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Neurogenesis in human fetal and adult SVZ. In the fetal brain, the neurogenic niche is organized into different strata: the ventricular zone (VZ), the subventricular zone (SVZ), the intermediate zone (IZ), and the marginal zone (MZ). Apical radial glial cells of the SVZ remain in contact with the ependymal cells and with the meninges and blood vessels, while the basal radial glial cells, which constitute the region of the SVZ called outer SVZ (oSVZ), lose contact with ventricles leading to a discontinuous scaffold of radial glial cells (RGCs). Apical and basal RGCs generate neurons through two mechanisms: either directly or indirectly through intermediate progenitor cells, which also originate astrocytes and oligodendrocytes. In the adult brain, the SVZ consists of four distinct stratified areas: layer I formed by ependymal cells in contact with the lumen of ventricles; the hypocellular gap (layer II), mainly formed by displaced ependymal cells and DCX+ astrocyte processes; layer III constituted by type B astrocytic cells; a transitional region to the brain parenchyma (layer IV) formed by mature neurons and oligodendrocytes.
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Neural stem cells (NSCs) are multipotent stem cells that reside in the fetal and adult mammalian brain, which can self-renew and differentiate into neurons and supporting cells. Intrinsic and extrinsic cues, from cells in the local niche and from distant sites, stringently orchestrates the self-renewal and differentiation competence of NSCs. Ample...
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Introduction
Acute kidney injury (AKI) is a common and severe clinical problem that is associated with high mortality, a long hospital stays and high healthcare resource consumption. Approximately a quarter of AKI survivors will develop chronic kidney disease. Mesenchymal stem cells (MSCs) are multipotent stem cells with antiapoptotic, immunomodula...
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... Prior studies have shown that viruses can disrupt NSCs either by direct infection or indirectly because of the inflammatory milieu (Chandwani et al., 2019;Das & Basu, 2011;Devhare et al., 2017;Fantetti et al., 2016;Ihunwo et al., 2022;Kamte et al., 2021;Kulkarni et al., 2016;Mutnal et al., 2011). NSC infection by many different viruses (e.g. ...
Viral infections of the central nervous system (CNS) often cause worse neurological outcomes in younger hosts. Throughout childhood, the brain undergoes extensive development and refinement to produce functional neural networks. Network function is maintained partly with the help of neural stem cells (NSCs) that replace neuronal and glia subtypes in the two neurogenic niches of the brain (the hippocampus and subventricular zone). Accumulating evidence suggests that viruses disrupt NSC function in adulthood and infancy, but the in vivo impact of childhood infections on acute and long‐term NSC function is unknown. Using a juvenile mouse model of measles virus (MeV) infection, where only mature neurons in the brain are infected, we defined the effects of the antiviral immune response on NSCs from juvenile to adult stages of life. We found that (a) virus persists in the brains of survivors despite an anti‐viral immune response; (b) NSC numbers decrease dramatically during early infection, but ultimately stabilize in adult survivors; (c) infection is associated with mild apoptosis throughout the juvenile brain, but NSC proliferation is unchanged; (d) the loss of NSC numbers is dependent upon the stage of NSC differentiation; and (e) immature neurons increase early during infection, concurrent with depletion of NSC pools. Collectively, we show that NSCs are exquisitely sensitive to the inflammatory microenvironment created during neuron‐restricted MeV infection in juveniles, responding with an early loss of NSCs but increased neurogenesis. These studies provide insight into potential cellular mechanisms associated with long‐term neurological deficits in survivors of childhood CNS infections. image
... Interestingly, ZIKV targets various cells in the brain, including radial glial cells, neural progenitor cells (NPCs), astrocytes, microglial and glioblastoma stem cells, affecting these brain cells by different mechanisms, such as apoptosis and cell cycle dysregulation, which may induce neurological complications and neuroimmunopathogenesis (Komarasamy et al., 2022), possibly causing the depletion of neural progenitors in the cortical layer of the brain (Ihunwo et al., 2022). Indeed, cell-intrinsic innate immune responses to ZIKV infection profoundly shape neuronal transcriptional profiles by inducing changes to neurologic gene expression associated with psychiatric disorders (Kung et al., 2022). ...
