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19 pages, 2145 KiB

Open AccessArticle

Transcriptional Effects of Psychoactive Drugs on Genes Involved in Neurogenesis

by Chiara C. Bortolasci, Briana Spolding, Srisaiyini Kidnapillai, Timothy Connor, Trang T.T. Truong, Zoe S.J. Liu, Bruna Panizzutti, Mark F. Richardson, Laura Gray, Michael Berk, Olivia M. Dean and Ken Walder

Int. J. Mol. Sci. 2020, 21(21), 8333; https://doi.org/10.3390/ijms21218333 - 6 Nov 2020

Cited by 9 | Viewed by 3332

Abstract

Although neurogenesis is affected in several psychiatric diseases, the effects and mechanisms of action of psychoactive drugs on neurogenesis remain unknown and/or controversial. This study aims to evaluate the effects of psychoactive drugs on the expression of genes involved in neurogenesis. Neuronal-like cells [...] Read more.

Although neurogenesis is affected in several psychiatric diseases, the effects and mechanisms of action of psychoactive drugs on neurogenesis remain unknown and/or controversial. This study aims to evaluate the effects of psychoactive drugs on the expression of genes involved in neurogenesis. Neuronal-like cells (NT2-N) were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), or valproate (0.5 mM) for 24 h. Genome wide mRNA expression was quantified and analysed using gene set enrichment analysis, with the neurogenesis gene set retrieved from the Gene Ontology database and the Mammalian Adult Neurogenesis Gene Ontology (MANGO) database. Transcription factors that are more likely to regulate these genes were investigated to better understand the biological processes driving neurogenesis. Targeted metabolomics were performed using gas chromatography-mass spectrometry. Six of the eight drugs decreased the expression of genes involved in neurogenesis in both databases. This suggests that acute treatment with these psychoactive drugs negatively regulates the expression of genes involved in neurogenesis in vitro. SOX2 and three of its target genes (CCND1, BMP4, and DKK1) were also decreased after treatment with quetiapine. This can, at least in part, explain the mechanisms by which these drugs decrease neurogenesis at a transcriptional level in vitro. These results were supported by the finding of increased metabolite markers of mature neurons following treatment with most of the drugs tested, suggesting increased proportions of mature relative to immature neurons consistent with reduced neurogenesis. Full article

(This article belongs to the Special Issue Mechanism of Adult Neurogenesis)

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21 pages, 6818 KiB

Open AccessArticle

Omega-3 Fatty Acid-Type Docosahexaenoic Acid Protects against Aβ-Mediated Mitochondrial Deficits and Pathomechanisms in Alzheimer’s Disease-Related Animal Model

by Yong Ho Park, Soo Jung Shin, Hyeon soo Kim, Sang Bum Hong, Sujin Kim, Yunkwon Nam, Jwa-Jin Kim, Kyu Lim, Jong-Seok Kim, Jin-il Kim, Seong Gak Jeon and Minho Moon

Int. J. Mol. Sci. 2020, 21(11), 3879; https://doi.org/10.3390/ijms21113879 - 29 May 2020

Cited by 35 | Viewed by 4861

Abstract

It has been reported that damage to the mitochondria affects the progression of Alzheimer’s disease (AD), and that mitochondrial dysfunction is improved by omega-3. However, no animal or cell model studies have confirmed whether omega-3 inhibits AD pathology related to mitochondria deficits. In [...] Read more.

It has been reported that damage to the mitochondria affects the progression of Alzheimer’s disease (AD), and that mitochondrial dysfunction is improved by omega-3. However, no animal or cell model studies have confirmed whether omega-3 inhibits AD pathology related to mitochondria deficits. In this study, we aimed to (1) identify mitigating effects of endogenous omega-3 on mitochondrial deficits and AD pathology induced by amyloid beta (Aβ) in fat-1 mice, a transgenic omega-3 polyunsaturated fatty acids (PUFAs)-producing animal; (2) identify if docosahexaenoic acid (DHA) improves mitochondrial deficits induced by Aβ in HT22 cells; and (3) verify improvement effects of DHA administration on mitochondrial deficits and AD pathology in B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (5XFAD), a transgenic Aβ-overexpressing model. We found that omega-3 PUFAs significantly improved Aβ-induced mitochondrial pathology in fat-1 mice. In addition, our in vitro and in vivo findings demonstrate that DHA attenuated AD-associated pathologies, such as mitochondrial impairment, Aβ accumulation, neuroinflammation, neuronal loss, and impairment of adult hippocampal neurogenesis. Full article

