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Open AccessEditorial

Frontiers in Neurogenesis

by Andreia Vaz, Inês Ribeiro and Luísa Pinto

Cells 2022, 11(22), 3567; https://doi.org/10.3390/cells11223567 - 11 Nov 2022

Cited by 6 | Viewed by 6049

Abstract

One of the most intriguing dogmas in neurosciences—the empirical lack of brain neuronal regeneration in adulthood onwards to late life—began to be debunked initially by research groups focused on understanding postnatal (early days/weeks of murine and guinea pigs) neurodevelopmental and neuroplastic events [...] [...] Read more.

One of the most intriguing dogmas in neurosciences—the empirical lack of brain neuronal regeneration in adulthood onwards to late life—began to be debunked initially by research groups focused on understanding postnatal (early days/weeks of murine and guinea pigs) neurodevelopmental and neuroplastic events [...] Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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Research

Jump to: Editorial, Review

27 pages, 11143 KiB

Open AccessArticle

Cerebral Organoids Maintain the Expression of Neural Stem Cell-Associated Glycoepitopes and Extracellular Matrix

by Lars Roll, Katrin Lessmann, Oliver Brüstle and Andreas Faissner

Cells 2022, 11(5), 760; https://doi.org/10.3390/cells11050760 - 22 Feb 2022

Cited by 10 | Viewed by 6075

Abstract

During development, the nervous system with its highly specialized cell types forms from a pool of relatively uniform stem cells. This orchestrated process requires tight regulation. The extracellular matrix (ECM) is a complex network rich in signaling molecules, and therefore, of interest in [...] Read more.

During development, the nervous system with its highly specialized cell types forms from a pool of relatively uniform stem cells. This orchestrated process requires tight regulation. The extracellular matrix (ECM) is a complex network rich in signaling molecules, and therefore, of interest in this context. Distinct carbohydrate structures, bound to ECM molecules like Tenascin C (TNC), are associated with neural stem/progenitor cells. We have analyzed the expression patterns of the LewisX (LeX) trisaccharide motif and of the sulfation-dependent DSD-1 chondroitin sulfate glycosaminoglycan epitope in human cerebral organoids, a 3D model for early central nervous system (CNS) development, immunohistochemically. In early organoids we observed distinct expression patterns of the glycoepitopes, associated with rosette-like structures that resemble the neural tube in vitro: Terminal LeX motifs, recognized by the monoclonal antibody (mAb) 487^LeX, were enriched in the lumen and at the outer border of neural rosettes. In contrast, internal LeX motif repeats detected with mAb 5750^LeX were concentrated near the lumen. The DSD-1 epitope, labeled with mAb 473HD, was detectable at rosette borders and in adjacent cells. The epitope expression was maintained in older organoids but appeared more diffuse. The differential glycoepitope expression suggests a specific function in the developing human CNS. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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24 pages, 43453 KiB

Open AccessFeature PaperArticle

L-Thyroxine Improves Vestibular Compensation in a Rat Model of Acute Peripheral Vestibulopathy: Cellular and Behavioral Aspects

by Guillaume Rastoldo, Emna Marouane, Nada El-Mahmoudi, David Péricat, Isabelle Watabe, Agnes Lapotre, Alain Tonetto, Alejandra López-Juárez, Abdessadek El-Ahmadi, Philippe Caron, Marie-José Esteve Fraysse, Christian Chabbert, Andreas Zwergal and Brahim Tighilet

Cells 2022, 11(4), 684; https://doi.org/10.3390/cells11040684 - 16 Feb 2022

Cited by 17 | Viewed by 3530

Abstract

Unilateral vestibular lesions induce a vestibular syndrome, which recovers over time due to vestibular compensation. The therapeutic effect of L-Thyroxine (L-T4) on vestibular compensation was investigated by behavioral testing and immunohistochemical analysis in a rat model of unilateral vestibular neurectomy (UVN). We demonstrated [...] Read more.