Maternal infections are among the main risk factors for cognitive impairments in the offspring. Zika virus (ZIKV) can be transmitted vertically, causing a set of heterogeneous birth defects, such as microcephaly, ventriculomegaly and corpus callosum dysgenesis. Nuclear distribution element like‐1 (Ndel1) oligopeptidase controls crucial aspects of cerebral cortex development underlying cortical malformations. Here, we examine Ndel1 activity in an animal model for ZIKV infection, which was associated with deregulated corticogenesis. We observed here a reduction in Ndel1 activity in the forebrain associated with the congenital syndrome induced by ZIKV isolates, in an in utero and postnatal injections of different inoculum doses in mice models. In addition, we observed a strong correlation between Ndel1 activity and brain size of animals infected by ZIKV, suggesting the potential of this measure as a biomarker for microcephaly. More importantly, the increase of interferon (IFN)‐beta signaling, which was used to rescue the ZIKV infection outcomes, also recovered Ndel1 activity to levels similar to those of uninfected healthy control mice, but with no influence on Ndel1 activity in uninfected healthy control animals. Taken together, we demonstrate for the first time here an association of corticogenesis impairments determined by ZIKV infection and the modulation of Ndel1 activity. Although further studies are still necessary to clarify the possible role(s) of Ndel1 activity in the molecular mechanism(s) underlying the congenital syndrome induced by ZIKV, we suggest here the potential of monitoring the Ndel1 activity to predict this pathological condition at early stages of embryos or offspring development, during while the currently employed methods are unable to detect impaired corticogenesis leading to microcephaly. Ndel1 activity may also be possibly used to follow up the positive response to the treatment, such as that employing the IFN‐beta that is able to rescue the ZIKV‐induced brain injury. image
... Of the remaining 45 articles, the majority (80%) were neurogenesis-related, including nine review articles (Ihunwo et al., , 2022Lipp, 2017;Oosthuizen, 2017;Martínez-Cerdeño et al., 2018;Bruguier et al., 2020;Yang et al., 2020;Dlamini et al., 2021;Samodien and Chellan, 2021). The focus of the remaining neurogenesis papers were similar, with the majority exploring neurogenesis across animal species (Table 1) including mole-rats (Amrein et al., 2014;Oosthuizen and Amrein, 2016), birds (Mazengenya et al., 2020(Mazengenya et al., , 2018, African elephants (Patzke et al., 2014b), primates (Fasemore et al., 2018), afrotherian mammals (Patzke et al., 2014a), microchiropterans (Chawana et al., 2014), African giant rats (Olude et al., 2014) and fourstriped mice (Olaleye and Ihunwo, 2014). ...
Neural stem cells (NSCs) are immature progenitor cells that are found in developing and adult brains that have the potential of dividing actively and renewing themselves, with a complex form of gene expression. The generation of new brain cells in adult individuals was initially considered impossible, however, the landmark discovery of human neural stem cells in the hippocampus has been followed by further discoveries in other discreet regions of the brain. Investigation into the current state in Africa of the research and use of NSCs shows relatively limited activities on the continent. Information on the African application of NSCs for modelling disease mechanisms, drug discovery, and therapeutics is still limited. The International Brain Research Organization (IBRO)-African Regional Committee (ARC), with support from the Company of Biologists, and the Movement Disorder Society, sponsored the first African Basic School on NSC in Ibadan, Nigeria, with the vision of bringing together young neuroscientists and physicians across different fields in neuroscience to learn from leaders who have applied NSCs in stem cell research, the pathophysiology of neurodegenerative diseases, neuroanatomy, and neurotherapeutics. Twenty early-career researchers in academic institutions at junior and senior faculty cadres were selected from South Africa, Uganda and Nigeria. The students and organizer of the school, who wrote this review on the state of NSCs research in Africa, recommended the following: (1) other African countries can take a cue from South Africa and Nigeria in probing the phenomena of adult neurogenesis in unique animal species on the continent; (2) Africa should leverage the expertise and facilities of South African scientists and international collaborators in scaling up NSC research into these unique species and (3) Centers of Excellence should be established on the continent to serve as research hubs for training postgraduate students, and facilities for African scientists who trained overseas on NSCs.
... In particular, in the latter, Yoon et al. demonstrated a preferential HCMV tropism for the dentate gyrus of the hippocampus . In this area neurogenesis is known to persist throughout adult life (Ihunwo et al. 2022). ...
Human cytomegalovirus (HCMV) causes congenital neurological lifelong disabilities. To date, the neuropathogenesis of brain injury related to congenital HCMV (cCMV) infection is poorly understood. This study evaluates the characteristics and pathogenetic mechanisms of encephalic damage in cCMV infection. Ten HCMV-infected human fetuses at 21 weeks of gestation were examined. Specifically, tissues from different brain areas were analyzed by: (i) immunohistochemistry (IHC) to detect HCMV-infected cell distribution, (ii) hematoxylin–eosin staining to evaluate histological damage and (iii) real-time PCR to quantify tissue viral load (HCMV-DNA). The differentiation stage of HCMV-infected neural/neuronal cells was assessed by double IHC to detect simultaneously HCMV-antigens and neural/neuronal markers: nestin (a marker of neural stem/progenitor cells), doublecortin (DCX, marker of cells committed to the neuronal lineage) and neuronal nuclei (NeuN, identifying mature neurons). HCMV-positive cells and viral DNA were found in the brain of 8/10 (80%) fetuses. For these cases, brain damage was classified as mild (n = 4, 50%), moderate (n = 3, 37.5%) and severe (n = 1, 12.5%) based on presence and frequency of pathological findings (necrosis, microglial nodules, microglial activation, astrocytosis, and vascular changes). The highest median HCMV-DNA level was found in the hippocampus (212 copies/5 ng of human DNA [hDNA], range: 10–7,505) as well as the highest mean HCMV-infected cell value (2.9 cells, range: 0–23), followed by that detected in subventricular zone (1.7 cells, range: 0–19). These findings suggested a preferential viral tropism for both neural stem/progenitor cells and neuronal committed cells, residing in these regions, confirmed by the expression of DCX and nestin in 94% and 63.3% of HCMV-positive cells, respectively. NeuN was not found among HCMV-positive cells and was nearly absent in the brain with severe damage, suggesting HCMV does not infect mature neurons and immature neural/neuronal cells do not differentiate into neurons. This could lead to known structural and functional brain defects from cCMV infection.
