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Advances in Research on Neurogenesis 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 17229

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Dr. Eva Terzibasi Tozzini

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Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, Naples, Italy
Interests: adult neurogenesis; aging; neurodegeneration; teleost animal models marine vertebrates; neurotrophins; immunohistochemistri; in situ hybridization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Adult neurogenesis (ANG) is the process by which new functional neurons are generated from stem cells and integrated into the pre-existing neuronal networks of an adult brain. This process has been observed in all major vertebrate taxa to variable extents. In mammals, ANG is mainly limited to two main regions (i.e., the hippocampal dentate gyrus and the olfactory bulb). On the other hand, neurogenic niches are found in many areas of the brain in teleost fish, distributed along the entire rostro–caudal axis. The rate of ANG is not fixed throughout an individual’s life, but it is strongly age-dependent and can be influenced by different stimuli, such as sensory stimulation and physical activity. Moreover, ANG is involved in a wide range of neural processes, such as age-associated neurodegenerative diseases, regeneration, psychiatric disorders, and cognitive as well as affective processes, such as learning, memory, and anxiety.

The aim of this Special Issue is to invite all scientists using canonical and noncanonical models in the context of ANG studies to contribute to this Special Issue, in order to provide the scientific community with the most updated and in-depth picture of the knowledge in this field at the cellular, molecular, and functional levels.

We welcome reviews, commentaries, and original articles that share novel data and open new perspectives on the topic at hand. Papers mainly focusing on the following subtopics are welcome:

ANG, neurodegeneration, and regeneration;
ANG and ageing;
ANG and psychiatric disorders;
ANG and cognition;
The evolution of adult neurogenesis in vertebrates.

Dr. Eva Terzibasi Tozzini
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

adult neurogenesis
neurodegeneration
aging
psychiatric disorders
cognition
regeneration
adult neurogenesis evolution

Related Special Issues

Advances in Research on Neurogenesis in International Journal of Molecular Sciences (6 articles)
Advances in Research on Neurogenesis 3.0 in International Journal of Molecular Sciences (3 articles)

Published Papers (9 papers)

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Research

Jump to: Review

14 pages, 3326 KiB

Open AccessArticle

Low Levels of Amyloid Precursor Protein (APP) Promote Neurogenesis and Decrease Gliogenesis in Human Neural Stem Cells

by Raquel Coronel, Victoria López-Alonso, Marta I. Gallego and Isabel Liste

Int. J. Mol. Sci. 2023, 24(19), 14635; https://doi.org/10.3390/ijms241914635 - 27 Sep 2023

Viewed by 992

Abstract

Amyloid precursor protein (APP) has been widely studied due to its association with Alzheimer’s disease (AD). However, the physiological functions of APP are still largely unexplored. APP is a transmembrane glycoprotein whose expression in humans is abundant in the central nervous system. Specifically, several studies have revealed the high expression of APP during brain development. Previous studies in our laboratory revealed that a transient increase in APP expression induces early cell cycle exit of human neural stem cells (hNSCs) and directs their differentiation towards glial cells (gliogenesis) while decreasing their differentiation towards neurons (neurogenesis). In the present study, we have evaluated the intrinsic cellular effects of APP down-expression (using siRNA) on cell death, cell proliferation, and cell fate specification of hNSCs. Our data indicate that APP silencing causes cellular effects opposite to those obtained in previous APP overexpression assays, inducing cell proliferation in hNS1 cells (a model line of hNSCs) and favoring neurogenesis instead of gliogenesis in these cells. In addition, we have analyzed the gene and protein expression levels of β-Catenin as a possible molecule involved in these cellular effects. These data could help to understand the biological role of APP, which is necessary to deepen the knowledge of AD. Full article

(This article belongs to the Special Issue Advances in Research on Neurogenesis 2.0)

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22 pages, 2451 KiB

Open AccessArticle

Progenitor Cells Play a Role in Reinstatement of Ethanol Seeking in Adult Male and Female Ethanol Dependent Rats

by Hannah A. Nonoguchi, Michael Jin, Rajitha Narreddy, Timothy Wee Shang Kouo, Mahasweta Nayak, Wulfran Trenet and Chitra D. Mandyam

Int. J. Mol. Sci. 2023, 24(15), 12233; https://doi.org/10.3390/ijms241512233 - 31 Jul 2023