Unilateral vestibular lesions induce a vestibular syndrome, which recovers over time due to vestibular compensation. The therapeutic effect of L-Thyroxine (L-T4) on vestibular compensation was investigated by behavioral testing and immunohistochemical analysis in a rat model of unilateral vestibular neurectomy (UVN). We demonstrated that a short-term L-T4 treatment reduced the vestibular syndrome and significantly promoted vestibular compensation. Thyroid hormone receptors (TRα and TRβ) and type II iodothyronine deiodinase (DIO2) were present in the vestibular nuclei (VN), supporting a local action of L-T4. We confirmed the T4-induced metabolic effects by demonstrating an increase in the number of cytochrome oxidase-labeled neurons in the VN three days after the lesion. L-T4 treatment modulated glial reaction by decreasing both microglia and oligodendrocytes in the deafferented VN three days after UVN and increased cell proliferation. Survival of newly generated cells in the deafferented vestibular nuclei was not affected, but microglial rather than neuronal differentiation was favored by L-T4 treatment. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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15 pages, 142806 KiB

Open AccessArticle

Distinct Actions of the Thyroid Hormone Transporters Mct8 and Oatp1c1 in Murine Adult Hippocampal Neurogenesis

by Steffen Mayerl, Andrea Alcaide Martin, Reinhard Bauer, Markus Schwaninger, Heike Heuer and Charles ffrench-Constant

Cells 2022, 11(3), 524; https://doi.org/10.3390/cells11030524 - 2 Feb 2022

Cited by 9 | Viewed by 2994

Abstract

Inactivating mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) result in Allan-Herndon-Dudley Syndrome, a severe form of psychomotor retardation, while inactivating mutations in another TH transporter, organic anion transporting polypeptide 1c1 (OATP1C1), are linked to juvenile neurodegeneration. These diseases point [...] Read more.

Inactivating mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) result in Allan-Herndon-Dudley Syndrome, a severe form of psychomotor retardation, while inactivating mutations in another TH transporter, organic anion transporting polypeptide 1c1 (OATP1C1), are linked to juvenile neurodegeneration. These diseases point to essential roles for TH transporters in CNS function. We recently defined the presence of Mct8 in adult hippocampal progenitors and mature granule cell neurons and unraveled cell-autonomous and indirect requirements for Mct8 in adult hippocampal neurogenesis. Here, we investigated whether Oatp1c1 is involved in the hippocampal neurogenic process in concert with Mct8. We detected Oatp1c1 gene expression activity and transcripts in subsets of progenitors, neurons and niche cells in the dentate gyrus. Absence of Oatp1c1 resulted in increased neuroblast and reduced immature neuron numbers in 6-month-old Oatp1c1ko and Mct8/Oatp1c1 double knockout (M/Odko) mice. Reduced EdU-label retention in Mct8ko and M/Odko mice confirmed the impact of Mct8 on neuron formation. In contrast, no significant effect of Oatp1c1 loss on granule cell neuron production and anxiety-like behavior in the open field arena were seen. Together, our results reinforce that distinct actions of each TH transporter are required at multiple stages to ensure proper adult hippocampal neurogenesis. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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18 pages, 2646 KiB

Open AccessArticle

Beyond New Neurons in the Adult Hippocampus: Imipramine Acts as a Pro-Astrogliogenic Factor and Rescues Cognitive Impairments Induced by Stress Exposure

by Ana R. Machado-Santos, Eduardo Loureiro-Campos, Patrícia Patrício, Bruna Araújo, Nuno Dinis Alves, António Mateus-Pinheiro, Joana Sofia Correia, Mónica Morais, João M. Bessa, Nuno Sousa, Ana J. Rodrigues, João Filipe Oliveira and Luísa Pinto

Cells 2022, 11(3), 390; https://doi.org/10.3390/cells11030390 - 24 Jan 2022

Cited by 10 | Viewed by 3610

Abstract

Depression is a prevalent, socially burdensome disease. Different studies have demonstrated the important role of astrocytes in the pathophysiology of depression as modulators of neurotransmission and neurovascular coupling. This is evidenced by astrocyte impairments observed in brains of depressed patients and the appearance [...] Read more.

Depression is a prevalent, socially burdensome disease. Different studies have demonstrated the important role of astrocytes in the pathophysiology of depression as modulators of neurotransmission and neurovascular coupling. This is evidenced by astrocyte impairments observed in brains of depressed patients and the appearance of depressive-like behaviors upon astrocytic dysfunctions in animal models. However, little is known about the importance of de novo generated astrocytes in the mammalian brain and in particular its possible involvement in the precipitation of depression and in the therapeutic actions of current antidepressants (ADs). Therefore, we studied the modulation of astrocytes and adult astrogliogenesis in the hippocampal dentate gyrus (DG) of rats exposed to an unpredictable chronic mild stress (uCMS) protocol, untreated and treated for two weeks with antidepressants—fluoxetine and imipramine. Our results show that adult astrogliogenesis in the DG is modulated by stress and imipramine. This study reveals that distinct classes of ADs impact differently in the astrogliogenic process, showing different cellular mechanisms relevant to the recovery from behavioral deficits induced by chronic stress exposure. As such, in addition to those resident, the newborn astrocytes in the hippocampal DG might also be promising therapeutic targets for future therapies in the neuropsychiatric field. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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44 pages, 15001 KiB