Graphical Abstract
The hippocampus is one of the most commonly studied brain regions in the context of depression. The volume of the hippocampus is significantly reduced in patients with depression, which severely disrupts hippocampal neuroplasticity. However, antidepressant therapies that target hippocampal neuroplasticity have not been identified as yet. Chinese medicine (CM) can slow the progression of depression, potentially by modulating hippocampal neuroplasticity. Xiaoyaosan (XYS) is a CM formula that has been clinically used for the treatment of depression. It is known to protect Gan (Liver) and Pi (Spleen) function, and may exert its antidepressant effects by regulating hippocampal neuroplasticity. In this review, we have summarized the association between depression and aberrant hippocampal neuroplasticity. Furthermore, we have discussed the researches published in the last 30 years on the effects of XYS on hippocampal neuroplasticity in order to elucidate the possible mechanisms underlying its therapeutic action against depression. The results of this review can aid future research on XYS for the treatment of depression.
Although 17β-estradiol (E2) can be locally synthesized in the brain, whether and how brain-derived E2 (BDE2) impacts neurogenesis with aging is largely unclear. In this study, we examined the hippocampal neural stem cells, neurogenesis, and gliogenesis of 1, 3, 6, 14, and 18-month (Mon) female rats. Female forebrain neuronal aromatase knockout (FBN-ARO-KO) rats and letrozole-treated rats were also employed. We demonstraed that (1) the number of neural stem cells declined over 14-Mon age, and the differentiation of astrocytes and microglia markedly elevated and exhibited excessive activation. KO rats showed declines in astrocyte A2 subtype and elevation in A1 subtype at 18 Mon; (2) neurogenesis sharply dropped from 1-Mon age; (3) KO suppressed dentate gyrus (DG) neurogenesis at 1, 6 and 18 Mon. Additionally, KO and letrozole treatment led to declined neurogenesis at 1-Mon age, compared to age-matched WT controls; (4) FBN-ARO-KO inhibited CREB-BDNF activation, and decreased protein levels of neurofilament, spinophilin and PSD95. Notably, hippocampal-dependent spatial learning and memory was impaired in juvenile (1 Mon) and adulthood (6 Mon) KO rats. Taken together, we demonstrated that BDE2 plays a pivotal role for hippocampal neurogenesis, as well as learning and memory during female aging, especially in juvenile and middle age.
Children exposed to various forms of adversity early in life are at increased risk for a broad range of developmental difficulties affecting the stress system, cognitive function, and emotional adjustment. Neurodevelopmental outcomes of adverse childhood experiences (ACEs) can begin as young as in the early stages of fetal development in utero and can have a lasting impact throughout the life course. In addition to the typical ACEs such as childhood maltreatment, adversity that occurs with prenatal exposures in the intrauterine environment such as to viruses and poor nutrition could alter neurodevelopment and contribute to neuropsychiatric disorders. Maternal immune activation (MIA) during pregnancy from viruses or a pro-inflammatory diet can impair neurodevelopment. ACEs increase vulnerability to substance use disorders that could result in intergenerational cycles if adult survivors of ACEs use substances during pregnancy and parenting. Marijuana and alcohol use by pregnant women and adolescents may be increasing because people think they are safe because they are legal. However, exposure to alcohol, marijuana, opioids, and/or other substances during fetal development and/or throughout adolescence and into adulthood can irreversibly impair neurodevelopment and brain function. Even paternal substance use can impair the child’s neurodevelopment. Potential interventions for prevention and optimal brain function are described here but more so throughout the chapters of Part IV. COVID-19 trauma is addressed briefly here and more so in Chap. 7.KeywordsAttention-deficit/hyperactivity disorder (ADHD)Autism spectrum disorder (ASD)Post-traumatic stress disorder (PTSD)Bipolar affective disorder (BP)Schizophrenia (SZ)Alcohol exposureSubstance exposureSubstance useIntrauterine environmentPrenatal infectionsMaternal immune activation (MIA)Neuro-inflammationZika virusCytomegalovirus (CMV)COVID-19Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)Prenatal dietTeen brain
