scholarly journals Ginsenoside Compound K Induces Adult Hippocampal Proliferation and Survival of Newly Generated Cells in Young and Elderly Mice

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 484 ◽  
Author(s):  
Jung-Mi Oh ◽  
Jae Hoon Jeong ◽  
Sun Young Park ◽  
Sungkun Chun
Keyword(s):  
Dentate Gyrus ◽  
Progenitor Cells ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Nuclear Antigen ◽  
Specific Marker ◽  
Compound K ◽  
Microbial Conversion ◽  
Mature Neuron ◽  
Number Of Cells

Cognitive impairment can be associated with reduced adult hippocampal neurogenesis, and it may contribute to age-associated neurodegenerative diseases such as Alzheimer’s (AD). Compound K (CK) is produced from the protopanaxadiol (PPD)-type ginsenosides Rb1, Rb2, and Rc by intestinal microbial conversion. Although CK has been reported as an inducing effector for neuroprotection and improved cognition in hippocampus, its effect on adult neurogenesis has not been explored yet. Here, we investigated the effect of CK on hippocampal neurogenesis in both young (2 months) and elderly (24 months) mice. CK treatment increased the number of cells co-labeled with 5-ethynyl-2′-deoxyuridine (EdU) and proliferating cell nuclear antigen (PCNA); also, Ki67, specific markers for progenitor cells, was more expressed, thus enhancing the generation of new cells and progenitor cells in the dentate gyrus of both young and elderly mice. Moreover, CK treatment increased the number of cells co-labeled with EdU and NeuN, a specific marker for mature neuron in the dentate gyrus, suggesting that newly generated cells survived and differentiated into mature neurons at both ages. These findings demonstrate that CK increases adult hippocampal neurogenesis, which may be beneficial against neurodegenerative disorders such as AD.

scholarly journals Capicua regulates the development of adult-born neurons in the hippocampus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Brenna Hourigan ◽  
Spencer D. Balay ◽  
Graydon Yee ◽  
Saloni Sharma ◽  
Qiumin Tan
Keyword(s):  
Dentate Gyrus ◽  
Progenitor Cells ◽  
Neural Progenitor Cells ◽  
Neural Progenitor Cell ◽  
Neural Progenitor ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Proliferative Potential ◽  
Cell Pool ◽  
Adult Born Neurons

AbstractNew neurons continuously arise from neural progenitor cells in the dentate gyrus of the adult hippocampus to support ongoing learning and memory formation. To generate functional adult-born neurons, neural progenitor cells proliferate to expand the precursor cell pool and differentiate into neurons. Newly generated cells then undergo postmitotic maturation to migrate to their final destination and develop elaborate dendritic branching, which allows them to receive input signals. Little is known about factors that regulate neuronal differentiation, migration, and dendrite maturation during adult hippocampal neurogenesis. Here, we show that the transcriptional repressor protein capicua (CIC) exhibits dynamic expression in the adult dentate gyrus. Conditional deletion of Cic from the mouse dentate gyrus compromises the adult neural progenitor cell pool without altering their proliferative potential. We further demonstrate that the loss of Cic impedes neuronal lineage development and disrupts dendritic arborization and migration of adult-born neurons. Our study uncovers a previously unrecognized role of CIC in neurogenesis of the adult dentate gyrus.

scholarly journals H3K9 Methyltransferases Suv39h1 and Suv39h2 Control the Differentiation of Neural Progenitor Cells in the Adult Hippocampus

2022 ◽  
Vol 9 ◽  
Author(s):  
Miguel V. Guerra ◽  
Matías I. Cáceres ◽  
Andrea Herrera-Soto ◽  
Sebastián B. Arredondo ◽  
Manuel Varas-Godoy ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Progenitor Cells ◽  
Neuronal Differentiation ◽  
Neural Progenitor Cells ◽  
Adult Mouse ◽  
Histone H3 ◽  
Neural Progenitor ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Adult Hippocampus