Open AccessArticle

The Transcriptome and Methylome of the Developing and Aging Brain and Their Relations to Gliomas and Psychological Disorders

by Henry Loeffler-Wirth, Lydia Hopp, Maria Schmidt, Roksana Zakharyan, Arsen Arakelyan and Hans Binder

Cells 2022, 11(3), 362; https://doi.org/10.3390/cells11030362 - 21 Jan 2022

Cited by 6 | Viewed by 4281

Abstract

Mutually linked expression and methylation dynamics in the brain govern genome regulation over the whole lifetime with an impact on cognition, psychological disorders, and cancer. We performed a joint study of gene expression and DNA methylation of brain tissue originating from the human [...] Read more.

Mutually linked expression and methylation dynamics in the brain govern genome regulation over the whole lifetime with an impact on cognition, psychological disorders, and cancer. We performed a joint study of gene expression and DNA methylation of brain tissue originating from the human prefrontal cortex of individuals across the lifespan to describe changes in cellular programs and their regulation by epigenetic mechanisms. The analysis considers previous knowledge in terms of functional gene signatures and chromatin states derived from independent studies, aging profiles of a battery of chromatin modifying enzymes, and data of gliomas and neuropsychological disorders for a holistic view on the development and aging of the brain. Expression and methylation changes from babies to elderly adults decompose into different modes associated with the serial activation of (brain) developmental, learning, metabolic and inflammatory functions, where methylation in gene promoters mostly represses transcription. Expression of genes encoding methylome modifying enzymes is very diverse reflecting complex regulations during lifetime which also associates with the marked remodeling of chromatin between permissive and restrictive states. Data of brain cancer and psychotic disorders reveal footprints of pathophysiologies related to brain development and aging. Comparison of aging brains with gliomas supports the view that glioblastoma-like and astrocytoma-like tumors exhibit higher cellular plasticity activated in the developing healthy brain while oligodendrogliomas have a more stable differentiation hierarchy more resembling the aged brain. The balance and specific shifts between volatile and stable and between more irreversible and more plastic epigenomic networks govern the development and aging of healthy and diseased brain. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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17 pages, 22065 KiB

Open AccessEditor’s ChoiceArticle

Neuron–Microglia Contact-Dependent Mechanisms Attenuate Methamphetamine-Induced Microglia Reactivity and Enhance Neuronal Plasticity

by Joana Bravo, Inês Ribeiro, Ana Filipa Terceiro, Elva B. Andrade, Camila Cabral Portugal, Igor M. Lopes, Maria M. Azevedo, Mafalda Sousa, Cátia D. F. Lopes, Andrea C. Lobo, Teresa Canedo, João Bettencourt Relvas and Teresa Summavielle

Cells 2022, 11(3), 355; https://doi.org/10.3390/cells11030355 - 21 Jan 2022

Cited by 11 | Viewed by 5128

Abstract

Exposure to methamphetamine (Meth) has been classically associated with damage to neuronal terminals. However, it is now becoming clear that addiction may also result from the interplay between glial cells and neurons. Recently, we demonstrated that binge Meth administration promotes microgliosis and microglia [...] Read more.

Exposure to methamphetamine (Meth) has been classically associated with damage to neuronal terminals. However, it is now becoming clear that addiction may also result from the interplay between glial cells and neurons. Recently, we demonstrated that binge Meth administration promotes microgliosis and microglia pro-inflammation via astrocytic glutamate release in a TNF/IP₃R2-Ca²⁺-dependent manner. Here, we investigated the contribution of neuronal cells to this process. As the crosstalk between microglia and neurons may occur by contact-dependent and/or contact-independent mechanisms, we developed co-cultures of primary neurons and microglia in microfluidic devices to investigate how their interaction affects Meth-induced microglia activation. Our results show that neurons exposed to Meth do not activate microglia in a cell-autonomous way but require astrocyte mediation. Importantly, we found that neurons can partially prevent Meth-induced microglia activation via astrocytes, which seems to be achieved by increasing arginase 1 expression and strengthening the CD200/CD200r pathway. We also observed an increase in synaptic individual area, as determined by co-localization of pre- and post-synaptic markers. The present study provides evidence that contact-dependent mechanisms between neurons and microglia can attenuate pro-inflammatory events such as Meth-induced microglia activation. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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17 pages, 3019 KiB