(This article belongs to the Special Issue Mechanism of Adult Neurogenesis)

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18 pages, 4475 KiB

Open AccessArticle

Rubrofusarin Attenuates Chronic Restraint Stress-Induced Depressive Symptoms

by Jee Hyun Yi, Jieun Jeon, Huiyoung Kwon, Eunbi Cho, Jeanho Yun, Young Choon Lee, Jong Hoon Ryu, Se Jin Park, Jong Hyun Cho and Dong Hyun Kim

Int. J. Mol. Sci. 2020, 21(10), 3454; https://doi.org/10.3390/ijms21103454 - 13 May 2020

Cited by 16 | Viewed by 3993

Abstract

The aim of this study was to examine whether rubrofusarin, an active ingredient of the Cassia species, has an antidepressive effect in chronic restraint stress (CRS) mouse model. Although acute treatment using rubrofusarin failed, chronic treatment using rubrofusarin ameliorated CRS-induced depressive symptoms. Rubrofusarin [...] Read more.

The aim of this study was to examine whether rubrofusarin, an active ingredient of the Cassia species, has an antidepressive effect in chronic restraint stress (CRS) mouse model. Although acute treatment using rubrofusarin failed, chronic treatment using rubrofusarin ameliorated CRS-induced depressive symptoms. Rubrofusarin treatment significantly reduced the number of Fluoro-Jade B-positive cells and caspase-3 activation within the hippocampus of CRS-treated mice. Moreover, rubrofusarin treatment significantly increased the number of newborn neurons in the hippocampus of CRS-treated mice. CRS induced activation of glycogen synthase kinase-3β and regulated development and DNA damage responses, and reductions in the extracellular-signal-regulated kinase pathway activity were also reversed by rubrofusarin treatment. Microglial activation and inflammasome markers, including nod-like receptor family pyrin domain containing 3 and adaptor protein apoptosis-associated speck-like protein containing CARD, which were induced by CRS, were ameliorated by rubrofusarin. Synaptic plasticity dysfunction within the hippocampus was also rescued by rubrofusarin treatment. Within in vitro experiments, rubrofusarin blocked corticosterone-induced long-term potentiation impairments. These were blocked by LY294002, which is an Akt inhibitor. Finally, we found that the antidepressant effects of rubrofusarin were blocked by an intracerebroventricular injection of LY294002. These results suggest that rubrofusarin ameliorated CRS-induced depressive symptoms through PI3K/Akt signaling. Full article

(This article belongs to the Special Issue Mechanism of Adult Neurogenesis)

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18 pages, 4985 KiB

Open AccessArticle

Bacopa monnieri (L.) Wettst. Extract Improves Memory Performance via Promotion of Neurogenesis in the Hippocampal Dentate Gyrus of Adolescent Mice

by Hang Thi Nguyet Pham, Hong Nguyen Tran, Phuong Thi Nguyen, Xoan Thi Le, Khoi Minh Nguyen, Sinh Viet Phan, Masanori Yoneyama, Kiyokazu Ogita, Taro Yamaguchi, William R. Folk, Masamitsu Yamaguchi and Kinzo Matsumoto

Int. J. Mol. Sci. 2020, 21(9), 3365; https://doi.org/10.3390/ijms21093365 - 9 May 2020

Cited by 19 | Viewed by 6079

Abstract

Bacopa monnieri L. Wettst. (BM) is a botanical component of Ayurvedic medicines and of dietary supplements used worldwide for cognitive health and function. We previously reported that administration of BM alcoholic extract (BME) prevents trimethyltin (TMT)-induced cognitive deficits and hippocampal cell damage and [...] Read more.

