1 is robust; however, these studies only ever examined these effects across longer time scales, with running manipulations of 4 weeks or longer. With such long periods of manipulation, the precise temporal nature of the relationship between running-induced neurogenesis and reduced perineuronal net density in CA1 is unknown. Here, we provided male and female mice with home cage access to running wheels for 0, 1, 2, or 4 weeks and quantified hippocampal neurogenesis and CA1 perineuronal net density. In doing so, we observed a 2-week delay period prior to the increase in neurogenesis, which coincided with the same delay prior to decreased CA1 perineuronal net density. These results highlight the closely linked temporal relationship between running-induced neurogenesis and decreased perineuronal net expression in CA1. [ABSTRACT FROM AUTHOR]

The therapeutic potential of suppressing polypyrimidine tract-binding protein 1 (Ptbp1) messenger RNA by viral transduction in a post-stroke dementia mouse model has not yet been examined. In this study, 3 days after cerebral ischemia, we injected a viral vector cocktail containing adeno-associated virus (AAV)-pGFAP-mCherry and AAV-pGFAP-CasRx (control vector) or a cocktail of AAV-pGFAP-mCherry and AAV-pGFAP-CasRx-SgRNA-(Ptbp1) (1:5, 1.0 × 1011 viral genomes) into post-stroke mice via the tail vein. We observed new mCherry/NeuN double-positive neuron-like cells in the hippocampus 56 days after cerebral ischemia. A portion of mCherry/GFAP double-positive astrocyte-like glia could have been converted into new mCherry/NeuN double-positive neuron-like cells with morphological changes. The new neuronal cells integrated into the dentate gyrus and recognition memory was significantly ameliorated. These results demonstrated that the in vivo conversion of hippocampal astrocyte-like glia into functional new neurons by the suppression of Ptbp1 might be a therapeutic strategy for post-stroke dementia. [ABSTRACT FROM AUTHOR]

Introduction: Treatment with the synaptic plasticity protein reelin has rapid antidepressant-like effects in adult corticosterone (CORT)-induced depressed rats, whether administered repeatedly or acutely. However, these effects remain unexplored in the context of post-partum depression (PPD). Methods: This study investigated the antidepressant-like effect of a single injection of reelin in a CORT-induced model of PPD. Long-Evans female dams received either daily subcutaneous CORT (40 mg/kg) or saline injections (controls) from the post-partum day (PD) 2 to 22, and on PD22 were treated with a single intravenous reelin (3 µg) or vehicle injection. Results: Reelin treatment fully normalized to control levels the CORT-induced increase in Forced Swim Test (FST) immobility and the decrease in reelin-positive cells in the subgranular zone of the intermediate hippocampus. It also increased the number of oxytocin-positive cells in the paraventricular nucleus (PVN), the number of reelin-positive cells in the dorsal and ventral hippocampus, and the dendritic complexity of newborn neurons in the intermediate hippocampus, causing a partial recovery compared to controls. None of these changes were associated with fluctuations in estrogen levels measured peripherally. Discussion: This study brings new insights into the putative antidepressant- like effect of peripherally administered reelin in an animal model of PPD. Future studies should be conducted to investigate these effects on a dose- response paradigm and to further elucidate the mechanisms underlying the antidepressant-like effects of reelin. [ABSTRACT FROM AUTHOR]

Vacuolar protein sorting 35 (VPS35), a critical component of the retromer complex, plays a pivotal role in the pathogenesis of neurodegenerative diseases (NDs). It is involved in protein transmembrane sorting, facilitating the transport from endosomes to the trans‐Golgi network (TGN) and plasma membrane. Recent investigations have compellingly associated mutations in the VPS35 gene with neurodegenerative disorders such as Parkinson's and Alzheimer's disease. These genetic alterations are implicated in protein misfolding, disrupted autophagic processes, mitochondrial dysregulation, and synaptic impairment. Furthermore, VPS35 exerts a notable impact on neurogenesis by influencing neuronal functionality, protein conveyance, and synaptic performance. Dysregulation or mutation of VPS35 may escalate the progression of neurodegenerative conditions, underscoring its pivotal role in safeguarding neuronal integrity. This review comprehensively discusses the role of VPS35 and its functional impairments in NDs. Furthermore, we provide an overview of the impact of VPS35 on neurogenesis and further explore the intricate relationship between neurogenesis and NDs. These research advancements offer novel perspectives and valuable insights for identifying potential therapeutic targets in the treatment of NDs. [ABSTRACT FROM AUTHOR]

