scholarly journals Inhibiting adult neurogenesis differentially affects spatial learning in females and males

2021 ◽  
Author(s):  
Timothy P O'Leary ◽  
Baran Askari ◽  
Bonnie Lee ◽  
Kathryn Darby ◽  
Cypress Knudson ◽  
...  
Keyword(s):  
Sex Differences ◽  
Search Strategy ◽  
Cold Water ◽  
Mossy Fiber ◽  
Dorsal Hippocampus ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Early Gene ◽  
Males And Females ◽  
Adult Born Neurons

Adult hippocampal neurogenesis has been implicated in the spatial processing functions of the hippocampus but ablating neurogenesis does not consistently lead to behavioral deficits in spatial tasks. Parallel studies have shown that adult-born neurons also regulate behavioral responses to stressful and aversive stimuli. We therefore hypothesized that spatial functions of adult-born neurons may be more prominent under conditions of stress, and may differ between males and females given established sex differences in stress responding. To test this we trained intact and neurogenesis-deficient rats in the spatial water maze at temperatures that vary in their degree of aversiveness. At standard temperatures (25°C) ablating neurogenesis did not alter learning and memory in either sex, consistent with prior work. However, in cold water (16°C), ablating neurogenesis had divergent sex-dependent effects: relative to intact rats, male neurogenesis-deficient rats were slower to escape and female neurogenesis-deficient rats were faster. Neurogenesis promoted temperature-related changes in search strategy in females, but it promoted search strategy stability in males. Females displayed greater recruitment of the dorsal hippocampus than males, particularly at 16°C. However, blocking neurogenesis did not alter activity-dependent immediate-early gene expression in either sex. Finally, morphological analyses of retrovirally-labelled neurons revealed greater experience-dependent plasticity in new neurons in males. Neurons had comparable morphology in untrained rats but 16°C training increased spine density, and 25°C training caused shrinkage of mossy fiber presynaptic terminals, specifically in males. Collectively, these findings indicate that neurogenesis functions in memory are prominent under conditions of stress, they provide the first evidence for sex differences in the behavioral function of newborn neurons, and they suggest possibly distinct roles for neurogenesis in cognition and mental health in males and females.

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.

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.

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 Social Instability is an Effective Chronic Stress Paradigm for both Male and Female Mice

2019 ◽  
Author(s):  
Christine N. Yohn ◽  
Sandra A. Ashamalla ◽  
Leshya Bokka ◽  
Mark M. Gergues ◽  
Alexander Garino ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Hpa Axis ◽  
Social Stress ◽  
Antidepressant Treatment ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Social Instability ◽  
Female Mice ◽  
Negative Valence ◽  
Males And Females

ABSTRACTDespite stress-associated disorders having a higher incidence rate in females, preclinical research mainly focuses on males. Chronic stress paradigms, such as chronic social defeat and chronic corticosterone administration, were mainly designed and validated in males and subsequent attempts to use these paradigms in females has demonstrated sex differences in the behavioral and HPA axis response to stress. Here, we developed a social stress paradigm, social instability stress (SIS), which exposes adult mice to unstable social hierarchies for 7 weeks. SIS effectively induces negative valence behaviors and hypothalamus-pituitary-adrenal (HPA) axis activation in both males and females. Importantly, while there were effects of estrous cycle on behavior, this variability did not impact the overall effects of SIS on behavior, suggesting estrous does not need to be tracked while utilizing SIS. Furthermore, the effects of SIS on negative valence behaviors were also reversed following chronic antidepressant treatment with fluoxetine (FLX) in both males and females. SIS also reduced adult hippocampal neurogenesis in female mice, while chronic FLX treatment increased adult hippocampal neurogenesis in both males and females. Overall, these data demonstrate that the SIS paradigm is an ethologically valid approach that effectively induces chronic stress in both adult male and adult female mice.

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.

scholarly journals Resilience to cognitive aging is associated with responsiveness of dentate neurons generated throughout adult life

2018 ◽  
Author(s):  
Marie-Françoise Montaron ◽  
Vanessa Charrier ◽  
Nicolas Blin ◽  
Pierre Garcia ◽  
Djoher Nora Abrous
Keyword(s):  
Cognitive Aging ◽  
Current Knowledge ◽  
Adult Life ◽  
Hippocampal Neurogenesis ◽  
Early Gene ◽  
Granule Neurons ◽  
Learning Abilities ◽  
Old Rats ◽  
Adult Born Neurons ◽  
Good Learning