Open AccessArticle

Interleukine-17 Modulates Neurogenesis and Behavior Following Exposure to Trauma in Mice

by Yehoshua Willinger and Gadi Turgeman

Cells 2022, 11(3), 343; https://doi.org/10.3390/cells11030343 - 20 Jan 2022

Cited by 11 | Viewed by 3017

Abstract

Post-traumatic stress disorder (PTSD) is a psychiatric disorder accompanied by deficits in cognitive and social skills. Adult hippocampal neurogenesis is a lifelong phenomenon, with new neurons being formed in the granular cell layer of the dentate gyrus. Impaired neurogenesis is associated with multiple [...] Read more.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder accompanied by deficits in cognitive and social skills. Adult hippocampal neurogenesis is a lifelong phenomenon, with new neurons being formed in the granular cell layer of the dentate gyrus. Impaired neurogenesis is associated with multiple behavioral disorders including Alzheimer’s disease and schizophrenia. PTSD patients often present hippocampal atrophy and animal models clearly present impaired neurogenesis. Previous studies on PTSD patients demonstrated elevated levels of Th17 cells and plasma levels of the pro-inflammatory cytokine interleukin-17A (IL-17A). Since IL-17A can impair neurogenesis in mice, we thus hypothesized that decreasing the serum levels of IL-17A will increase hippocampal neurogenesis and alleviate symptoms in a murine model of PTSD. Surprisingly, our results showed that attempting to neutralize IL-17A with an antibody resulted in increased serum levels of IL-17A, while targeting IL-23, the upstream regulator of IL-17, did lower the levels of IL-17A in trauma-exposed mice. As expected, increased levels of serum IL-17A (in anti-IL-17A treated mice) resulted in impaired neurogenesis, reflected by reduced number of proliferating Ki67⁺ neural progenitors and newly formed DCX⁺ neurons, which was correlated with increased expression of Hes1. Nevertheless, increased maturation was noted by the expression of Slit2 and Ache. In contrast, treatment with anti-IL-23 indeed resulted in increased neurogenesis. Behaviorally, both treatments did not affect trauma-related freezing behavior but did affect trauma-related social deficits. Unexpectedly, increased levels of serum IL-17A (in anti-IL-17A treated mice) prevented social deficits in trauma-exposed mice while anti-IL-23 exacerbated these deficits. We thus conclude that IL-17 is involved in regulating neurogenesis following exposure to stress but may be important in maintaining social behavior. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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20 pages, 2798 KiB

Open AccessFeature PaperArticle

Sensorimotor Rehabilitation Promotes Vestibular Compensation in a Rodent Model of Acute Peripheral Vestibulopathy by Promoting Microgliogenesis in the Deafferented Vestibular Nuclei

by Emna Marouane, Nada El Mahmoudi, Guillaume Rastoldo, David Péricat, Isabelle Watabe, Agnès Lapôtre, Alain Tonetto, Frédéric Xavier, Olivier Dumas, Christian Chabbert, Vincent Artzner and Brahim Tighilet

Cells 2021, 10(12), 3377; https://doi.org/10.3390/cells10123377 - 1 Dec 2021

Cited by 19 | Viewed by 3226

Abstract

Acute peripheral vestibulopathy leads to a cascade of symptoms involving balance and gait disorders that are particularly disabling for vestibular patients. Vestibular rehabilitation protocols have proven to be effective in improving vestibular compensation in clinical practice. Yet, the underlying neurobiological correlates remain unknown. [...] Read more.

Acute peripheral vestibulopathy leads to a cascade of symptoms involving balance and gait disorders that are particularly disabling for vestibular patients. Vestibular rehabilitation protocols have proven to be effective in improving vestibular compensation in clinical practice. Yet, the underlying neurobiological correlates remain unknown. The aim of this study was to highlight the behavioural and cellular consequences of a vestibular rehabilitation protocol adapted to a rat model of unilateral vestibular neurectomy. We developed a progressive sensory-motor rehabilitation task, and the behavioural consequences were quantified using a weight-distribution device. This analysis method provides a precise and ecological analysis of posturolocomotor vestibular deficits. At the cellular level, we focused on the analysis of plasticity mechanisms expressed in the vestibular nuclei. The results obtained show that vestibular rehabilitation induces a faster recovery of posturolocomotor deficits during vestibular compensation associated with a decrease in neurogenesis and an increase in microgliogenesis in the deafferented medial vestibular nucleus. This study reveals for the first time a part of the underlying adaptative neuroplasticity mechanisms of vestibular rehabilitation. These original data incite further investigation of the impact of rehabilitation on animal models of vestibulopathy. This new line of research should improve the management of vestibular patients. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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26 pages, 10771 KiB

