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Advances in Neurogenesis: Volume 2

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 22698

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Dr. Luisa Alexandra Meireles Pinto

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Life and Health Sciences Research Institute, School of Medicine, Universidade do Minho, Braga, Portugal
Interests: neurogenesis; gliogenesis; epigenetics; transcription factors; depression; neural circuits
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

The adult brain displays different forms of neural plasticity, ranging from neuronal synapto-dendritic rearrangements to the generation of novel neuronal and glial cells from neural stem cells (NSCs), processes known as adult neuro- and gliogenesis, respectively.

Postnatal neuro- and glioplasticity are largely driven by the transduction of environmental stimuli into essential neuroadaptations. Neuro- and glioplastic maladaptations often result in the manifestation of pathological traits, from which depressive behavior is a paradigmatic example.

Though increasing evidence supports the role of the hippocampal cytogenesis in brain physiology, its precise function is still debatable. The heterogeneity of the experimental models, timeframes, and methodological approaches used to address this subject has yielded conflicting results regarding the impact of the newborn cells on behavior. Still, converging data reveal a role for adult hippocampal cytogenesis in long-term spatial memory, cognitive flexibility, pattern separation, and clearance of hippocampal memories. Given the involvement of adult neurogenesis in such complex behaviors, it has become plausible to anticipate that its disruption could impact the neuronal circuitry and, ultimately, be implicated in the development of psychiatric and neurodegenerative disorders.

Understanding the role of novel genes and cytogenic regulators and better dissecting their impact throughout developmental periods and at different behavioral domains is of paramount importance to increase our current comprehension of this topic.

Dr. Luisa Alexandra Meireles Pinto
Guest Editor

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Keywords

neurogenesis
gliogenesis
cell plasticity
neurophysiology
behavior
neural circuits
cytogenic regulators
neuropsychiatric disorders
neurodegenerative disorders

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Frontiers in Neurogenesis in Cells (18 articles)

Published Papers (10 papers)

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Research

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26 pages, 5238 KiB

Open AccessArticle

MicroRNA-375 Is Induced during Astrocyte-to-Neuron Reprogramming and Promotes Survival of Reprogrammed Neurons when Overexpressed

by Xuanyu Chen, Ivan Sokirniy, Xin Wang, Mei Jiang, Natalie Mseis-Jackson, Christine Williams, Kristopher Mayes, Na Jiang, Brendan Puls, Quansheng Du, Yang Shi and Hedong Li

Cells 2023, 12(17), 2202; https://doi.org/10.3390/cells12172202 - 03 Sep 2023

Cited by 1 | Viewed by 1417

Abstract

While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain elusive. To understand the function of miRNAs during the AtN reprogramming process, we performed RNA-seq of both mRNAs and miRNAs on human astrocyte (HA) cultures upon NeuroD1 overexpression. Bioinformatics analyses showed that NeuroD1 not only activated essential neuronal genes to initiate the reprogramming process but also induced miRNA changes in HA. Among the upregulated miRNAs, we identified miR-375 and its targets, neuronal ELAVL genes (nELAVLs), which encode a family of RNA-binding proteins and were also upregulated by NeuroD1. We further showed that manipulating the miR-375 level regulated nELAVLs’ expression during NeuroD1-mediated reprogramming. Interestingly, miR-375/nELAVLs were also induced by the reprogramming factors Neurog2 and ASCL1 in HA, suggesting a conserved function to neuronal reprogramming, and by NeuroD1 in the mouse astrocyte culture and spinal cord. Functionally, we showed that miR-375 overexpression improved NeuroD1-mediated reprogramming efficiency by promoting cell survival at early stages in HA and did not appear to compromise the maturation of the reprogrammed neurons. Lastly, overexpression of miR-375-refractory ELAVL4 induced apoptosis and reversed the cell survival-promoting effect of miR-375 during AtN reprogramming. Together, we demonstrated a neuroprotective role of miR-375 during NeuroD1-mediated AtN reprogramming. Full article

(This article belongs to the Special Issue Advances in Neurogenesis: Volume 2)

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19 pages, 4703 KiB

Open AccessArticle

Atypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated with the Development of Post-Traumatic Epilepsy

by Erwin Kristobal Gudenschwager-Basso, Oleksii Shandra, Troy Volanth, Dipan C. Patel, Colin Kelly, Jack L. Browning, Xiaoran Wei, Elizabeth A. Harris, Dzenis Mahmutovic, Alexandra M. Kaloss, Fernanda Guilhaume Correa, Jeremy Decker, Biswajit Maharathi, Stefanie Robel, Harald Sontheimer, Pamela J. VandeVord, Michelle L. Olsen and Michelle H. Theus