ABSTRACTDuring aging some individuals are resilient to the decline of cognitive functions whereas others are vulnerable. These inter-individual differences in memory abilities have been associated with differences in the rate of hippocampal neurogenesis measured at old age. Whether the maintenance of the functionality of neurons generated throughout adult life is linked to resilience to cognitive aging remains completely unexplored. Using the immediate early gene Zif268, we analysed the activation of dentate granule neurons born in adult (3 month-old), middle-aged (12 month-old) or senescent (18 month-old) rats (n=96) in response to learning when animals reached 21 month-old. The activation of neurons born during the developmental period was also examined. We show that neurons generated 4, 10 or 19 months before learning (and not developmentally born neurons) are activated in senescent rats with good learning abilities. In contrast, aged rats with bad learning abilities do not exhibit an activity-dependent regulation of Zif268. In conclusion, we propose that resilience to cognitive aging is associated to the responsiveness of neurons born during adult-life. These data add to our current knowledge by showing that the aging of memory abilities stems not only from the number but also from the responsiveness of adult-born neurons.

scholarly journals Active Fraction Combination From Liuwei Dihuang Decoction Improves Adult Hippocampal Neurogenesis and Neurogenic Microenvironment in Cranially Irradiated Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Mingxiao Wei ◽  
Shufang Feng ◽  
Lin Zhang ◽  
Chen Wang ◽  
Shasha Chu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Dorsal Hippocampus ◽  
Cranial Irradiation ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Active Fraction ◽  
Cranial Radiotherapy ◽  
Contextual Fear ◽  
Immature Neurons

Background: Cranial radiotherapy is clinically used in the treatment of brain tumours; however, the consequent cognitive and emotional dysfunctions seriously impair the life quality of patients. LW-AFC, an active fraction combination extracted from classical traditional Chinese medicine prescription Liuwei Dihuang decoction, can improve cognitive and emotional dysfunctions in many animal models; however, the protective effect of LW-AFC on cranial irradiation–induced cognitive and emotional dysfunctions has not been reported. Recent studies indicate that impairment of adult hippocampal neurogenesis (AHN) and alterations of the neurogenic microenvironment in the hippocampus constitute critical factors in cognitive and emotional dysfunctions following cranial irradiation. Here, our research further investigated the potential protective effects and mechanisms of LW-AFC on cranial irradiation–induced cognitive and emotional dysfunctions in mice.Methods: LW-AFC (1.6 g/kg) was intragastrically administered to mice for 14 days before cranial irradiation (7 Gy γ-ray). AHN was examined by quantifying the number of proliferative neural stem cells and immature neurons in the dorsal and ventral hippocampus. The contextual fear conditioning test, open field test, and tail suspension test were used to assess cognitive and emotional functions in mice. To detect the change of the neurogenic microenvironment, colorimetry and multiplex bead analysis were performed to measure the level of oxidative stress, neurotrophic and growth factors, and inflammation in the hippocampus.Results: LW-AFC exerted beneficial effects on the contextual fear memory, anxiety behaviour, and depression behaviour in irradiated mice. Moreover, LW-AFC increased the number of proliferative neural stem cells and immature neurons in the dorsal hippocampus, displaying a regional specificity of neurogenic response. For the neurogenic microenvironment, LW-AFC significantly increased the contents of superoxide dismutase, glutathione peroxidase, glutathione, and catalase and decreased the content of malondialdehyde in the hippocampus of irradiated mice, accompanied by the increase in brain-derived neurotrophic factor, insulin-like growth factor-1, and interleukin-4 content. Together, LW-AFC improved cognitive and emotional dysfunctions, promoted AHN preferentially in the dorsal hippocampus, and ameliorated disturbance in the neurogenic microenvironment in irradiated mice.Conclusion: LW-AFC ameliorates cranial irradiation–induced cognitive and emotional dysfunctions, and the underlying mechanisms are mediated by promoting AHN in the dorsal hippocampus and improving the neurogenic microenvironment. LW-AFC might be a promising therapeutic agent to treat cognitive and emotional dysfunctions in patients receiving cranial radiotherapy.

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 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 Involvement of Adult Hippocampal Neurogenesis in Learning and Forgetting

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Suk-yu Yau ◽  
Ang Li ◽  
Kwok-Fai So
Keyword(s):  
Learning And Memory ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Pattern Separation ◽  
Detailed Mechanism ◽  
Continuous Generation ◽  
Adult Born Neurons ◽  
Newborn Neurons ◽  
Dependent Learning ◽  
The Relationship

Adult hippocampal neurogenesis is a process involving the continuous generation of newborn neurons in the hippocampus of adult animals. Mounting evidence has suggested that hippocampal neurogenesis contributes to some forms of hippocampus-dependent learning and memory; however, the detailed mechanism concerning how this small number of newborn neurons could affect learning and memory remains unclear. In this review, we discuss the relationship between adult-born neurons and learning and memory, with a highlight on recently discovered potential roles of neurogenesis in pattern separation and forgetting.

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