Viewed by 1022

Abstract

Female and male glial fibrillary acidic protein-thymidine kinase (GFAP-TK) transgenic rats were made ethanol dependent via a six-week chronic intermittent ethanol vapor (CIE) and ethanol drinking (ED) procedure. During the last week of CIE, a subset of male and female TK rats was fed valcyte to ablate dividing progenitor cells and continued the diet until the end of this study. Following week six, all CIE rats experienced two weeks of forced abstinence from CIE-ED, after which they experienced relapse to drinking, extinction, and reinstatement of ethanol seeking sessions. CIE increased ED in female and male rats, with females having higher ethanol consumption during CIE and relapse sessions compared with males. In both sexes, valcyte reduced the levels of Ki-67-labeled progenitor cells in the subgranular zone of the dentate gyrus and did not alter the levels in the medial prefrontal cortex (mPFC). Valcyte increased ED during relapse, increased lever responses during extinction and, interestingly, enhanced latency to extinguish ethanol-seeking behaviors in males. Valcyte reduced the reinstatement of ethanol-seeking behaviors triggered by ethanol cues in females and males. Reduced seeking by valcyte was associated with the normalization of cytokines and chemokines in plasma isolated from trunk blood, indicating a role for progenitor cells in peripheral inflammatory responses. Reduced seeking by valcyte was associated with increases in tight junction protein claudin-5 and oligodendrogenesis in the dentate gyrus and reduction in microglial activity in the dentate gyrus and mPFC in females and males, demonstrating a role for progenitor cells in the dentate gyrus in dependence-induced endothelial and microglial dysfunction. These data suggest that progenitor cells born during withdrawal and abstinence from CIE in the dentate gyrus are aberrant and could play a role in strengthening ethanol memories triggered by ethanol cues via central and peripheral immune responses. Full article

(This article belongs to the Special Issue Advances in Research on Neurogenesis 2.0)

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18 pages, 8049 KiB

Open AccessArticle

CCN3/NOV Regulates Proliferation and Neuronal Differentiation in Mouse Hippocampal Neural Stem Cells via the Activation of the Notch/PTEN/AKT Pathway

by Yan Luan, Hanyue Zhang, Kaige Ma, Yingfei Liu, Haixia Lu, Xinlin Chen, Yong Liu and Zhichao Zhang

Int. J. Mol. Sci. 2023, 24(12), 10324; https://doi.org/10.3390/ijms241210324 - 19 Jun 2023

Cited by 1 | Viewed by 1456

Abstract

Neural stem cells (NSCs) persist in the subgranular zone (SGZ) throughout the lifespan and hold immense potential for the repair and regeneration of the central nervous system, including hippocampal-related diseases. Several studies have demonstrated that cellular communication network protein 3 (CCN3) regulates multiple types of stem cells. However, the role of CCN3 in NSCs remains unknown. In this study, we identified CCN3 expression in mouse hippocampal NSCs and observed that supplementing CCN3 improved cell viability in a concentration-dependent manner. Additionally, in vivo results showed that the injection of CCN3 in the dentate gyrus (DG) increased Ki-67- and SOX2-positive cells while decreasing neuron-specific class III beta-tubulin (Tuj1) and doublecortin (DCX)-positive cells. Consistently with the in vivo results, supplementing CCN3 in the medium increased the number of BrdU and Ki-67 cells and the proliferation index but decreased the number of Tuj1 and DCX cells. Conversely, both the in vivo and in vitro knockdown of the Ccn3 gene in NSCs had opposite effects. Further investigations revealed that CCN3 promoted cleaved Notch1 (NICD) expression, leading to the suppression of PTEN expression and eventual promotion of AKT activation. In contrast, Ccn3 knockdown inhibited the activation of the Notch/PTEN/AKT pathway. Finally, the effects of changes in CCN3 protein expression on NSC proliferation and differentiation were eliminated by FLI-06 (a Notch inhibitor) and VO-OH (a PTEN inhibitor). Our findings imply that while promoting proliferation, CCN3 inhibits the neuronal differentiation of mouse hippocampal NSCs and that the Notch/PTEN/AKT pathway may be a potential intracellular target of CCN3. Our findings may help develop strategies to enhance the intrinsic potential for brain regeneration after injuries, particularly stem cell treatment for hippocampal-related diseases. Full article