In the dentate gyrus of the adult hippocampus new neurons are generated from neural precursor cells through different stages including proliferation and differentiation of neural progenitor cells and maturation of newborn neurons. These stages are controlled by the expression of specific transcription factors and epigenetic mechanisms, which together orchestrate the progression of the neurogenic process. However, little is known about the involvement of histone posttranslational modifications, a crucial epigenetic mechanism in embryonic neurogenesis that regulates fate commitment and neuronal differentiation. During embryonic development, the repressive modification trimethylation of histone H3 on lysine 9 (H3K9me3) contributes to the cellular identity of different cell-types. However, the role of this modification and its H3K9 methyltransferases has not been elucidated in adult hippocampal neurogenesis. We determined that during the stages of neurogenesis in the adult mouse dentate gyrus and in cultured adult hippocampal progenitors (AHPs), there was a dynamic change in the expression and distribution of H3K9me3, being enriched at early stages of the neurogenic process. A similar pattern was observed in the hippocampus for the dimethylation of histone H3 on lysine 9 (H3K9me2), another repressive modification. Among H3K9 methyltransferases, the enzymes Suv39h1 and Suv39h2 exhibited high levels of expression at early stages of neurogenesis and their expression decreased upon differentiation. Pharmacological inhibition of these enzymes by chaetocin in AHPs reduced H3K9me3 and concomitantly decreased neuronal differentiation while increasing proliferation. Moreover, Suv39h1 and Suv39h2 knockdown in newborn cells of the adult mouse dentate gyrus by retrovirus-mediated RNA interference impaired neuronal differentiation of progenitor cells. Our results indicate that H3K9me3 and H3K9 methyltransferases Suv39h1 and Suv39h2 are critically involved in the regulation of adult hippocampal neurogenesis by controlling the differentiation of neural progenitor cells.

scholarly journals Canonical Wnt-signaling modulates the tempo of dendritic growth of adult-born hippocampal neurons

2020 ◽  
Author(s):  
Jana Heppt ◽  
Marie-Theres Wittmann ◽  
Jingzhong Zhang ◽  
Daniela Vogt-Weisenhorn ◽  
Nilima Prakash ◽  
...  
Keyword(s):  
Young Adult ◽  
Wnt Signaling ◽  
Progenitor Cells ◽  
Dendritic Growth ◽  
Functional Integration ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Canonical Wnt Signaling ◽  
Adult Born Neurons ◽  
Canonical Wnt

AbstractIn adult hippocampal neurogenesis neural stem/progenitor cells generate new dentate granule neurons that contribute to hippocampal plasticity. The establishment of a morphologically defined dendritic arbor is central to the functional integration of adult-born neurons. Here, we investigated the role of canonical Wnt/β-catenin-signaling in dendritogenesis of adult-born neurons. We show that canonical Wnt-signaling follows a biphasic pattern, with high activity in stem/progenitor cells, attenuation in early immature neurons, and re-activation during maturation, and demonstrate that the biphasic activity pattern is required for proper dendrite development. Increasing β-catenin-signaling in maturing neurons of young adult mice transiently accelerated dendritic growth, but eventually resulted in dendritic defects and excessive spine numbers. In middle-aged mice, in which protracted dendrite and spine development was paralleled by lower canonical Wnt-signaling activity, enhancement of β-catenin-signaling restored dendritic growth and spine formation to levels observed in young adult animals. Our data indicate that precise timing and strength of β-catenin-signaling is essential for the correct functional integration of adult-born neurons and suggest Wnt/β-catenin-signaling as a pathway to ameliorate deficits in adult neurogenesis during aging.