Bacopa monnieri L. Wettst. (BM) is a botanical component of Ayurvedic medicines and of dietary supplements used worldwide for cognitive health and function. We previously reported that administration of BM alcoholic extract (BME) prevents trimethyltin (TMT)-induced cognitive deficits and hippocampal cell damage and promotes TMT-induced hippocampal neurogenesis. In this study, we demonstrate that administration of BME improves spatial working memory in adolescent (5-week- old) healthy mice but not adult (8-week-old) mice. Moreover, improved spatial working memory was retained even at 4 weeks after terminating 1-week treatment of adolescent mice. One-week BME treatment of adolescent mice significantly enhanced hippocampal BrdU incorporation and expression of genes involved in neurogenesis determined by RNAseq analysis. Cell death, as detected by histochemistry, appeared not to be significant. A significant increase in neurogenesis was observed in the dentate gyrus region 4 weeks after terminating 1-week treatment of adolescent mice with BME. Bacopaside I, an active component of BME, promoted the proliferation of neural progenitor cells in vitro in a concentration-dependent manner via the facilitation of the Akt and ERK1/2 signaling. These results suggest that BME enhances spatial working memory in healthy adolescent mice by promoting hippocampal neurogenesis and that the effects of BME are due, in significant amounts, to bacopaside I. Full article

(This article belongs to the Special Issue Mechanism of Adult Neurogenesis)

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Review

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28 pages, 1391 KiB

Open AccessReview

Extracellular Vesicles, Influential Players of Intercellular Communication within Adult Neurogenic Niches

by Morris Losurdo and Mariagrazia Grilli

Int. J. Mol. Sci. 2020, 21(22), 8819; https://doi.org/10.3390/ijms21228819 - 21 Nov 2020

Cited by 12 | Viewed by 4089

Abstract

Adult neurogenesis, involving the generation of functional neurons from adult neural stem cells (NSCs), occurs constitutively in discrete brain regions such as hippocampus, sub-ventricular zone (SVZ) and hypothalamus. The intrinsic structural plasticity of the neurogenic process allows the adult brain to face the [...] Read more.

Adult neurogenesis, involving the generation of functional neurons from adult neural stem cells (NSCs), occurs constitutively in discrete brain regions such as hippocampus, sub-ventricular zone (SVZ) and hypothalamus. The intrinsic structural plasticity of the neurogenic process allows the adult brain to face the continuously changing external and internal environment and requires coordinated interplay between all cell types within the specialized microenvironment of the neurogenic niche. NSC-, neuronal- and glia-derived factors, originating locally, regulate the balance between quiescence and self-renewal of NSC, their differentiation programs and the survival and integration of newborn cells. Extracellular Vesicles (EVs) are emerging as important mediators of cell-to-cell communication, representing an efficient way to transfer the biologically active cargos (nucleic acids, proteins, lipids) by which they modulate the function of the recipient cells. Current knowledge of the physiological role of EVs within adult neurogenic niches is rather limited. In this review, we will summarize and discuss EV-based cross-talk within adult neurogenic niches and postulate how EVs might play a critical role in the regulation of the neurogenic process. Full article

(This article belongs to the Special Issue Mechanism of Adult Neurogenesis)

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14 pages, 1435 KiB

Open AccessReview

Adult Neurogenesis in the Drosophila Brain: The Evidence and the Void

by Guiyi Li and Alicia Hidalgo

Int. J. Mol. Sci. 2020, 21(18), 6653; https://doi.org/10.3390/ijms21186653 - 11 Sep 2020

Cited by 17 | Viewed by 9435

Abstract

Establishing the existence and extent of neurogenesis in the adult brain throughout the animals including humans, would transform our understanding of how the brain works, and how to tackle brain damage and disease. Obtaining convincing, indisputable experimental evidence has generally been challenging. Here, [...] Read more.

Establishing the existence and extent of neurogenesis in the adult brain throughout the animals including humans, would transform our understanding of how the brain works, and how to tackle brain damage and disease. Obtaining convincing, indisputable experimental evidence has generally been challenging. Here, we revise the state of this question in the fruit-fly Drosophila. The developmental neuroblasts that make the central nervous system and brain are eliminated, either through apoptosis or cell cycle exit, before the adult fly ecloses. Despite this, there is growing evidence that cell proliferation can take place in the adult brain. This occurs preferentially at, but not restricted to, a critical period. Adult proliferating cells can give rise to both glial cells and neurons. Neuronal activity, injury and genetic manipulation in the adult can increase the incidence of both gliogenesis and neurogenesis, and cell number. Most likely, adult glio- and neuro-genesis promote structural brain plasticity and homeostasis. However, a definitive visualisation of mitosis in the adult brain is still lacking, and the elusive adult progenitor cells are yet to be identified. Resolving these voids is important for the fundamental understanding of any brain. Given its powerful genetics, Drosophila can expedite discovery into mammalian adult neurogenesis in the healthy and diseased brain. Full article