Open AccessArticle

Transcriptome Profiling of Dysregulated GPCRs Reveals Overlapping Patterns across Psychiatric Disorders and Age-Disease Interactions

by Roudabeh Vakil Monfared, Wedad Alhassen, Tri Minh Truong, Michael Angelo Maglalang Gonzales, Vincent Vachirakorntong, Siwei Chen, Pierre Baldi, Olivier Civelli and Amal Alachkar

Cells 2021, 10(11), 2967; https://doi.org/10.3390/cells10112967 - 31 Oct 2021

Cited by 15 | Viewed by 4144

Abstract

G-protein-coupled receptors (GPCRs) play an integral role in the neurobiology of psychiatric disorders. Almost all neurotransmitters involved in psychiatric disorders act through GPCRs, and GPCRs are the most common targets of therapeutic drugs currently used in the treatment of psychiatric disorders. However, the [...] Read more.

G-protein-coupled receptors (GPCRs) play an integral role in the neurobiology of psychiatric disorders. Almost all neurotransmitters involved in psychiatric disorders act through GPCRs, and GPCRs are the most common targets of therapeutic drugs currently used in the treatment of psychiatric disorders. However, the roles of GPCRs in the etiology and pathophysiology of psychiatric disorders are not fully understood. Using publically available datasets, we performed a comprehensive analysis of the transcriptomic signatures of G-protein-linked signaling across the major psychiatric disorders: autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BP), and major depressive disorder (MDD). We also used the BrainSpan transcriptomic dataset of the developing human brain to examine whether GPCRs that exhibit chronological age-associated expressions have a higher tendency to be dysregulated in psychiatric disorders than age-independent GPCRs. We found that most GPCR genes were differentially expressed in the four disorders and that the GPCR superfamily as a gene cluster was overrepresented in the four disorders. We also identified a greater amplitude of gene expression changes in GPCRs than other gene families in the four psychiatric disorders. Further, dysregulated GPCRs overlapped across the four psychiatric disorders, with SCZ exhibiting the highest overlap with the three other disorders. Finally, the results revealed a greater tendency of age-associated GPCRs to be dysregulated in ASD than random GPCRs. Our results substantiate the central role of GPCR signaling pathways in the etiology and pathophysiology of psychiatric disorders. Furthermore, our study suggests that common GPCRs’ signaling may mediate distinct phenotypic presentations across psychiatric disorders. Consequently, targeting these GPCRs could serve as a common therapeutic strategy to treat specific clinical symptoms across psychiatric disorders. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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18 pages, 2495 KiB

Open AccessArticle

Foxd4l1.1 Negatively Regulates Chordin Transcription in Neuroectoderm of Xenopus Gastrula

by Vijay Kumar, Ravi Shankar Goutam, Zobia Umair, Soochul Park, Unjoo Lee and Jaebong Kim

Cells 2021, 10(10), 2779; https://doi.org/10.3390/cells10102779 - 17 Oct 2021

Cited by 7 | Viewed by 2635

Abstract

Inhibition of the bone morphogenetic proteins (BMPs) is the primary step toward neuroectoderm formation in vertebrates. In this process, the Spemann organizer of the dorsal mesoderm plays a decisive role by secreting several extracellular BMP inhibitors such as Chordin (Chrd). Chrd physically interacts [...] Read more.

Inhibition of the bone morphogenetic proteins (BMPs) is the primary step toward neuroectoderm formation in vertebrates. In this process, the Spemann organizer of the dorsal mesoderm plays a decisive role by secreting several extracellular BMP inhibitors such as Chordin (Chrd). Chrd physically interacts with BMP proteins and inhibits BMP signaling, which triggers the expression of neural-specific transcription factors (TFs), including Foxd4l1.1. Thus, Chrd induces in a BMP-inhibited manner and promotes neuroectoderm formation. However, the regulatory feedback mechanism of Foxd4l1.1 on mesodermal genes expression during germ-layer specification has not been fully elucidated. In this study, we investigated the regulatory mechanism of Foxd4l1.1 on chrd (a mesodermal gene). We demonstrate that Foxd4l1.1 inhibits chrd expression during neuroectoderm formation in two ways: First, Foxd4l1.1 directly binds to FRE (Foxd4l1.1 response elements) within the chrd promoter region to inhibit transcription. Second, Foxd4l1.1 physically interacts with Smad2 and Smad3, and this interaction blocks Smad2 and Smad3 binding to activin response elements (AREs) within the chrd promoter. Site-directed mutagenesis of FRE within the chrd(-2250) promoter completely abolished repressor activity of the Foxd4l1.1. RT-PCR and reporter gene assay results indicate that Foxd4l1.1 strongly inhibits mesoderm- and ectoderm-specific marker genes to maintain neural fate. Altogether, these results suggest that Foxd4l1.1 negatively regulates chrd transcription by dual mechanism. Thus, our study demonstrates the existence of precise reciprocal regulation of chrd transcription during neuroectoderm and mesoderm germ-layer specification in Xenopus embryos. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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17 pages, 4318 KiB