Cells 2023, 12(9), 1248; https://doi.org/10.3390/cells12091248 - 25 Apr 2023

Cited by 2 | Viewed by 2381

Abstract

Background: Traumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under investigation. The dentate gyrus—a structure that is highly susceptible to injury—has been implicated in the evolution of seizure development. Methods: Utilizing the murine unilateral focal control cortical impact (CCI) injury, we evaluated seizure onset using 24/7 EEG video analysis at 2–4 months post-injury. Cellular changes in the dentate gyrus and hilus of the hippocampus were quantified by unbiased stereology and Imaris image analysis to evaluate Prox1-positive cell migration, astrocyte branching, and morphology, as well as neuronal loss at four months post-injury. Isolation of region-specific astrocytes and RNA-Seq were performed to determine differential gene expression in animals that developed post-traumatic epilepsy (PTE⁺) vs. those animals that did not (PTE⁻), which may be associated with epileptogenesis. Results: CCI injury resulted in 37% PTE incidence, which increased with injury severity and hippocampal damage. Histological assessments uncovered a significant loss of hilar interneurons that coincided with aberrant migration of Prox1-positive granule cells and reduced astroglial branching in PTE⁺ compared to PTE⁻ mice. We uniquely identified Cst3 as a PTE⁺-specific gene signature in astrocytes across all brain regions, which showed increased astroglial expression in the PTE⁺ hilus. Conclusions: These findings suggest that epileptogenesis may emerge following TBI due to distinct aberrant cellular remodeling events and key molecular changes in the dentate gyrus of the hippocampus. Full article

(This article belongs to the Special Issue Advances in Neurogenesis: Volume 2)

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16 pages, 1916 KiB

Open AccessArticle

Environmental Enrichment Engages Vesicular Zinc Signaling to Enhance Hippocampal Neurogenesis

by Michael J. Chrusch, Selena Fu, Simon C. Spanswick, Haley A. Vecchiarelli, Payal P. Patel, Matthew N. Hill and Richard H. Dyck

Cells 2023, 12(6), 883; https://doi.org/10.3390/cells12060883 - 13 Mar 2023

Cited by 3 | Viewed by 1589

Abstract

Zinc is highly concentrated in synaptic vesicles throughout the mammalian telencephalon and, in particular, the hippocampal dentate gyrus. A role for zinc in modulating synaptic plasticity has been inferred, but whether zinc has a particular role in experience-dependent plasticity has yet to be determined. The aim of the current study was to determine whether vesicular zinc is important for modulating adult hippocampal neurogenesis in an experience-dependent manner and, consequently, hippocampal-dependent behaviour. We assessed the role of vesicular zinc in modulating hippocampal neurogenesis and behaviour by comparing ZnT3 knockout (KO) mice, which lack vesicular zinc, to wild-type (WT) littermates exposed to either standard housing conditions (SH) or an enriched environment (EE). We found that vesicular zinc is necessary for a cascade of changes in hippocampal plasticity following EE, such as increases in hippocampal neurogenesis and elevations in mature brain-derived neurotrophic factor (mBDNF), but was otherwise dispensable under SH conditions. Using the Spatial Object Recognition task and the Morris Water task we show that, unlike WT mice, ZnT3 KO mice showed no improvements in spatial memory following EE. These experiments demonstrate that vesicular zinc is essential for the enhancement of adult hippocampal neurogenesis and behaviour following enrichment, supporting a role for zincergic neurons in contributing to experience-dependent plasticity in the hippocampus. Full article

(This article belongs to the Special Issue Advances in Neurogenesis: Volume 2)

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24 pages, 3393 KiB

Open AccessArticle

Vesicular Zinc Modulates Cell Proliferation and Survival in the Developing Hippocampus

