scholarly journals Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging

2018 ◽  
Author(s):  
Greer S. Kirshenbaum ◽  
Victoria K. Robson ◽  
Rebecca M. Shansky ◽  
Lisa M. Savage ◽  
E. David Leonardo ◽  
...  
Keyword(s):  
Working Memory ◽  
Adult Neurogenesis ◽  
Hippocampal Neurons ◽  
Normal Function ◽  
Hippocampal Neurogenesis ◽  
Stress Memory ◽  
Brain Connectome ◽  
Adult Born Neurons ◽  
Memory Deterioration

SummaryAdult neurogenesis is impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in a progressing decline in hippocampal acetylcholine and the slow emergence of profound working memory deficits. These deficits were accompanied by compensatory rewiring of cholinergic dentate gyrus inputs such that ventrally projecting neurons were recruited by the dorsal projection. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.

scholarly journals The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis

2020 ◽  
Vol 29 (12) ◽  
pp. 1950-1968
Author(s):  
Charlotte Castillon ◽  
Laurine Gonzalez ◽  
Florence Domenichini ◽  
Sandrine Guyon ◽  
Kevin Da Silva ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Spatial Memory ◽  
Adult Neurogenesis ◽  
Hippocampal Neurons ◽  
Memory Task ◽  
Clinical Signs ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Adult Born Neurons

Abstract The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18–28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.

scholarly journals Long-lasting effects of transient, perinatal fluoxetine exposure on cell proliferation in the dentate gyrus of mice

2019 ◽  
Author(s):  
Simon C. Spanswick ◽  
Michael J. Chrusch ◽  
Veronika Kiryanova ◽  
Richard H. Dyck
Keyword(s):  
Hippocampal Neurons ◽  
Developmental Period ◽  
Hippocampal Neurogenesis ◽  
Mammalian Brain ◽  
Long Term Effects ◽  
Neuronal Proliferation ◽  
Adult Born Neurons ◽  
Adult Mammalian Brain ◽  
Homeostatic Mechanisms

AbstractIn the adult mammalian brain, up-regulation of serotonin via the selective serotonin reuptake inhibitor fluoxetine increases hippocampal neurogenesis. However, research assessing the long-term effects of modulating serotonin during the developmental period on hippocampal neurogenesis, is sparse. Here we evaluated hippocampal neurogenesis early (postnatal day 12), and later in life (postnatal day 60), in the offspring of mouse dams that were administered fluoxetine in their drinking water from embryonic day 15 (E15) through postnatal day 12 (P12). Fluoxetine-exposed mice had significantly higher levels of neuronal proliferation at P12, and P60, despite cessation of fluoxetine on P12. These effects were limited to proliferation, as survival of postnatal-born hippocampal neurons was unaltered. Mice exposed to fluoxetine also showed significantly higher levels of cell death, suggesting that homeostatic mechanisms present within the hippocampus may limit integration of adult-born neurons into the existing neuronal network. These findings demonstrate modulation of serotonin during development may be sufficient to induce long-lasting changes in hippocampal neurogenesis.

scholarly journals Haploinsufficiency of the psychiatric risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms

2018 ◽  
Author(s):  
Niels Haan ◽  
Laura J Westacott ◽  
Jenny Carter ◽  
Michael J Owen ◽  
William P Gray ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Hippocampal Neurons ◽  
Hippocampal Neurogenesis ◽  
Actin Dynamics ◽  
Biological Processes ◽  
Risk Gene ◽  
A Cell ◽  
Adult Born Neurons ◽  
Newborn Neurons ◽  
And Migration

AbstractGenetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1-BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult born hippocampal neurons due to reduced apoptosis, without altering proliferation. We confirm this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.

scholarly journals De novo DNA methylation controls neuronal maturation during adult hippocampal neurogenesis

2020 ◽  
Author(s):  
Sara Zocher ◽  
Rupert W Overall ◽  
Gabriel Berdugo-Vega ◽  
Nicole Rund ◽  
Anne Karasinsky ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Fate ◽  
Adult Neurogenesis ◽  
Hippocampal Neurons ◽  
De Novo ◽  
Functional Integration ◽  
Stem Cell Differentiation ◽  
Dna Methyltransferases ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis

SummaryDynamic DNA methylation controls gene-regulatory networks underlying cell fate specification. How DNA methylation patterns change during adult hippocampal neurogenesis and their relevance for adult neural stem cell differentiation and related brain function has, however, remained unknown. Here, we show that neurogenesis-associated de novo DNA methylation is critical for maturation and functional integration of adult-born hippocampal neurons. Cell stage-specific bisulfite sequencing revealed a pronounced gain of DNA methylation at neuronal enhancers, gene bodies and binding sites of pro-neuronal transcription factors during adult neurogenesis, which mostly correlated with transcriptional up-regulation of the associated loci. Inducible deletion of both de novo DNA methyltransferases Dnmt3a and Dnmt3b in adult neural stem cells specifically impaired dendritic outgrowth and synaptogenesis of new-born neurons, resulting in reduced hippocampal excitability and specific deficits in hippocampus-dependent learning and memory. Our results highlight that, during adult neurogenesis, remodeling of neuronal methylomes is fundamental for proper hippocampal function.

scholarly journals Haploinsufficiency of the schizophrenia and autism risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Niels Haan ◽  
Laura J. Westacott ◽  
Jenny Carter ◽  
Michael J. Owen ◽  
William P. Gray ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Hippocampal Neurons ◽  
Hippocampal Neurogenesis ◽  
Actin Dynamics ◽  
Biological Processes ◽  
Risk Gene ◽  
A Cell ◽  
Adult Born Neurons ◽  
Newborn Neurons ◽  
And Migration

AbstractGenetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1–BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.

scholarly journals Androgens Increase Survival of Adult-Born Neurons in the Dentate Gyrus by an Androgen Receptor-Dependent Mechanism in Male Rats

Endocrinology ◽  
2013 ◽  
Vol 154 (9) ◽  
pp. 3294-3304 ◽  
Author(s):  
D. K. Hamson ◽  
S. R. Wainwright ◽  
J. R. Taylor ◽  
B. A. Jones ◽  
N. V. Watson ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Dentate Gyrus ◽  
Adult Neurogenesis ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Male Rats ◽  
Male Rat ◽  
Testicular Feminization ◽  
Wild Type ◽  
Adult Born Neurons

Gonadal steroids are potent regulators of adult neurogenesis. We previously reported that androgens, such as testosterone (T) and dihydrotestosterone (DHT), but not estradiol, increased the survival of new neurons in the dentate gyrus of the male rat. These results suggest androgens regulate hippocampal neurogenesis via the androgen receptor (AR). To test this supposition, we examined the role of ARs in hippocampal neurogenesis using 2 different approaches. In experiment 1, we examined neurogenesis in male rats insensitive to androgens due to a naturally occurring mutation in the gene encoding the AR (termed testicular feminization mutation) compared with wild-type males. In experiment 2, we injected the AR antagonist, flutamide, into castrated male rats and compared neurogenesis levels in the dentate gyrus of DHT and oil-treated controls. In experiment 1, chronic T increased hippocampal neurogenesis in wild-type males but not in androgen-insensitive testicular feminization mutation males. In experiment 2, DHT increased hippocampal neurogenesis via cell survival, an effect that was blocked by concurrent treatment with flutamide. DHT, however, did not affect cell proliferation. Interestingly, cells expressing doublecortin, a marker of immature neurons, did not colabel with ARs in the dentate gyrus, but ARs were robustly expressed in other regions of the hippocampus. Together these studies provide complementary evidence that androgens regulate adult neurogenesis in the hippocampus via the AR but at a site other than the dentate gyrus. Understanding where in the brain androgens act to increase the survival of new neurons in the adult brain may have implications for neurodegenerative disorders.

scholarly journals Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior

2008 ◽  
Vol 105 (40) ◽  
pp. 15570-15575 ◽  
Author(s):  
Matteo Bergami ◽  
Roberto Rimondini ◽  
Spartaco Santi ◽  
Robert Blum ◽  
Magdalena Götz ◽  
...  
Keyword(s):  
Adult Neurogenesis ◽  
Long Term Potentiation ◽  
Functional Networks ◽  
Synaptic Connections ◽  
Newborn Neuron ◽  
Molecular Control ◽  
Term Potentiation ◽  
Adult Born Neurons