(This article belongs to the Special Issue Advances in Research on Neurogenesis 2.0)

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15 pages, 2295 KiB

Open AccessArticle

Repeated Anodal Transcranial Direct Current Stimulation (RA-tDCS) over the Left Frontal Lobe Increases Bilateral Hippocampal Cell Proliferation in Young Adult but Not Middle-Aged Female Mice

by Stéphanie Dumontoy, Bahrie Ramadan, Pierre-Yves Risold, Solène Pedron, Christophe Houdayer, Adeline Etiévant, Lidia Cabeza, Emmanuel Haffen, Yvan Peterschmitt and Vincent Van Waes

Int. J. Mol. Sci. 2023, 24(10), 8750; https://doi.org/10.3390/ijms24108750 - 14 May 2023

Cited by 1 | Viewed by 1528

Abstract

Repeated anodal transcranial direct current stimulation (RA-tDCS) is a neuromodulatory technique consisting of stimulating the cerebral cortex with a weak electric anodal current in a non-invasive manner. RA-tDCS over the dorsolateral prefrontal cortex has antidepressant-like properties and improves memory both in humans and laboratory animals. However, the mechanisms of action of RA-tDCS remain poorly understood. Since adult hippocampal neurogenesis is thought to be involved in the pathophysiology of depression and memory functioning, the purpose of this work was to evaluate the impact of RA-tDCS on hippocampal neurogenesis levels in mice. RA-tDCS was applied for 20 min per day for five consecutive days over the left frontal cortex of young adult (2-month-old, high basal level of neurogenesis) and middle-aged (10-month-old, low basal level of neurogenesis) female mice. Mice received three intraperitoneal injections of bromodeoxyuridine (BrdU) on the final day of RA-tDCS. The brains were collected either 1 day or 3 weeks after the BrdU injections to quantify cell proliferation and cell survival, respectively. RA-tDCS increased hippocampal cell proliferation in young adult female mice, preferentially (but not exclusively) in the dorsal part of the dentate gyrus. However, the number of cells that survived after 3 weeks was the same in both the Sham and the tDCS groups. This was due to a lower survival rate in the tDCS group, which suppressed the beneficial effects of tDCS on cell proliferation. No modulation of cell proliferation or survival was observed in middle-aged animals. Our RA-tDCS protocol may, therefore, influence the behavior of naïve female mice, as we previously described, but its effect on the hippocampus is only transient in young adult animals. Future studies using animal models for depression in male and female mice should provide further insights into RA-tDCS detailed age- and sex-dependent effects on hippocampal neurogenesis. Full article

(This article belongs to the Special Issue Advances in Research on Neurogenesis 2.0)

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10 pages, 9226 KiB

Open AccessCommunication

Endogenous Neural Stem Cell Activation after Low-Intensity Focused Ultrasound-Induced Blood–Brain Barrier Modulation

by Younghee Seo, Sangheon Han, Byeong-Wook Song, Jin Woo Chang, Young Cheol Na and Won Seok Chang

Int. J. Mol. Sci. 2023, 24(6), 5712; https://doi.org/10.3390/ijms24065712 - 16 Mar 2023

Cited by 3 | Viewed by 1910

Abstract

Endogenous neural stem cells (eNSCs) in the adult brain, which have the potential to self-renew and differentiate into functional, tissue-appropriate cell types, have raised new expectations for neurological disease therapy. Low-intensity focused ultrasound (LIFUS)-induced blood–brain barrier modulation has been reported to promote neurogenesis. Although these studies have reported improved behavioral performance and enhanced expression of brain biomarkers after LIFUS, indicating increased neurogenesis, the precise mechanism remains unclear. In this study, we evaluated eNSC activation as a mechanism for neurogenesis after LIFUS-induced blood–brain barrier modulation. We evaluated the specific eNSC markers, Sox-2 and nestin, to confirm the activation of eNSCs. We also performed 3′-deoxy-3′[¹⁸F] fluoro-L-thymidine positron emission tomography ([¹⁸F] FLT-PET) to evaluate the activation of eNSCs. The expression of Sox-2 and nestin was significantly upregulated 1 week after LIFUS. After 1 week, the upregulated expression decreased sequentially; after 4 weeks, the upregulated expression returned to that of the control group. [¹⁸F] FLT-PET images also showed higher stem cell activity after 1 week. The results of this study indicated that LIFUS could activate eNSCs and induce adult neurogenesis. These results show that LIFUS may be useful as an effective treatment for patients with neurological damage or neurological disorders in clinical settings. Full article