Depression is a highly prevalent and disabling psychiatric disorder. The hippocampus, which plays a central role in mood regulation and memory, has received considerable attention in depression research. Electroconvulsive therapy (ECT) is the most effective treatment for severe pharmacotherapy‐resistant depression. Although the working mechanism of ECT remains unclear, recent magnetic resonance imaging (MRI) studies have consistently reported increased hippocampal volumes following ECT. The clinical implications of these volumetric increases and the specific cellular and molecular significance are not yet fully understood. This narrative review brings together evidence from animal models and human studies to provide a detailed examination of hippocampal volumetric increases following ECT. In particular, our preclinical MRI research using a mouse model is consistent with human findings, demonstrating a marked increase in hippocampal volume following ECT. Notable changes were observed in the ventral hippocampal CA1 region, including dendritic growth and increased synaptic density at excitatory synapses. Interestingly, inhibition of neurogenesis did not affect the ECT‐related hippocampal volumetric increases detected on MRI. However, it remains unclear whether these histological and volumetric changes would be correlated with the clinical effect of ECT. Hence, future research on the relationships between cellular changes, ECT‐related brain volumetric changes, and antidepressant effect could benefit from a bidirectional translational approach that integrates human and animal models. Such translational research may provide important insights into the mechanisms and potential biomarkers associated with ECT‐induced hippocampal volumetric changes, thereby advancing our understanding of ECT for the treatment of depression. [ABSTRACT FROM AUTHOR]

The role of Drosophila numb in regulating Notch signaling and neurogenesis has been extensively studied, with a particular focus on its effects on the peripheral nervous system (PNS). Previous studies based on a single loss-of-function allele of numb, numb1, showed an antineurogenic effect on the peripheral nervous system (PNS), which revealed that the wild-type numb suppresses Notch signaling. In the current study, we examined whether this phenotype is consistently observed in loss-of-function mutations of numb. Two more numb alleles, numbEY03840 and numbEY03852, were shown to have an antineurogenic phenotype in the PNS. We also found that introducing a wild-type numb genomic fragment into numb1 homozygotes rescued their antineurogenic phenotype. These results demonstrated that loss-of-function mutations of numb universally induce this phenotype. Many components of Notch signaling are encoded by maternal effect genes, but no maternal effect of numb was observed in this study. The antineurogenic phenotype of numb was found to be dependent on the Enhancer of split (E(spl)), a downstream gene of Notch signaling. We found that the combination of E(spl) homozygous and numb1 homozygous suppressed the neurogenic phenotype of the embryonic central nervous system (CNS) associated with the E(spl) mutation. In the E(spl) allele, genes encoding basic helix-loop-helix proteins, such as m5, m6, m7, and m8, remain. Thus, in the E(spl) allele, derepression of Notch activity by numb mutation can rescue the neurogenic phenotype by increasing the expression of the remaining genes in the E(spl) complex. We also uncovered a role for numb in regulating neuronal projections. Our results further support an important role for numb in the suppression of Notch signaling during embryonic nervous system development. [ABSTRACT FROM AUTHOR]

Brain mosaicism has diverse origins, from early embryogenesis to neurogenesis and in the mature brain. Prezygotic chromosomal abnormalities can be postzygotically corrected, thus leading to tissue-restricted mosaicism. Complex clonal dynamics during embryogenesis determines lineage allocation. Postmitotic neurons continue to accumulate somatic genetic variation. The complexity of the brain is closely tied to its nature as a genetic mosaic, wherein each cell is distinguished by a unique constellation of somatic variants that contribute to functional and phenotypic diversity. Postzygotic variation arising during neurogenesis is recognized as a key contributor to brain mosaicism; however, recent advances have broadened our understanding to include sources of neural genomic diversity that develop throughout the entire lifespan, from embryogenesis through aging. Moving beyond the traditional confines of neurodevelopment, in this review, we delve into the complex mechanisms that enable various origins of brain mosaicism. [ABSTRACT FROM AUTHOR]

Intravascularly transplanted bone marrow cells, including bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells, transfer water-soluble molecules to cerebral endothelial cells via gap junctions. After transplantation of BM-MNC, this fosters hippocampal neurogenesis and enhancement of neuronal function. Herein, we report the impact of transplanted BM-MNC on neural stem cells (NSC) in the brain. Surprisingly, direct transfer of water-soluble molecules from transplanted BM-MNC and peripheral mononuclear cells to NSC in the hippocampus was observed already 10 min after cell transplantation, and transfer from BM-MNC to GFAP-positive cortical astrocytes was also observed. In vitro investigations revealed that BM-MNC abolish the expression of hypoxia-inducible factor-1α in astrocytes. We suggest that the transient and direct transfer of water-soluble molecules between cells in circulation and NSC in the brain may be one of the biological mechanisms underlying the repair of brain function. [ABSTRACT FROM AUTHOR]