scholarly journals VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis

2016 ◽  
Vol 113 (48) ◽  
pp. E7828-E7836 ◽  
Author(s):  
Tamar Licht ◽  
Gadiel Rothe ◽  
Tirzah Kreisel ◽  
Brachi Wolf ◽  
Ofra Benny ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Age Related ◽  
Terminal Arbor ◽  
Neuronal Stem Cell ◽  
Cell Remodeling ◽  
Elevated Rate

Several factors are known to enhance adult hippocampal neurogenesis but a factor capable of inducing a long-lasting neurogenic enhancement that attenuates age-related neurogenic decay has not been described. Here, we studied hippocampal neurogenesis following conditional VEGF induction in the adult brain and showed that a short episode of VEGF exposure withdrawn shortly after the generation of durable new vessels (but not under conditions where newly made vessels failed to persist) is sufficient for neurogenesis to proceed at a markedly elevated level for many months later. Continual neurogenic increase over several months was not accompanied by accelerated exhaustion of the neuronal stem cell (NSC) reserve, thereby allowing neurogenesis to proceed at a markedly elevated rate also in old mice. Neurogenic enhancement by VEGF preconditioning was, in part, attributed to rescue of age-related NSC quiescence. Remarkably, VEGF caused extensive NSC remodelling manifested in transition of the enigmatic NSC terminal arbor onto long cytoplasmic processes engaging with and spreading over even remote blood vessels, a configuration reminiscent of early postnatal “juvenile” NSCs. Together, these findings suggest that VEGF preconditioning might be harnessed for long-term neurogenic enhancement despite continued exposure to an “aged” systemic milieu.

scholarly journals Follistatin mediates learning and synaptic plasticity via regulation of Asic4 expression in the hippocampus

2021 ◽  
Vol 118 (39) ◽  
pp. e2109040118
Author(s):  
Yu-Ju Chen ◽  
Shin-Meng Deng ◽  
Hui-Wen Chen ◽  
Chi-Hui Tsao ◽  
Wei-Ting Chen ◽  
...  
Keyword(s):  
Adult Neurogenesis ◽  
Chromatin Immunoprecipitation ◽  
Critical Role ◽  
Long Term Potentiation ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Learning Deficits ◽  
Age Related ◽  
Term Potentiation

The biological mechanisms underpinning learning are unclear. Mounting evidence has suggested that adult hippocampal neurogenesis is involved although a causal relationship has not been well defined. Here, using high-resolution genetic mapping of adult neurogenesis, combined with sequencing information, we identify follistatin (Fst) and demonstrate its involvement in learning and adult neurogenesis. We confirmed that brain-specific Fst knockout (KO) mice exhibited decreased hippocampal neurogenesis and demonstrated that FST is critical for learning. Fst KO mice exhibit deficits in spatial learning, working memory, and long-term potentiation (LTP). In contrast, hippocampal overexpression of Fst in KO mice reversed these impairments. By utilizing RNA sequencing and chromatin immunoprecipitation, we identified Asic4 as a target gene regulated by FST and show that Asic4 plays a critical role in learning deficits caused by Fst deletion. Long-term overexpression of hippocampal Fst in C57BL/6 wild-type mice alleviates age-related decline in cognition, neurogenesis, and LTP. Collectively, our study reveals the functions for FST in adult neurogenesis and learning behaviors.

scholarly journals Ablation of proliferating neural stem cells during early life is sufficient to reduce adult hippocampal neurogenesis

2018 ◽  
Author(s):  
Mary Youssef ◽  
Varsha S. Krish ◽  
Greer S. Kirshenbaum ◽  
Piray Atsak ◽  
Tamara J. Lass ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Early Life ◽  
Cell Function ◽  
Cell Lineage ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Stem Cell Lineage

AbstractEnvironmental exposures during early life, but not during adolescence or adulthood, lead to persistent reductions in neurogenesis in the adult hippocampal dentate gyrus (DG). The mechanisms by which early life exposures lead to long-term deficits in neurogenesis remain unclear. Here, we investigated whether targeted ablation of dividing neural stem cells during early life is sufficient to produce long-term decreases in DG neurogenesis. Having previously found that the stem cell lineage is resistant to long-term effects of transient ablation of dividing stem cells during adolescence or adulthood (Kirshenbaum et al., 2014), we used a similar pharmacogenetic approach to target dividing neural stem cells for elimination during early life periods sensitive to environmental insults. We then assessed the Nestin stem cell lineage in adulthood. We found that the adult neural stem cell reservoir was depleted following ablation during the first postnatal week, when stem cells were highly proliferative, but not during the third postnatal week, when stem cells were more quiescent. Remarkably, ablating proliferating stem cells during either the first or third postnatal week led to reduced adult neurogenesis out of proportion to the changes in the stem cell pool, indicating a disruption of the stem cell function or niche following stem cell ablation in early life. These results highlight the first three postnatal weeks as a series of sensitive periods during which elimination of dividing stem cells leads to lasting alterations in adult DG neurogenesis and stem cell function. These findings contribute to our understanding of the relationship between DG development and adult neurogenesis, as well as suggest a possible mechanism by which early life experiences may lead to lasting deficits in adult hippocampal neurogenesis.