New neurons in the adult dentate gyrus are widely held to incorporate into hippocampal circuitry via a stereotypical sequence of morphological and physiological transitions, yet the molecular control over this process remains unclear. We studied the role of brain-derived neurotrophic factor (BDNF)/TrkB signaling in adult neurogenesis by deleting the full-length TrkB via Cre expression within adult progenitors in TrkBlox/lox mice. By 4 weeks after deletion, the growth of dendrites and spines is reduced in adult-born neurons demonstrating that TrkB is required to create the basic organization of synaptic connections. Later, when new neurons normally display facilitated synaptic plasticity and become preferentially recruited into functional networks, lack of TrkB results in impaired neurogenesis-dependent long-term potentiation and cell survival becomes compromised. Because of the specific lack of TrkB signaling in recently generated neurons a remarkably increased anxiety-like behavior was observed in mice carrying the mutation, emphasizing the contribution of adult neurogenesis in regulating mood-related behavior.

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 Hippocampal neurogenesis promotes preference for future rewards

2018 ◽  
Author(s):  
Désirée R. Seib ◽  
Delane Espinueva ◽  
Oren Princz-Lebel ◽  
Erin Chahley ◽  
Stan B. Floresco ◽  
...  
Keyword(s):  
Decision Making ◽  
Dentate Gyrus ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Neuronal Recruitment ◽  
Adult Born Neurons ◽  
Activity Dependent ◽  
Reward Behaviors

ABSTRACTAdult hippocampal neurogenesis is implicated in a number of disorders where reward processes are disrupted but whether new neurons regulate specific reward behaviors remains unknown. We find that blocking neurogenesis in rats reduces activation of the ventral dentate gyrus and causes a profound aversion for delayed rewards. Delay-based decision-making restructured dendrites and spines in adult-born neurons, consistent with activity-dependent neuronal recruitment. These findings identify a novel role for neurogenesis in decisions about future rewards, which is compromised in disorders where short-sighted gains are preferred at the expense of long-term health.

scholarly journals Sex Differences in Maturation and Attrition of Adult Neurogenesis in the Hippocampus

2019 ◽  
Author(s):  
Shunya Yagi ◽  
Jared E.J. Splinter ◽  
Daria Tai ◽  
Sarah Wong ◽  
Yanhua Wen ◽  
...  
Keyword(s):  
Sex Differences ◽  
Dentate Gyrus ◽  
Adult Neurogenesis ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Female Rats ◽  
Sprague Dawley ◽  
Male And Female Rats ◽  
Maturation Rate ◽  
Adult Born Neurons

ABSTRACTSex differences exist in the regulation of adult neurogenesis in the hippocampus in response to hormones and cognitive training. Here we investigated the trajectory and maturation rate of adult-born neurons in the dentate gyrus (DG) of male and female rats. Sprague-Dawley rats were perfused two hours, 24 hours, one, two or three weeks after BrdU injection, a DNA synthesis marker that labels dividing progenitor cells and their progeny. Adult-born neurons (BrdU/NeuN-ir) matured faster in males compared to females. Males had a greater density of neural stem cells (Sox2-ir) in the dorsal, but not in the ventral, DG and had higher levels of cell proliferation (Ki67-ir) than non-proestrous females. However, males showed a greater reduction in neurogenesis between one and two weeks after mitosis, whereas females showed similar levels of neurogenesis throughout the weeks. The faster maturation and greater attrition of new neurons in males compared to females suggests greater potential for neurogenesis to respond to external stimuli in males and emphasizes the importance of studying sex on adult hippocampal neurogenesis.Significance StatementPreviously studies examining the characteristics of adult-born neurons in the dentate gyrus have used almost exclusively male subjects. Researchers have assumed the two sexes have a similar maturation and attrition of new neurons in the dentate gyrus of adults. However, this study highlights notable sex differences in the attrition, maturation rate and potential of neurogenesis in the adult hippocampus that has significant implications for the field of neuroplasticity. These findings are important in understanding the relevance of sex differences in the regulation of neurogenesis in the hippocampus in response to stimuli or experience and may have consequences for our understanding of diseases that involve neurodegeneration of the hippocampus, particularly those that involve sex differences, such as Alzheimer’s disease and depression.

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