(This article belongs to the Special Issue Advances in Research on Neurogenesis 2.0)

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35 pages, 54233 KiB

Open AccessArticle

Localization and Characterization of Major Neurogenic Niches in the Brain of the Lesser-Spotted Dogfish Scyliorhinus canicula

by Sara Bagnoli, Elena Chiavacci, Alessandro Cellerino and Eva Terzibasi Tozzini

Int. J. Mol. Sci. 2023, 24(4), 3650; https://doi.org/10.3390/ijms24043650 - 11 Feb 2023

Cited by 1 | Viewed by 1880

Abstract

Adult neurogenesis is defined as the ability of specialized cells in the postnatal brain to produce new functional neurons and to integrate them into the already-established neuronal network. This phenomenon is common in all vertebrates and has been found to be extremely relevant for numerous processes, such as long-term memory, learning, and anxiety responses, and it has been also found to be involved in neurodegenerative and psychiatric disorders. Adult neurogenesis has been studied extensively in many vertebrate models, from fish to human, and observed also in the more basal cartilaginous fish, such as the lesser-spotted dogfish, Scyliorhinus canicula, but a detailed description of neurogenic niches in this animal is, to date, limited to the telencephalic areas. With this article, we aim to extend the characterization of the neurogenic niches of S. canicula in other main areas of the brain: we analyzed via double immunofluorescence sections of telencephalon, optic tectum, and cerebellum with markers of proliferation (PCNA) and mitosis (pH3) in conjunction with glial cell (S100β) and stem cell (Msi1) markers, to identify the actively proliferating cells inside the neurogenic niches. We also labeled adult postmitotic neurons (NeuN) to exclude double labeling with actively proliferating cells (PCNA). Lastly, we observed the presence of the autofluorescent aging marker, lipofuscin, contained inside lysosomes in neurogenic areas. Full article

(This article belongs to the Special Issue Advances in Research on Neurogenesis 2.0)

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28 pages, 3908 KiB

Open AccessArticle

Dimethyl Fumarate Alleviates Adult Neurogenesis Disruption in Hippocampus and Olfactory Bulb and Spatial Cognitive Deficits Induced by Intracerebroventricular Streptozotocin Injection in Young and Aged Rats

by Ewelina Kurowska-Rucińska, Jan Ruciński, Dorota Myślińska, Beata Grembecka, Danuta Wrona and Irena Majkutewicz

Int. J. Mol. Sci. 2022, 23(24), 15449; https://doi.org/10.3390/ijms232415449 - 7 Dec 2022

Cited by 3 | Viewed by 1633

Abstract

The disorder of adult neurogenesis is considered an important mechanism underlying the learning and memory impairment observed in Alzheimer’s disease (AD). The sporadic nonhereditary form of AD (sAD) affects over 95% of AD patients and is related to interactions between genetic and environmental factors. An intracerebroventricular injection of streptozotocin (STZ-ICV) is a representative and well-established method to induce sAD-like pathology. Dimethyl fumarate (DMF) has antioxidant and anti-inflammatory properties and is used for multiple sclerosis treatment. The present study determines whether a 26-day DMF therapy ameliorates the disruption of adult neurogenesis and BDNF-related neuroprotection in the hippocampus and olfactory bulb (OB) in an STZ-ICV rat model of sAD. Considering age as an important risk factor for developing AD, this study was performed using 3-month-old (the young group) and 22-month-old (the aged group) male Wistar rats. Spatial cognitive functions were evaluated with the Morris water maze task. Immunofluorescent labelling was used to assess the parameters of adult neurogenesis and BDNF-related neuroprotection in the hippocampus and OB. Our results showed that the STZ-ICV evoked spatial learning and memory impairment and disturbances in adult neurogenesis and BDNF expression in both examined brain structures. In the aged animals, the deficits were more severe. We found that the DMF treatment significantly alleviated STZ-ICV-induced behavioural and neuronal disorders in both age groups of the rats. Our findings suggest that DMF, due to its beneficial effect on the formation of new neurons and BDNF-related neuroprotection, may be considered as a promising new therapeutic agent in human sAD. Full article