Mitochondrial dysfunction-induced KDM5A degradation impairs adult hippocampal neurogenesis in Alzheimer’s disease

2020 ◽  
Author(s):  
Dong Kyu Kim ◽  
Hyobin Jeong ◽  
Jingi Bae ◽  
Moon-Yong Cha ◽  
Moonkyung Kang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Mitochondrial Dysfunction ◽  
Progenitor Cells ◽  
Neuronal Differentiation ◽  
Neural Progenitor Cells ◽  
Neural Progenitor ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Amyloid Pathology ◽  
Neural Stem Progenitor Cells

Abstract Background Adult hippocampal neurogenesis (AHN) is a process of continuously generating functional mature neurons from neural stem cells in the dentate gyrus. In Alzheimer’s disease (AD) brains, amyloid pathology has deleterious effects on AHN, but molecular mechanisms for dysregulated AHN are unclear. Mitochondria of neural stem/progenitor cells play crucial roles in determining cell fate. Since mitochondrial dysfunction by amyloid pathology is the typical symptom of AD pathogenesis, we aim to study whether mitochondrial dysfunction of neural stem/progenitor cells by amyloid pathology causes the impairment of AHN, and elucidate the molecular mechanism of the phenomenon. Methods To investigate the effect of mitochondrial dysfunction of neural stem/progenitor cells on neuronal differentiation, we expressed mitochondria-targeted amyloid beta (mitoAβ) in neural stem/progenitor cells in vitro and in vivo. Proteomic analysis of the hippocampal tissue implicated mitochondrial dysfunction by mitoAβ as a cause of AHN deficits. We identified epigenetic regulators of neural progenitor cells that are regulated by mitoAβ expression or drug-induced mitochondrial toxicity and proposed a link between mitochondria and AHN. Results Amyloid pathology characteristically inhibited the neuronal differentiation stage, not the proliferation of neural stem/progenitor cells during AHN in early AD model mice. Mitochondrial dysfunction in neural stem/progenitor cells by expressing mitoAβ inhibited the neuronal differentiation and AHN with cognitive impairment. Mechanistic studies revealed that lysine demethylase 5A (KDM5A) was involved in the neuronal differentiation and could be degraded by mitochondrial dysfunction in neural progenitor cells, thereby inhibiting the differentiation and cognitive functions. Conclusions These results reveal the new role of KDM5A as a mediator of retrograde signaling, reflecting mitochondrial status, and that the decrease of KDM5A in neural progenitor cells by mitochondrial dysfunction impairs the neuronal differentiation and AHN, finally leading to memory deficits. These findings and its relationship to mitochondrial dysfunction suggest that mitochondrial failure in neural progenitor cells by amyloid pathology closely associates with reduced AHN in AD.

scholarly journals Metabolic tuning of inhibition regulates hippocampal neurogenesis in the adult brain

2020 ◽  
Vol 117 (41) ◽  
pp. 25818-25829
Author(s):  
Xinxing Wang ◽  
Hanxiao Liu ◽  
Johannes Morstein ◽  
Alexander J. E. Novak ◽  
Dirk Trauner ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Energy Homeostasis ◽  
Inhibitory Neuron ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Neuron Activity ◽  
Adult Mice ◽  
Sphingosine 1 Phosphate ◽  
Underlying Mechanisms

Hippocampus-engaged behaviors stimulate neurogenesis in the adult dentate gyrus by largely unknown means. To explore the underlying mechanisms, we used tetrode recording to analyze neuronal activity in the dentate gyrus of freely moving adult mice during hippocampus-engaged contextual exploration. We found that exploration induced an overall sustained increase in inhibitory neuron activity that was concomitant with decreased excitatory neuron activity. A mathematical model based on energy homeostasis in the dentate gyrus showed that enhanced inhibition and decreased excitation resulted in a similar increase in neurogenesis to that observed experimentally. To mechanistically investigate this sustained inhibitory regulation, we performed metabolomic and lipidomic profiling of the hippocampus during exploration. We found sustainably increased signaling of sphingosine-1-phosphate, a bioactive metabolite, during exploration. Furthermore, we found that sphingosine-1-phosphate signaling through its receptor 2 increased interneuron activity and thus mediated exploration-induced neurogenesis. Taken together, our findings point to a behavior-metabolism circuit pathway through which experience regulates adult hippocampal neurogenesis.