by Selena Fu, Ashley T. Cho, Simon C. Spanswick and Richard H. Dyck

Cells 2023, 12(6), 880; https://doi.org/10.3390/cells12060880 - 11 Mar 2023

Cited by 1 | Viewed by 1868

Abstract

In the brain, vesicular zinc, which refers to a subset of zinc that is sequestered into synaptic vesicles by zinc transporter 3 (ZnT3), has extensive effects on neuronal signalling and modulation. Vesicular zinc-focused research has mainly been directed to its role in the hippocampus, particularly in adult neurogenesis. However, whether vesicular zinc is involved in modulating neurogenesis during the early postnatal period has been less studied. As a first step to understanding this, we used ZnT3 knockout (KO) mice, which lack ZnT3 and, thus, vesicular zinc, to evaluate cell proliferation at three different age points spanning postnatal development (P6, P14, and P28). The survival and the neuronal phenotype of these cells was also assessed in adulthood. We found that male ZnT3 KO mice exhibited lower rates of cell proliferation at P14, but a greater number of these cells survived to adulthood. Additionally, significantly more cells labelled on P6 survived to adulthood in male and female ZnT3 KO mice. We also found sex-dependent differences, whereby male mice showed higher levels of cell proliferation at P28, as well as higher levels of cell survival for P14-labelled cells, compared to female mice. However, female mice showed greater percentages of neuronal differentiation for P14-labelled cells. Finally, we found significant effects of age of BrdU injections on cell proliferation, survival, and neuronal differentiation. Collectively, our results suggest that the loss of vesicular zinc affects normal proliferation and survival of cells born at different age points during postnatal development and highlight prominent sex- and age-dependent differences. Our findings provide the foundation for future studies to further probe the role of vesicular zinc in the modulation of developmental neurogenesis. Full article

(This article belongs to the Special Issue Advances in Neurogenesis: Volume 2)

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12 pages, 4058 KiB

Open AccessFeature PaperArticle

StressMatic: A Novel Automated System to Induce Depressive- and Anxiety-like Phenotype in Rats

by Joana Martins-Macedo, António Mateus-Pinheiro, Cátia Alves, Fernando Veloso, Eduardo D. Gomes, Inês Ribeiro, Joana S. Correia, Tiago Silveira-Rosa, Nuno D. Alves, Ana J. Rodrigues, João M. Bessa, Nuno Sousa, João F. Oliveira, Patrícia Patrício and Luísa Pinto

Cells 2023, 12(3), 381; https://doi.org/10.3390/cells12030381 - 20 Jan 2023

Cited by 2 | Viewed by 1645

Abstract

Major depressive disorder (MDD) is a multidimensional psychiatric disorder that is estimated to affect around 350 million people worldwide. Generating valid and effective animal models of depression is critical and has been challenging for neuroscience researchers. For preclinical studies, models based on stress exposure, such as unpredictable chronic mild stress (uCMS), are amongst the most reliable and used, despite presenting concerns related to the standardization of protocols and time consumption for operators. To overcome these issues, we developed an automated system to expose rodents to a standard uCMS protocol. Here, we compared manual (uCMS) and automated (auCMS) stress-exposure protocols. The data shows that the impact of the uCMS exposure by both methods was similar in terms of behavioral (cognition, mood, and anxiety) and physiological (cell proliferation and endocrine variations) measurements. Given the advantages of time and standardization, this automated method represents a step forward in this field of preclinical research. Full article

(This article belongs to the Special Issue Advances in Neurogenesis: Volume 2)

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11 pages, 5208 KiB

Open AccessArticle

Influence of SARS-CoV-2 on Adult Human Neurogenesis

by Tomasz Stępień, Sylwia Tarka, Natalia Chmura, Michał Grzegorczyk, Albert Acewicz, Paulina Felczak and Teresa Wierzba-Bobrowicz

Cells 2023, 12(2), 244; https://doi.org/10.3390/cells12020244 - 06 Jan 2023

Cited by 6 | Viewed by 2220

Abstract

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with the onset of neurological and psychiatric symptoms during and after the acute phase of illness. Inflammation and hypoxia induced by SARS-CoV-2 affect brain regions essential for fine motor function, learning, memory, and emotional responses. The mechanisms of these central nervous system symptoms remain largely unknown. While looking for the causes of neurological deficits, we conducted a study on how SARS-CoV-2 affects neurogenesis. In this study, we compared a control group with a group of patients diagnosed with COVID-19. Analysis of the expression of neurogenesis markers showed a decrease in the density of neuronal progenitor cells and newborn neurons in the SARS-CoV-2 group. Analysis of COVID-19 patients revealed increased microglial activation compared with the control group. The unfavorable effect of the inflammatory process in the brain associated with COVID-19 disease increases the concentration of cytokines that negatively affect adult human neurogenesis. Full article

(This article belongs to the Special Issue Advances in Neurogenesis: Volume 2)

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9 pages, 1750 KiB

Open AccessArticle

Vestibular Nuclei: A New Neural Stem Cell Niche?

by Guillaume Rastoldo, Isabelle Watabe, Agnes Lapotre, Alain Tonetto, Alejandra López-Juárez and Brahim Tighilet