Open AccessArticle

Effects of Combined Anti-Hypertensive and Statin Treatment on Memory, Fear Extinction, Adult Neurogenesis, and Angiogenesis in Adult and Middle-Aged Mice

by Seungwoo Yoo, Matthew Stremlau, Alejandro Pinto, Hyewon Woo, Olivia Curtis and Henriette van Praag

Cells 2021, 10(7), 1778; https://doi.org/10.3390/cells10071778 - 14 Jul 2021

Cited by 3 | Viewed by 3759

Abstract

Hyperlipidemia and hypertension are modifiable risk factors for cognitive decline. About 25% of adults over age 65 use both antihypertensives (AHTs) and statins to treat these conditions. Recent research in humans suggests that their combined use may delay or prevent dementia onset. However, [...] Read more.

Hyperlipidemia and hypertension are modifiable risk factors for cognitive decline. About 25% of adults over age 65 use both antihypertensives (AHTs) and statins to treat these conditions. Recent research in humans suggests that their combined use may delay or prevent dementia onset. However, it is not clear whether and how combination treatment may benefit brain function. To begin to address this question, we examined effects of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and Captopril, an angiotensin-converting enzyme inhibitor (ACEI), administration on memory function, anxiety-like behavior, adult hippocampal neurogenesis and angiogenesis in adult and middle-aged male C57Bl/6J mice. In adult mice (3-months-old) combination (combo) treatment, as well as administration of each compound individually, for six weeks, accelerated memory extinction in contextual fear conditioning. However, pattern separation in the touchscreen-based location discrimination test, a behavior linked to adult hippocampal neurogenesis, was unchanged. In addition, dentate gyrus (DG) neurogenesis and vascularization were unaffected. In middle-aged mice (10-months-old) combo treatment had no effect on spatial memory in the Morris water maze, but did reduce anxiety in the open field test. A potential underlying mechanism may be the modest increase in new hippocampal neurons (~20%) in the combo as compared to the control group. DG vascularization was not altered. Overall, our findings suggest that statin and anti-hypertensive treatment may serve as a potential pharmacotherapeutic approach for anxiety, in particular for post-traumatic stress disorder (PTSD) patients who have impairments in extinction of aversive memories. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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Review

Jump to: Editorial, Research

20 pages, 1610 KiB

Open AccessEditor’s ChoiceReview

Postnatal and Adult Neurogenesis in Mammals, Including Marsupials

by Katarzyna Bartkowska, Beata Tepper, Krzysztof Turlejski and Ruzanna Djavadian

Cells 2022, 11(17), 2735; https://doi.org/10.3390/cells11172735 - 1 Sep 2022

Cited by 16 | Viewed by 4340

Abstract

In mammals, neurogenesis occurs during both embryonic and postnatal development. In eutherians, most brain structures develop embryonically; conversely, in marsupials, a number of brain structures develop after birth. The exception is the generation of granule cells in the dentate gyrus, olfactory bulb, and [...] Read more.

In mammals, neurogenesis occurs during both embryonic and postnatal development. In eutherians, most brain structures develop embryonically; conversely, in marsupials, a number of brain structures develop after birth. The exception is the generation of granule cells in the dentate gyrus, olfactory bulb, and cerebellum of eutherian species. The formation of these structures starts during embryogenesis and continues postnatally. In both eutherians and marsupials, neurogenesis continues in the subventricular zone of the lateral ventricle (SVZ) and the dentate gyrus of the hippocampal formation throughout life. The majority of proliferated cells from the SVZ migrate to the olfactory bulb, whereas, in the dentate gyrus, cells reside within this structure after division and differentiation into neurons. A key aim of this review is to evaluate advances in understanding developmental neurogenesis that occurs postnatally in both marsupials and eutherians, with a particular emphasis on the generation of granule cells during the formation of the olfactory bulb, dentate gyrus, and cerebellum. We debate the significance of immature neurons in the piriform cortex of young mammals. We also synthesize the knowledge of adult neurogenesis in the olfactory bulb and the dentate gyrus of marsupials by considering whether adult-born neurons are essential for the functioning of a given area. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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10 pages, 655 KiB