(This article belongs to the Special Issue Advances in Research on Neurogenesis 2.0)

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Review

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28 pages, 1865 KiB

Open AccessReview

Migratory Response of Cells in Neurogenic Niches to Neuronal Death: The Onset of Harmonic Repair?

by Noelia Geribaldi-Doldán, Livia Carrascal, Patricia Pérez-García, José M. Oliva-Montero, Ricardo Pardillo-Díaz, Samuel Domínguez-García, Carlos Bernal-Utrera, Ricardo Gómez-Oliva, Sergio Martínez-Ortega, Cristina Verástegui, Pedro Nunez-Abades and Carmen Castro

Int. J. Mol. Sci. 2023, 24(7), 6587; https://doi.org/10.3390/ijms24076587 - 1 Apr 2023

Cited by 4 | Viewed by 1891

Abstract

Harmonic mechanisms orchestrate neurogenesis in the healthy brain within specific neurogenic niches, which generate neurons from neural stem cells as a homeostatic mechanism. These newly generated neurons integrate into existing neuronal circuits to participate in different brain tasks. Despite the mechanisms that protect the mammalian brain, this organ is susceptible to many different types of damage that result in the loss of neuronal tissue and therefore in alterations in the functionality of the affected regions. Nevertheless, the mammalian brain has developed mechanisms to respond to these injuries, potentiating its capacity to generate new neurons from neural stem cells and altering the homeostatic processes that occur in neurogenic niches. These alterations may lead to the generation of new neurons within the damaged brain regions. Notwithstanding, the activation of these repair mechanisms, regeneration of neuronal tissue within brain injuries does not naturally occur. In this review, we discuss how the different neurogenic niches respond to different types of brain injuries, focusing on the capacity of the progenitors generated in these niches to migrate to the injured regions and activate repair mechanisms. We conclude that the search for pharmacological drugs that stimulate the migration of newly generated neurons to brain injuries may result in the development of therapies to repair the damaged brain tissue. Full article

(This article belongs to the Special Issue Advances in Research on Neurogenesis 2.0)

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28 pages, 2699 KiB

Open AccessReview

Minocycline as Treatment for Psychiatric and Neurological Conditions: A Systematic Review and Meta-Analysis

by Bruna Panizzutti, David Skvarc, Sylvia Lin, Sarah Croce, Alcy Meehan, Chiara Cristina Bortolasci, Wolfgang Marx, Adam J. Walker, Kyoko Hasebe, Bianca E. Kavanagh, Margaret J. Morris, Mohammadreza Mohebbi, Alyna Turner, Laura Gray, Lesley Berk, Ken Walder, Michael Berk and Olivia M. Dean

Int. J. Mol. Sci. 2023, 24(6), 5250; https://doi.org/10.3390/ijms24065250 - 9 Mar 2023

Cited by 12 | Viewed by 3529

Abstract

Minocycline has anti-inflammatory, antioxidant, and anti-apoptotic properties that explain the renewed interest in its use as an adjunctive treatment for psychiatric and neurological conditions. Following the completion of several new clinical trials using minocycline, we proposed an up-to-date systematic review and meta-analysis of the data available. The PICO (patient/population, intervention, comparison and outcomes) framework was used to search 5 databases aiming to identify randomized controlled trials that used minocycline as an adjunctive treatment for psychiatric and neurological conditions. Search results, data extraction, and risk of bias were performed by two independent authors for each publication. Quantitative meta-analysis was performed using RevMan software. Literature search and review resulted in 32 studies being included in this review: 10 in schizophrenia, 3 studies in depression, and 7 in stroke, with the benefit of minocycline being used in some of the core symptoms evaluated; 2 in bipolar disorder and 2 in substance use, without demonstrating a benefit for using minocycline; 1 in obsessive-compulsive disorder, 2 in brain and spinal injuries, 2 in amyotrophic lateral sclerosis, 1 in Alzheimer’s disease, 1 in multiple systems atrophy, and 1 in pain, with mixes results. For most of the conditions included in this review the data is still limited and difficult to interpret, warranting more well-designed and powered studies. On the other hand, the studies available for schizophrenia seem to suggest an overall benefit favoring the use of minocycline as an adjunctive treatment. Full article

(This article belongs to the Special Issue Advances in Research on Neurogenesis 2.0)

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