scholarly journals Association of adult hippocampal neurogenesis with alzheimer’s disease

2020 ◽  
Vol 7 (12) ◽  
pp. 5208
Author(s):  
Atryee Gope
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cell ◽  
Neural Stem Cell ◽  
Hippocampal Neurons ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Sharp Decline ◽  
Cell Based Therapy

Neurogenesis in the adult brain has been reported to occur within three distinct regions, of which Hippocampus is the most studied one because of its importance in cognition and memory. Alzheimer’s disease attributes to almost 62% of all dementia cases. A recent study has established a link between adult hippocampal neurogenesis and alzheimer’s disease wherein a sharp decline in AHN is observed in patients suffering from alzheimer’s. This review summarizes alzheimer’s disease, the decline in AHN in alzheimer’s patients and probes into the efficacy of the newly generated hippocampal neurons in the context of memory and cognition. It also discusses the potential of targeting reduced AHN in alzheimer’s patients using neural stem cell-based therapy.

scholarly journals Mitochondrial and Autophagic Regulation of Adult Neurogenesis in the Healthy and Diseased Brain

2021 ◽  
Vol 22 (7) ◽  
pp. 3342
Author(s):  
Hansruedi Büeler
Keyword(s):  
Stem Cell ◽  
Mood Disorders ◽  
Adult Neurogenesis ◽  
Cell Function ◽  
Natural Aging ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Induced Mood ◽  
Newborn Neurons

Adult neurogenesis is a highly regulated process during which new neurons are generated from neural stem cells in two discrete regions of the adult brain: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Defects of adult hippocampal neurogenesis have been linked to cognitive decline and dysfunction during natural aging and in neurodegenerative diseases, as well as psychological stress-induced mood disorders. Understanding the mechanisms and pathways that regulate adult neurogenesis is crucial to improving preventative measures and therapies for these conditions. Accumulating evidence shows that mitochondria directly regulate various steps and phases of adult neurogenesis. This review summarizes recent findings on how mitochondrial metabolism, dynamics, and reactive oxygen species control several aspects of adult neural stem cell function and their differentiation to newborn neurons. It also discusses the importance of autophagy for adult neurogenesis, and how mitochondrial and autophagic dysfunction may contribute to cognitive defects and stress-induced mood disorders by compromising adult neurogenesis. Finally, I suggest possible ways to target mitochondrial function as a strategy for stem cell-based interventions and treatments for cognitive and mood disorders.

Is adult hippocampal neurogenesis really relevant for the treatment of psychiatric disorders?

2020 ◽  
Vol 18 ◽  
Author(s):  
Marco Carli ◽  
Stefano Aringhieri ◽  
Shivakumar Kolachalam ◽  
Biancamaria Longoni ◽  
Giovanna Grenno ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Emotional Processing ◽  
Imaging Techniques ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Mood Stabilizers ◽  
Post Traumatic Stress ◽  
Newborn Neurons ◽  
Hippocampal Circuitry

: Adult neurogenesis consists in the generation of newborn neurons from neural stem cells taking place in the adult brain. In mammals, this process is limited to very few areas of the brain, and one of these neurogenic niches is the subgranular layer of the dentate gyrus (DG) of the hippocampus. Adult newborn neurons are generated from quiescent neural progenitors (QNPs), which differentiate through different steps into mature granule cells (GCs), to be finally integrated into the existing hippocampal circuitry. In animal models, adult hippocampal neurogenesis (AHN) is relevant for pattern discrimination, cognitive flexibility, emotional processing and resilience to stressful situations. Imaging techniques allow to visualize newborn neurons within the hippocampus through all their stages of development and differentiation. In humans, the evidence of AHN is more challenging, and, based on recent findings, it persists through the adulthood, even if it declines with age. Whether this process has an important role in human brain function and how it integrates into the existing hippocampal circuitry is still a matter of exciting debate. Importantly, AHN deficiency has been proposed to be relevant in many psychiatric disorders, including mood disorders, anxiety, post-traumatic stress disorder and schizophrenia. This review aims to investigate how AHN is altered in different psychiatric conditions and how pharmacological treatments can rescue this process. In fact, many psychoactive drugs, such as antidepressants, mood stabilizers and atypical antipsychotics (AAPs), can boost AHN with different results. In addition, some non-pharmacological approaches are discussed as well.