Open AccessReview

Targeting the Subventricular Zone to Promote Myelin Repair in the Aging Brain

by Arthur Morgan Butt, Andrea Dominico Rivera, Daniel Fulton and Kasum Azim

Cells 2022, 11(11), 1809; https://doi.org/10.3390/cells11111809 - 31 May 2022

Cited by 15 | Viewed by 3444

Abstract

The subventricular zone (SVZ) is the largest and most active germinal zone in the adult forebrain. Neural stem cells (NSCs) of the SVZ generate olfactory interneurons throughout life and retain the intrinsic ability to generate oligodendrocytes (OLs), the myelinating cells of the central [...] Read more.

The subventricular zone (SVZ) is the largest and most active germinal zone in the adult forebrain. Neural stem cells (NSCs) of the SVZ generate olfactory interneurons throughout life and retain the intrinsic ability to generate oligodendrocytes (OLs), the myelinating cells of the central nervous system. OLs and myelin are targets in demyelinating diseases such as multiple sclerosis (MS). Remyelination is dependent on the ability of oligodendrocyte progenitor cells (OPCs) to proliferate, migrate, and terminally differentiate into myelinating OLs. During aging, there is a gradual decrease in the regenerative capacity of OPCs, and the consequent loss of OLs and myelin is a contributing factor in cognitive decline and the failure of remyelination in MS and other pathologies with aging contexts, including Alzheimer’s disease (AD) and stroke. The age-related decrease in oligodendrogenesis has not been fully characterised but is known to reflect changes in intrinsic and environmental factors affecting the ability of OPCs to respond to pro-differentiation stimuli. Notably, SVZ-derived OPCs are an important source of remyelinating OLs in addition to parenchymal OPCs. In this mini-review, we briefly discuss differences between SVZ-derived and parenchymal OPCs in their responses to demyelination and highlight challenges associated with their study in vivo and how they can be targeted for regenerative therapies in the aged brain. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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23 pages, 1086 KiB

Open AccessReview

Adult Neurogenesis under Control of the Circadian System

by Amira A. H. Ali and Charlotte von Gall

Cells 2022, 11(5), 764; https://doi.org/10.3390/cells11050764 - 22 Feb 2022

Cited by 24 | Viewed by 6130

Abstract

The mammalian circadian system is a hierarchically organized system, which controls a 24-h periodicity in a wide variety of body and brain functions and physiological processes. There is increasing evidence that the circadian system modulates the complex multistep process of adult neurogenesis, which [...] Read more.

The mammalian circadian system is a hierarchically organized system, which controls a 24-h periodicity in a wide variety of body and brain functions and physiological processes. There is increasing evidence that the circadian system modulates the complex multistep process of adult neurogenesis, which is crucial for brain plasticity. This modulatory effect may be exercised via rhythmic systemic factors including neurotransmitters, hormones and neurotrophic factors as well as rhythmic behavior and physiology or via intrinsic factors within the neural progenitor cells such as the redox state and clock genes/molecular clockwork. In this review, we discuss the role of the circadian system for adult neurogenesis at both the systemic and the cellular levels. Better understanding of the role of the circadian system in modulation of adult neurogenesis can help develop new treatment strategies to improve the cognitive deterioration associated with chronodisruption due to detrimental light regimes or neurodegenerative diseases. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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17 pages, 1620 KiB

Open AccessReview

Implication of Adult Hippocampal Neurogenesis in Alzheimer’s Disease and Potential Therapeutic Approaches

by Hesham Essa, Lee Peyton, Whidul Hasan, Brandon Emanuel León and Doo-Sup Choi

Cells 2022, 11(2), 286; https://doi.org/10.3390/cells11020286 - 15 Jan 2022

Cited by 13 | Viewed by 4765

Abstract

Alzheimer’s disease is the most common neurodegenerative disease, affecting more than 6 million US citizens and representing the most prevalent cause for dementia. Neurogenesis has been repeatedly reported to be impaired in AD mouse models, but the reason for this impairment remains unclear. [...] Read more.