scholarly journals Expression of progenitor cell/immature neuron markers does not present definitive evidence for adult neurogenesis

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Hideo Hagihara ◽  
Tomoyuki Murano ◽  
Koji Ohira ◽  
Miki Miwa ◽  
Katsuki Nakamura ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Neural Progenitor Cells ◽  
Adult Life ◽  
Neural Progenitor ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Mature Adult ◽  
Neuronal Markers ◽  
Definitive Evidence ◽  
Immature Neurons

AbstractIt is agreed upon that adult hippocampal neurogenesis (AHN) occurs in the dentate gyrus (DG) in rodents. However, the existence of AHN in humans, particularly in elderly individuals, remains to be determined. Recently, several studies reported that neural progenitor cells, neuroblasts, and immature neurons were detected in the hippocampus of elderly humans, based on the expressions of putative markers for these cells, claiming that this provides evidence of the persistence of AHN in humans. Herein, we briefly overview the phenomenon that we call “dematuration,” in which mature neurons dedifferentiate to a pseudo-immature status and re-express the molecular markers of neural progenitor cells and immature neurons. Various conditions can easily induce dematuration, such as inflammation and hyper-excitation of neurons, and therefore, the markers for neural progenitor cells and immature neurons may not necessarily serve as markers for AHN. Thus, the aforementioned studies have not presented definitive evidence for the persistence of hippocampal neurogenesis throughout adult life in humans, and we would like to emphasize that those markers should be used cautiously when presented as evidence for AHN. Increasing AHN has been considered as a therapeutic target for Alzheimer’s disease (AD); however, given that immature neuronal markers can be re-expressed in mature adult neurons, independent of AHN, in various disease conditions including AD, strategies to increase the expression of these markers in the DG may be ineffective or may worsen the symptoms of such diseases.

scholarly journals Postnatal NG2 proteoglycan–expressing progenitor cells are intrinsically multipotent and generate functional neurons

2003 ◽  
Vol 161 (1) ◽  
pp. 169-186 ◽  
Author(s):  
Shibeshih Belachew ◽  
Ramesh Chittajallu ◽  
Adan A. Aguirre ◽  
Xiaoqing Yuan ◽  
Martha Kirby ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Intrinsic Property ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
High Rate ◽  
Fast Kinetics ◽  
Sizeable Fraction ◽  
Ng2 Proteoglycan

Neurogenesis is known to persist in the adult mammalian central nervous system (CNS). The identity of the cells that generate new neurons in the postnatal CNS has become a crucial but elusive issue. Using a transgenic mouse, we show that NG2 proteoglycan–positive progenitor cells that express the 2′,3′-cyclic nucleotide 3′-phosphodiesterase gene display a multipotent phenotype in vitro and generate electrically excitable neurons, as well as astrocytes and oligodendrocytes. The fast kinetics and the high rate of multipotent fate of these NG2+ progenitors in vitro reflect an intrinsic property, rather than reprogramming. We demonstrate in the hippocampus in vivo that a sizeable fraction of postnatal NG2+ progenitor cells are proliferative precursors whose progeny appears to differentiate into GABAergic neurons capable of propagating action potentials and displaying functional synaptic inputs. These data show that at least a subpopulation of postnatal NG2-expressing cells are CNS multipotent precursors that may underlie adult hippocampal neurogenesis.

scholarly journals Shaping hippocampal neurogenesis: exercising the brain with cannabinoids

2020 ◽  
Author(s):  
Rui S Rodrigues ◽  
Joao B. Moreira ◽  
Ana M. Sebastião ◽  
Carlos P. Fitzsimons ◽  
Sara Xapelli
Keyword(s):  
Physical Exercise ◽  
Progenitor Cells ◽  
Neurotrophic Factors ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Fine Tuning ◽  
Mammalian Brain ◽  
Potential Conflict ◽  
Brain Physiology ◽  
The Brain