Potential Role of Adult Hippocampal Neurogenesis in Traumatic Brain Injury

2021 ◽  
Vol 28 ◽  
Author(s):  
Lucas Alexandre Santos Marzano ◽  
Fabyolla Lúcia Macedo de Castro ◽  
Caroline Amaral Machado ◽  
João Luís Vieira Monteiro de Barros ◽  
Thiago Macedo e Cordeiro ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Hippocampal Neurogenesis ◽  
Cognitive Outcomes ◽  
Adult Hippocampal Neurogenesis ◽  
The Brain

: Traumatic brain injury (TBI) is a serious cause of disability and death among young and adult individuals, displaying complex pathophysiology including cellular and molecular mechanisms that are not fully elucidated. Many experimental and clinical studies investigated the potential relationship between TBI and the process by which neurons are formed in the brain, known as neurogenesis. Currently, there are no available treatments for TBI’s long-term consequences being the search for novel therapeutic targets, a goal of highest scientific and clinical priority. Some studies evaluated the benefits of treatments aimed at improving neurogenesis in TBI. In this scenario, herein, we reviewed current pre-clinical studies that evaluated different approaches to improving neurogenesis after TBI while achieving better cognitive outcomes, which may consist in interesting approaches for future treatments.

Estrogenic Regulation of Hippocampal Neurogenesis Throughout the Lifespan

2020 ◽  
pp. 253-281
Author(s):  
Shunya Yagi ◽  
Rand S. Eid ◽  
Wansu Qiu ◽  
Paula Duarte-Guterman ◽  
Liisa A. M. Galea
Keyword(s):  
Steroid Hormones ◽  
Cognitive Training ◽  
Adult Female ◽  
Ovarian Hormones ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Maternal Experience ◽  
Number Of Factors ◽  
Estrogenic Regulation

Neurogenesis in the hippocampus exists across a number of species, including humans. Steroid hormones, such as estrogens, modulate neurogenesis dependent on age, reproductive experience and sex. Findings are discussed in the chapter with reference to how neurogenesis in the hippocampus is related to learning and memory. Natural fluctuations in ovarian hormones or removal of ovaries modulate neurogenesis in the short term but not in the long term. Maternal experience has long-lasting effects on neurogenesis in the hippocampus. Acute estrogens increase proliferation in adult female rodents, but influence survival of new neurons dependent on a number of factors including sex, cognitive training, type of estrogen, and whether or not cells were produced under estrogens. This chapter outlines findings indicating that estrogens can be strong modulators of adult hippocampal neurogenesis, which may have implications for disorders involving hippocampal dysfunction that target women.

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 Telomere length and human hippocampal neurogenesis

2020 ◽  
Vol 45 (13) ◽  
pp. 2239-2247 ◽  
Author(s):  
Alish B. Palmos ◽  
Rodrigo R. R. Duarte ◽  
Demelza M. Smeeth ◽  
Erin C. Hedges ◽  
Douglas F. Nixon ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Psychiatric Disorder ◽  
Telomere Length ◽  
Gene Networks ◽  
Hippocampal Neurogenesis ◽  
Telomere Maintenance ◽  
Adult Hippocampal Neurogenesis ◽  
Telomere Shortening ◽  
Age Related

Abstract Short telomere length is a risk factor for age-related disease, but it is also associated with reduced hippocampal volumes, age-related cognitive decline and psychiatric disorder risk. The current study explored whether telomere shortening might have an influence on cognitive function and psychiatric disorder pathophysiology, via its hypothesised effects on adult hippocampal neurogenesis. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Serially passaged progenitors demonstrated shorter telomeres (P ≤ 0.05), and reduced rates of cell proliferation (P ≤ 0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene-set enrichment analyses revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts in our model showed a significant overlap with genes regulating cognitive function (P ≤ 1 × 10−5), and risk for schizophrenia (P ≤ 1 × 10−10) and bipolar disorder (P ≤ 0.005). Collectively, our results suggest that telomere shortening could represent a mechanism that moderates the proliferative capacity of human hippocampal progenitors, which may subsequently impact on human cognitive function and psychiatric disorder pathophysiology.

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