(This article belongs to the Special Issue Mechanism of Adult Neurogenesis)

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15 pages, 8497 KiB

Open AccessReview

Role of Excitatory Amino Acid Carrier 1 (EAAC1) in Neuronal Death and Neurogenesis After Ischemic Stroke

by Minwoo Lee, Dong Gyun Ko, Dae Ki Hong, Man-Sup Lim, Bo Young Choi and Sang Won Suh

Int. J. Mol. Sci. 2020, 21(16), 5676; https://doi.org/10.3390/ijms21165676 - 7 Aug 2020

Cited by 6 | Viewed by 3660

Abstract

Although there have been substantial advances in knowledge regarding the mechanisms of neuron death after stroke, effective therapeutic measures for stroke are still insufficient. Excitatory amino acid carrier 1 (EAAC1) is a type of neuronal glutamate transporter and considered to have [...] Read more.

Although there have been substantial advances in knowledge regarding the mechanisms of neuron death after stroke, effective therapeutic measures for stroke are still insufficient. Excitatory amino acid carrier 1 (EAAC1) is a type of neuronal glutamate transporter and considered to have an additional action involving the neuronal uptake of cysteine, which acts as a crucial substrate for glutathione synthesis. Previously, our lab demonstrated that genetic deletion of EAAC1 leads to decreased neuronal glutathione synthesis, increased oxidative stress, and subsequent cognitive impairment. Therefore, we hypothesized that reduced neuronal transport of cysteine due to deletion of the EAAC1 gene might exacerbate neuronal injury and impair adult neurogenesis in the hippocampus after transient cerebral ischemia. EAAC1 gene deletion profoundly increased ischemia-induced neuronal death by decreasing the antioxidant capacity. In addition, genetic deletion of EAAC1 also decreased the overall neurogenesis processes, such as cell proliferation, differentiation, and survival, after cerebral ischemia. These studies strongly support our hypothesis that EAAC1 is crucial for the survival of newly generated neurons, as well as mature neurons, in both physiological and pathological conditions. Here, we present a comprehensive review of the role of EAAC1 in neuronal death and neurogenesis induced by ischemic stroke, focusing on its potential cellular and molecular mechanisms. Full article

(This article belongs to the Special Issue Mechanism of Adult Neurogenesis)

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30 pages, 1710 KiB

Open AccessReview

Protective Effects of Melatonin on Neurogenesis Impairment in Neurological Disorders and Its Relevant Molecular Mechanisms

by Joseph Wai-Hin Leung, Kwok-Kuen Cheung, Shirley Pui-Ching Ngai, Hector Wing-Hong Tsang and Benson Wui-Man Lau

Int. J. Mol. Sci. 2020, 21(16), 5645; https://doi.org/10.3390/ijms21165645 - 6 Aug 2020

Cited by 25 | Viewed by 4779

Abstract

Neurogenesis is the process by which functional new neurons are generated from the neural stem cells (NSCs) or neural progenitor cells (NPCs). Increasing lines of evidence show that neurogenesis impairment is involved in different neurological illnesses, including mood disorders, neurogenerative diseases, and central [...] Read more.

Neurogenesis is the process by which functional new neurons are generated from the neural stem cells (NSCs) or neural progenitor cells (NPCs). Increasing lines of evidence show that neurogenesis impairment is involved in different neurological illnesses, including mood disorders, neurogenerative diseases, and central nervous system (CNS) injuries. Since reversing neurogenesis impairment was found to improve neurological outcomes in the pathological conditions, it is speculated that modulating neurogenesis is a potential therapeutic strategy for neurological diseases. Among different modulators of neurogenesis, melatonin is a particularly interesting one. In traditional understanding, melatonin controls the circadian rhythm and sleep–wake cycle, although it is not directly involved in the proliferation and survival of neurons. In the last decade, it was reported that melatonin plays an important role in the regulation of neurogenesis, and thus it may be a potential treatment for neurogenesis-related disorders. The present review aims to summarize and discuss the recent findings regarding the protective effects of melatonin on the neurogenesis impairment in different neurological conditions. We also address the molecular mechanisms involved in the actions of melatonin in neurogenesis modulation. Full article

(This article belongs to the Special Issue Mechanism of Adult Neurogenesis)

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