Adult neural stem/progenitor cells (NSPC) are present in specialized niches of the mammalian brain and their proliferative and differentiative potential is modulated by a myriad of factors. Recent evidence sheds light on the interaction between cannabinoids and neurotrophic factors underlying a major regulative force of adult hippocampal neurogenesis, with important effects upon cognitive plasticity and mood flexibility. Herein, we aimed at evaluating the actions of cannabinoid type 2 receptor (CB2R) together with exercise upon hippocampal neurogenesis and whether this has significant behavioral implications. Our data suggests a participation of CB2Rs in fine-tuning the actions of physical exercise upon adult hippocampal neurogenesis. Specifically, CB2R ligands as well as exercise-regulated neurotrophic factors promote an acceleration in the differentiation of progenitor cells accompanied by an increase in the number of mature neurons in vitro. Moreover, preliminary results show that CB2Rs play an impactful role in controlling cognitive and depressive-like behavior. This is particularly important because brain physiology and mental health are known to be greatly affected by physical exercise, with adult neurogenesis playing a significant role in this process. Ultimately, this work will contribute to unravel the mechanisms behind the actions of cannabinoids and exercise in the brain and to develop strategies utilizing CB2Rs and physical exercise to boost neural stem cell capacity and treat several brain disorders. Acknowledgements: Supported by Fundação para a Ciência e a Tecnologia (FCT), projects SFRH/BD/129710/2017 and IF/01227/2015. No potential conflict of interest.

scholarly journals Extracranial 125I Seed Implantation Allows Non-invasive Stereotactic Radioablation of Hippocampal Adult Neurogenesis in Guinea Pigs

2021 ◽  
Vol 15 ◽  
Author(s):  
Lily Wan ◽  
Rou-Jie Huang ◽  
Chen Yang ◽  
Jia-Qi Ai ◽  
Qian Zhou ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Hippocampal Formation ◽  
Dorsal Hippocampus ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Granule Cell Layer ◽  
Nuclear Antigen ◽  
Proliferating Cells ◽  
Seed Implantation ◽  
Non Invasive

Adult hippocampal neurogenesis (AHN) is important for multiple cognitive functions. We sort to establish a minimal or non-invasive radiation approach to ablate AHN using guinea pigs as an animal model. 125I seeds with different radiation dosages (1.0, 0.8, 0.6, 0.3 mCi) were implanted unilaterally between the scalp and skull above the temporal lobe for 30 and 60 days, with the radiation effect on proliferating cells, immature neurons, and mature neurons in the hippocampal formation determined by assessment of immunolabeled (+) cells for Ki67, doublecortin (DCX), and neuron-specific nuclear antigen (NeuN), as well as Nissl stain cells. Spatially, the ablation effect of radiation occurred across the entire rostrocaudal and largely the dorsoventral dimensions of the hippocampus, evidenced by a loss of DCX+ cells in the subgranular zone (SGZ) of dentate gyrus (DG) in the ipsilateral relative to contralateral hemispheres in reference to the 125I seed implant. Quantitatively, Ki67+ and DCX+ cells at the SGZ in the dorsal hippocampus were reduced in all dosage groups at the two surviving time points, more significant in the ipsilateral than contralateral sides, relative to sham controls. NeuN+ neurons and Nissl-stained cells were reduced in the granule cell layer of DG and the stratum pyramidale of CA1 in the groups with 0.6-mCi radiation for 60 days and 1.0 mCi for 30 and 60 days. Minimal cranial trauma was observed in the groups with 0.3– 1.0-mCi radiation at 60 days. These results suggest that extracranial radiation with 125I seed implantation can be used to deplete HAN in a radioactivity-, duration-, and space-controllable manner, with a “non-invasive” stereotactic ablation achievable by using 125I seeds with relatively low radioactivity dosages.

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