Cells 2022, 11(22), 3598; https://doi.org/10.3390/cells11223598 - 14 Nov 2022

Cited by 1 | Viewed by 1530

Abstract

We previously reported adult reactive neurogliogenesis in the deafferented vestibular nuclei following unilateral vestibular neurectomy (UVN) in the feline and the rodent model. Recently, we demonstrated that UVN induced a significant increase in a population of cells colocalizing the transcription factor sex determining region Y-box 2 (SOX2) and the glial fibrillary acidic protein (GFAP) three days after the lesion in the deafferented medial vestibular nucleus. These two markers expressed on the same cell population could indicate the presence of lesion-reactive multipotent neural stem cells in the vestibular nuclei. The aim of our study was to provide insight into the potential neurogenic niche status of the vestibular nuclei in physiological conditions by using specific markers of stem cells (Nestin, SOX2, GFAP), cell proliferation (BrdU) and neuronal differentiation (NeuN). The present study confirmed the presence of quiescent and activated adult neural stem cells generating some new neurons in the vestibular nuclei of control rats. These unique features provide evidence that the vestibular nuclei represent a novel NSC site for the generation of neurons and/or glia in the adult rodent under physiological conditions. Full article

(This article belongs to the Special Issue Advances in Neurogenesis: Volume 2)

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Review

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17 pages, 1105 KiB

Open AccessReview

Microglia at the Tripartite Synapse during Postnatal Development: Implications for Autism Spectrum Disorders and Schizophrenia

by Laura Ferrucci, Iva Cantando, Federica Cordella, Silvia Di Angelantonio, Davide Ragozzino and Paola Bezzi

Cells 2023, 12(24), 2827; https://doi.org/10.3390/cells12242827 - 13 Dec 2023

Cited by 3 | Viewed by 1850

Abstract

Synapses are the fundamental structures of neural circuits that control brain functions and behavioral and cognitive processes. Synapses undergo formation, maturation, and elimination mainly during postnatal development via a complex interplay with neighboring astrocytes and microglia that, by shaping neural connectivity, may have a crucial role in the strengthening and weakening of synaptic functions, that is, the functional plasticity of synapses. Indeed, an increasing number of studies have unveiled the roles of microglia and astrocytes in synapse formation, maturation, and elimination as well as in regulating synaptic function. Over the past 15 years, the mechanisms underlying the microglia- and astrocytes-dependent regulation of synaptic plasticity have been thoroughly studied, and researchers have reported that the disruption of these glial cells in early postnatal development may underlie the cause of synaptic dysfunction that leads to neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. Full article

(This article belongs to the Special Issue Advances in Neurogenesis: Volume 2)

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18 pages, 1179 KiB

Open AccessReview

Role of Oligodendrocyte Lineage Cells in Multiple System Atrophy

by Jen-Hsiang T. Hsiao, Onur Tanglay, Anne A. Li, Aysha Y. G. Strobbe, Woojin Scott Kim, Glenda M. Halliday and YuHong Fu

Cells 2023, 12(5), 739; https://doi.org/10.3390/cells12050739 - 25 Feb 2023

Cited by 3 | Viewed by 3093

Abstract

Multiple system atrophy (MSA) is a debilitating movement disorder with unknown etiology. Patients present characteristic parkinsonism and/or cerebellar dysfunction in the clinical phase, resulting from progressive deterioration in the nigrostriatal and olivopontocerebellar regions. MSA patients have a prodromal phase subsequent to the insidious onset of neuropathology. Therefore, understanding the early pathological events is important in determining the pathogenesis, which will assist with developing disease-modifying therapy. Although the definite diagnosis of MSA relies on the positive post-mortem finding of oligodendroglial inclusions composed of α-synuclein, only recently has MSA been verified as an oligodendrogliopathy with secondary neuronal degeneration. We review up-to-date knowledge of human oligodendrocyte lineage cells and their association with α-synuclein, and discuss the postulated mechanisms of how oligodendrogliopathy develops, oligodendrocyte progenitor cells as the potential origins of the toxic seeds of α-synuclein, and the possible networks through which oligodendrogliopathy induces neuronal loss. Our insights will shed new light on the research directions for future MSA studies. Full article

(This article belongs to the Special Issue Advances in Neurogenesis: Volume 2)

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27 pages, 3936 KiB

Open AccessReview

Current Understanding of the Neural Stem Cell Niches

by Vicente Llorente, Pedro Velarde, Manuel Desco and María Victoria Gómez-Gaviro

Cells 2022, 11(19), 3002; https://doi.org/10.3390/cells11193002 - 26 Sep 2022

Cited by 16 | Viewed by 4046

Abstract

Neural stem cells (NSCs) are self-renewing, multipotent cells which give rise to all components of the central nervous system (CNS) during embryogenesis, but also activate in response to injury and disease and maintain a certain level of neurogenic activity throughout adulthood. This activity takes place in specialized regions of the brain, the neurovascular niches, whose main role is to control the behaviour of the CNS. In adult mammals, two main “canonical” niches have been described: The subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus. This review discusses our current understanding of the neural stem cells and their canonical niches, as well as their structure, behaviours, and role in neural disease. Full article

(This article belongs to the Special Issue Advances in Neurogenesis: Volume 2)

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