Alzheimer’s disease is the most common neurodegenerative disease, affecting more than 6 million US citizens and representing the most prevalent cause for dementia. Neurogenesis has been repeatedly reported to be impaired in AD mouse models, but the reason for this impairment remains unclear. Several key factors play a crucial role in AD including Aβ accumulation, intracellular neurofibrillary tangles accumulation, and neuronal loss (specifically in the dentate gyrus of the hippocampus). Neurofibrillary tangles have been long associated with the neuronal loss in the dentate gyrus. Of note, Aβ accumulation plays an important role in the impairment of neurogenesis, but recent studies started to shed a light on the role of APP gene expression on the neurogenesis process. In this review, we will discuss the recent approaches to neurogenesis in Alzheimer disease and update the development of therapeutic methods. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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15 pages, 754 KiB

Open AccessFeature PaperReview

Multifaceted Microcephaly-Related Gene MCPH1

by Martina Kristofova, Alessandro Ori and Zhao-Qi Wang

Cells 2022, 11(2), 275; https://doi.org/10.3390/cells11020275 - 14 Jan 2022

Cited by 16 | Viewed by 3925

Abstract

MCPH1, or BRIT1, is often mutated in human primary microcephaly type 1, a neurodevelopmental disorder characterized by a smaller brain size at birth, due to its dysfunction in regulating the proliferation and self-renewal of neuroprogenitor cells. In the last 20 years or so, [...] Read more.

MCPH1, or BRIT1, is often mutated in human primary microcephaly type 1, a neurodevelopmental disorder characterized by a smaller brain size at birth, due to its dysfunction in regulating the proliferation and self-renewal of neuroprogenitor cells. In the last 20 years or so, genetic and cellular studies have identified MCPH1 as a multifaceted protein in various cellular functions, including DNA damage signaling and repair, the regulation of chromosome condensation, cell-cycle progression, centrosome activity and the metabolism. Yet, genetic and animal model studies have revealed an unpredicted essential function of MPCH1 in gonad development and tumorigenesis, although the underlying mechanism remains elusive. These studies have begun to shed light on the role of MPCH1 in controlling various pathobiological processes of the disorder. Here, we summarize the biological functions of MCPH1, and lessons learnt from cellular and mouse models of MCPH1. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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Novel Galectin-3 Roles in Neurogenesis, Inflammation and Neurological Diseases

by Luana C. Soares, Osama Al-Dalahmah, James Hillis, Christopher C. Young, Isaiah Asbed, Masanori Sakaguchi, Eric O’Neill and Francis G. Szele

Cells 2021, 10(11), 3047; https://doi.org/10.3390/cells10113047 - 5 Nov 2021

Cited by 40 | Viewed by 10809

Abstract

Galectin-3 (Gal-3) is an evolutionarily conserved and multifunctional protein that drives inflammation in disease. Gal-3’s role in the central nervous system has been less studied than in the immune system. However, recent studies show it exacerbates Alzheimer’s disease and is upregulated in a [...] Read more.

Galectin-3 (Gal-3) is an evolutionarily conserved and multifunctional protein that drives inflammation in disease. Gal-3’s role in the central nervous system has been less studied than in the immune system. However, recent studies show it exacerbates Alzheimer’s disease and is upregulated in a large variety of brain injuries, while loss of Gal-3 function can diminish symptoms of neurodegenerative diseases such as Alzheimer’s. Several novel molecular pathways for Gal-3 were recently uncovered. It is a natural ligand for TREM2 (triggering receptor expressed on myeloid cells), TLR4 (Toll-like receptor 4), and IR (insulin receptor). Gal-3 regulates a number of pathways including stimulation of bone morphogenetic protein (BMP) signaling and modulating Wnt signalling in a context-dependent manner. Gal-3 typically acts in pathology but is now known to affect subventricular zone (SVZ) neurogenesis and gliogenesis in the healthy brain. Despite its myriad interactors, Gal-3 has surprisingly specific and important functions in regulating SVZ neurogenesis in disease. Gal-1, a similar lectin often co-expressed with Gal-3, also has profound effects on brain pathology and adult neurogenesis. Remarkably, Gal-3’s carbohydrate recognition domain bears structural similarity to the SARS-CoV-2 virus spike protein necessary for cell entry. Gal-3 can be targeted pharmacologically and is a valid target for several diseases involving brain inflammation. The wealth of molecular pathways now known further suggest its modulation could be therapeutically useful. Full article

(This article belongs to the Special Issue Frontiers in Neurogenesis)

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